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AWMF online - S3-Leitlinien Ernährungsmedizin: Parenterale Ernährung
1
Arbeitsgemeinschaft der
AWMF online
Wissenschaftlichen
Medizinischen
Fachgesellschaften
Leitlinien der Deutschen Gesellschaft für Ernährungsmedizin
AWMF-Leitlinien-Register
Nr. 073-018
Entwicklungsstufe:
3
Zitierbare Quelle:
Deutsche Fassung: Akt Ernähr Med 2007; 32: 3-6 DOI: 10.1055/s-2006-951870
Englische Fassung: GMS German Medical Science 2009;7:Doc27. DOI: 10.3205/000086, URN: urn:nbn:de:01830000863,
http://www.egms.de/static/de/journals/gms/2009-7/000086.shtml
Parenterale Ernährung / Parenteral Nutrition
Die einzelnen Kapitel sind jeweils als eigene HTML-Dateien hinterlegt.
Inhaltsverzeichnis:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Introduction and Methodology
Nutritional Status (see "ESPEN Guidelines on Enteral Nutrition"; Clinical Nutr 2006;25)
Energy expenditure and Energy intake
Amino Acids
Carbohydrates
Lipid emulsions
Water, Electrolytes, Vitamins and Trace Elements
Organisation, Regulations, Preparation and Logistics of Parenteral Nutrition in Hospitals and
Homes; the Role of the Nutrition support team
Access Technique and its Problems in Parenteral Nutrition
Practical Handling of AIO Admixturesn
Complications and Monitoring
Ethical and Legal Points of View in Parenteral Nutrition
Neonatology/Paediatrics
Intensive medicine
Gastroenterology
Hepatology
Parenteral Nutrition in Patients with Renal Failure
Surgery and Transplantation
Non-surgical Oncology
Bei der Übersetzung ins Englische wurden die Texte aktualisiert. Deshalb werden hier nur noch die englischen Text
publiziert.
Verfahren zur Konsensbildung:
siehe auch: Einleitung und Methodik
Leitlinie der Deutschen Gesellschaft für Ernährungsmedizin e. V. (www.dgem.de, externer Link), erstellt in
Zusammenarbeit mit den Fachgesellschaften Deutsche Gesellschaft für Anästhesiologie und Intensivmedizin e.
V. (www.dgai.de, externer Link), Deutsche Gesellschaft für Chirurgie e. V. (www.dgch.de, externer Link),
Deutsche Gesellschaft für Kinder- und Jugendmedizin e. V. (www.dgkj.de, externer Link), Deutsche Gesellschaft
für Innere Medizin e. V. (www.dgim.de, externer Link), Deutsche Gesellschaft für Internistische Intensivmedizin
und Notfallmedizin e. V. (www.dgiin.de, externer Link), Deutsche Gesellschaft für Verdauungs- und
Stoffwechselerkrankungen e. V. (www.dgvs.de, externer Link), Deutsche Diabetes Gesellschaft e. V.
PDF erzeugt: 17.01.2011
AWMF online - S3-Leitlinien Ernährungsmedizin: Parenterale Ernährung
2
(www.deutsche-diabetes-gesellschaft.de, externer Link), Deutsche Interdisziplinäre Vereinigung für Intensiv- und
Notfallmedizin e. V. (www.divi-org.de, externer Link) und Gesellschaft für Pädiatrische Gastroenterologie und
Ernährung e. V. (www.gpge.de, externer Link).
Koletzko B1, Celik I2, Jauch KW3, Koller M4, Kopp JB5, Verwied-Jorky S1, Mittal R1 *
1Dept.
Metabolic Diseases & Nutritional Medicine, Dr. von Hauner Children's Hospital, University of Munich,
for Theoretical Surgery, Philipps University Hospital, Marburg, 3Dept Surgery Grosshadern, University
Hospital, Munich, 4Centre for Clinical Studies, University of Regensburg, 5Institute for Theoretical Surgery,
Philipps University of Marburg
2Institute
* English version edited by Sabine Verwied-Jorky, Rashmi Mittal and Berthold Koletzko, Univ. of Munich Medical
Centre, Munich, Germany
Erstellungsdatum:
Deutsche Fassung: 05/2007
Letzte Überarbeitung:
Englische Fassung: 04/2009
Nächste Überprüfung geplant:
04/2014
Zurück zum Index Leitlinien Ernährungsmedizin
Zurück zur Liste der Leitlinien
Zurück zur AWMF-Leitseite
Stand der letzten Aktualisierung: 07/2007
© Deutsche Gesellschaft für Ernährungsmedizin
Autorisiert für elektronische Publikation: AWMF online
HTML-Code optimiert: 07.12.2009; 14:32:57
AWMF online - Guidelines on Parenteral Nutrition: Introduction and Methology
1
AWMF online
Wissenschaftlichen
Medizinischen
Fachgesellschaften
Guidelines on Parenteral Nutrition
Nr. 073-018e_01
Entwicklungsstufe:
3
Zitierbare Quelle:
GMS German Medical Science 2009; 7:Doc26. DOI: 10.3205/000085, URN: urn:nbn:de:0183-0000859
Parenteral Nutrition
Chapter 1: Introduction and Methology
Leitlinie Parenterale Ernährung
Kapitel 1: Einleitung und Methodik
Key words: Guideline, parenteral nutrition, nominal group process, degree of adequacy, recommendation
categories
Schlüsselwörter: Leitlinie, parenterale Ernährung, nominaler Gruppenprozess, "Evidenz"-Härtegrade,
Empfehlungsklassen
Abstract
Guidelines for Parenteral Nutrition were prepared by the German Society for Nutritional Medicine (www.dgem.de
external link), in collaboration with other medical associations to provide guidance for quality assurance for PN
practice, and to promoting health and quality of life of patients concerned. A coordination team proposed topics,
working group leaders who along with working group members performed systematic literatur searches and
drafted recommendations in a nominal group process. Recommendations were discussed and agreed upon in a
structured consensus conference process, followed by a Delphi consensus. The current English version of the
guidelines was written and updated during the period between the last quarter of 2007 and the first quarter of
2009. The recommendations of the guidelines should be reviewed, and if necessary updated five years after
publication.
Zusammenfassung
Die "Leitlinie Parenterale Ernährung" wurde unter Federführung der Deutschen Gesellschaft für
Ernährungsmedizin e.V. (www.dgem.de externer Link) in Zusammenarbeit mit weiteren medizinischen
Fachgesellschaften erstellt mit den Zielen einer Qualitätssicherung der PE-Praxis und der Förderung von
Gesundheit und Lebensqualität der betroffenen Patienten. Das Koordinationsteam entwarf einen Projektplan für
die einzelnen, zu behandelnden Themen und schlug Arbeitsgruppenleiter vor. Diese führten zusammen mit
ihren Arbeitsgruppenmitgliedern eine systematische Literaturrecherche durch und erarbeiteten in einem
nominalen Gruppenprozess Kernaussagen und Empfehlungen. Die Empfehlungen wurden diskutiert und in
einem strukturierten Konsensuskonferenzprozess abgestimmt, gefolgt von einer Delphi-Runde. Die derzeitige
englische Fassung der Leitlinie wurde zwischen dem letzten Quartal 2007 und dem ersten Quartal 2009
geschrieben und aktualisiert. Die Empfehlungen der Leitlinie sollten fünf Jahre nach Publikation geprüft und
gegebenenfalls aktualisiert werden.
Introduction
2
Parenteral nutrition (PN) is, for many patients, not only an important but also a life-saving therapeutic measure.
These 'Guidelines for Parenteral Nutrition' were prepared with the aims of providing guidance for quality
assurance for PN practice, and of promoting the health and quality of life of the patients concerned. The
guidelines are intended to provide a reference for professional groups involved in the application of PN, based
on either scientific evidence or, in case of inadequate scientific evidence, on expert consensus. The guidelines
were prepared under the direction of the German Society for Nutritional Medicine (Deutsche Gesellschaft für
Ernährungsmedizin e. V., www.dgem.de external link), in collaboration with specialist medical associations
named on the title page. The principles in preparing guidelines provided by the Joint Committee for Scientific
Specialist Medical Associations (AWMF) and the Agency for Quality in Medicine (AQuMed/AEZQ ) were
followed [1-4].
Methodology
The DGEM appointed Professor Dr. Berthold Koletzko, M.D. and Professor Dr. Karl-Walter Jauch, M.D. (Table
1) to be the managers of the guideline development project. They formed a coordination team together with
Sabine Verwied-Jorky, Ph.D. (responsible for the organisation of the project), Kathrin Krohn, M.D. and MariaAngelica Trak-Fellermeier, M.Sc., who were joined by Rashmi Mittal, M.D. during the preparation of english
version of the guideline. The coordination team drew up a project plan which included the individual topics to be
covered, proposed leaders of the working groups (WG) for these topics, and also compiled an inital list of
possible working group members. The project plan was reviewed and approved by the DGEM council (Table 1).
Table 1: Timeline and steps involved in the planning, organisation and execution of the project plan for the
production of the guidelines (DGEM = The German Society for Nutritional Medicine)
July 2002
1. DGEM
Appointment of managers for the guidelines development project.
July 2002
2. Project managers
Setting up of the project office.
Formation of a coordination team.
August 2002
3. Coordination team
Devising 18 individual topics, and proposing a working group leader
for each topic.
August 2002
4. DGEM Presidium
Preview and agreement of the project plan.
August to
October 2002
Letters to potential working group leaders and recording of their
answers.
25 October
2002
and working group
leaders
First meeting of the working group leaders to discuss the topic for
each working group, the interdisciplinary make-up of the working
groups, methodology, and searches in the literature.
until November
2002
7. Working group
leaders
Appointing the members of the working groups (WG).
until December
2002
8. Working groups
Devising the key questions for core statements of the guidelines;
circulating these to the main coordinators.
until January
2003
9. Working groups
Discussion and agreement on the contents of the various topics,
and determining keywords of literature search.
January to June 10. Working groups
2003
Literature search and evaluation, drawing up the first proposals and
circulating them.
12.-15.06.2003
11. Working groups
Exchanging the first proposals.
till February
2004
12. Working groups
Amending the proposals, circulating the amendments to all working
groups, receiving the first comments.
12/13. March
2004
13. Working groups
and coordination
team
First consensus conference: 1. Amending the proposals and voting
on the amended proposals in the working groups; 2. Presenting the
proposals to the whole conference, discussion, amending and
voting.
13.03. - 06. 08.
2004
14.
Internet-based Delphi consensus.
08. 05. 2004
Working groups
15. and coordination
team
Second consensus conference: presentation of the amended
proposals to the whole conference, discussion, further
amendments and voting.
till July 2004
16. Working groups
Further amendments of the proposals and passing them on to the
coordination team.
Information regarding the amended proposal sent to all working
groups (Delphi round).
March 2005
and working group
leaders
3
Information to the Association of Medical Specialty Societies
(AWMF) on the preparation of the guidelines.
Agreement on formal collaboration of the following associations in
the preparation of the guidelines: The German Society for
Anaesthesiology und Intensive Medicine, The German Society for
Surgery, The German Society for Paediatrics, The German Society
for Internal Medicine, The German Society for Internal Intensive
Medicine und Emergency Medicine, The German Society for
Digestive and Metabolic Diseases, The German Diabetes Society,
The German Interdisciplinary Alliance for Intensive and Emergency
Medicine, and the Society for Paediatric Gastroenterology and
Nutrition.
August 2004 to 19. Coordination team
December 2006
and working group
leaders
Final editing of the proposals, and completion of the final German
version ready for publication.
October 2007 to 20. Coordination team
May 2008
Translation into English, and editing and updating of the final
English version ready for publication.
In order to finance the expenses incurred during the development of the guidelines (organisational costs and
costs of consensus conferences), requests were made for financial grants to the German Federal Ministry for
Health and Social Security, as well as to various health insurance companies. All of these requests were
rejected and some insurance companies did not even answer. Subsequent to negotiations by the DGEM
council, agreements were signed on the donation of external funds to the University Hospital of Munich by
various manufacturers of PN products (Baxter Germany GmbH, B. Braun Melsungen AG, and Fresenius Kabi
Germany GmbH). The donors of the funds agreed to bear the logistic and organisational costs for the
development of the guidelines, including travelling expenses to meetings and consensus conferences by the
working group leaders. In these contracts, it was explicitly stated that the companies donating these funds would
not in any way influence topics, structure and content of the guidelines. Accordingly, no representative of these
companies took part in any of the meetings or conferences of the working groups.
Setting up of the working groups; declaration of conflict of interest
The coordination team and the working group leaders selected by voting the other members of the working
groups. The voting aimed to ensure that each team was multidisciplinary and included members from various
professional groups such as doctors from various specialities, pharmacists, nutrition scientists, dietitians,
professional carers and legal experts. Experts from the industry were excluded from being members of the
working groups. The authors working together on the guidelines are named in the list of authors provided at the
beginning of these guidelines, with the list indicating both, the leaders of the working groups and the affiliations
of the experts involved. All working group members worked on a voluntary basis, and received no fees.
Travelling expenses were reimbursed in line with the guidelines for travelling expenses according to the usual
guidelines for public institutes of higher education.
During the meetings between the coordination team and working group leaders, possible conflicts of interest
were discussed. In the interest of transparency, it was decided to request a completed declaration of potential
conflicts of interest from participant (Table 2). These were reviewed by the coordination team who concluded
that none of the experts working on the development of these guidelines were either a representative or
spokesperson for any particular company or range of products.
Table 2: Declaration of conflict of interest by members of working groups for preparing the Guidelines for
Parenteral Nutrition (according to the guidelines manual provided by the AWMF and the
AQuMed/AEZQ [4])
Declaration of conflict of interest by members of the working groups for preparing the guidelines for
According to the manual of the AQuMed (Agency for Quality in Medicine) and the AWMF (Joint Committee for
Scientific Specialist Medical Association) recommend that the members of working groups set up for preparing
guidelines, in our case for parenteral nutrition, be free from any conflict of interest. Therefore, we ask you to
answer the following questions. All information will be treated confidentially.
1. Possible personal conflicts of interest:
4
Have you, in connection with the topics of the working group, parenteral nutrition, carried out any consulting,
expert witness or contractual activity that was connected with financial or other personal advantages, or any
comparable activity?
yes
no
If so, in which way?
2. Possible professional conflicts of interest:
Does the institution with which you are employed or your employer, receive any financial or other benefits for
projects or measures which are connected with the topics of the working groups?
yes
no
If so, what are they?
Signature___________________________________Date_______________________
With your signature you confirm that there are no conflicts of interest between your activity in a working group,
for preparing guidelines for parenteral nutrition, and your personal or professional commitments.
Literature searches and evaluation
The individual working groups carried out a comprehensive literature search of scientific publications since 1990
in English or German (Table 3). Some relevant publications, which had been published prior to 1990, were also
considered, if deemed necessary by the concerned working group. The publications relevant to the proposed
questions were evaluated, with regards to the degree of adequacy as scientific evidence, by at least two working
group members, independently of each other (Table 4). The recommendations were then derived, in a stepwise
manner, from this information as recommended by the Scottish Intercollegiate Guidelines Network (Figure1) [5].
Table 3: Minimum requirements for literature searches to be carried out by the individual working groups
Period:
from 01.01.1990 onwards
Languages: German, English
Filter:
Human
Databases: Pubmed/Medline, EMBASE, Cochrane
Literature: Original work, guidelines, recommendations, meta-analyses, systematic reviews of literature,
randomised control studies, observational studies
Prescribed keyword for all working groups
parenteral nutrition (in combination with keywords from each individual topic)
Table 4: Degree of adequacy as scientific evidence for evaluating studies according to ZQ (in accordance with
the guidelines manual from the AWMF und AQuMed/AEZQ [4])
Degree of
adequacy
Evidence on the basis of ...
Ia
meta-analyses of randomised control studies
Ib
at least one randomised control study
IIa
at least one well designed control study without randomisation
IIb
at least one other type of well designed quasi-experimental study
III
well designed, non-experimental, descriptive studies, e.g. comparative studies, correlation
studies and case control studies
IV
reports of expert committees or expert opinions and/or clinical experience of recognised
authorities
5
Nominal Group Process
The various working groups made core statements and recommendations on the basis of the systematic
literature searches. The working groups were encouraged to follow the 'Nominal Group Process' method, i.e. the
individual members of the working groups were expected to develop their own proposals, which were then
combined to form a group consensus [4]. Individual working groups were responsible for processing the texts
using the Delphi method (written questions and answers in several rounds). The final version was accessible for
comments and criticisms, via a password-protected home page, by members of all working groups and
representatives of other specialist medical associations. The suggested amendments were considered by the
pertinent working group as well as the coordination team. The initial recommendations were discussed,
amended if considered necessary, and voted upon by the working groups in separate rooms at the working
group meetings held before the first consensus conference. This method of working in small groups was in
accordance with the Nominal Group Process, which ensured that all members of the groups made their opinions
clear, and had the chance to influence the group voting. However, as the number of groups (18) was large, with
each group having only a maximum of six members, it was decided not to carry out a formal Nominal Group
Process. The experts in the methodology of guideline development, Koller M und Celik I, assisted the process
by visiting the individual working groups, and performing the role of methodology enforcers and observers.
Consensus conferences, Delphi consensus and the final editing
A first consensus conference was held in Munich in March, 2005 with 29 working group members, at which the
members of the individual working groups presented their recommendations. These provisional
recommendations were discussed, if necessary revised, and then voted upon. The recommendations were
allocated into categories according to the guidelines provided by the AWMF and AQuMed/AEZQ (Table 5). The
results as well as an account of the proceedings of the consensus conference were recorded in writing.
Table 5: Allocation to recommendation categories (in accordance with the guidelines manual from the AWMF
und AQuMed/AEZQ [4])
Category
Degree of
adequacy
A
Ia, Ib
Convincing literature of high quality that contains at least one randomised study
(recommended without reservations)
B
IIa, IIb, III
Well performed, non-randomised studies (recommended)
C
IV
Reports and opinions of expert groups and/or clinical experience of recognised
authorities. Indicates a lack of directly applicable clinical studies of good quality
(recommended with reservations)
Explanation is substantiate by:
Figure. 1: Derivation of degrees of adequacy as scientific evidence (modified according to [5])
The suggested amendments, discussed in the consensus conference, were incorporated into the
6
recommendations using another round of the Delphi method. A password-protected home page was set up by
the DGEM, was made accessible to all working group members, who then voted on the amendments.
At a second consensus conference in May, 2004, also held in Munich, the amended manuscripts were again
discussed, amended where necessary, and voted upon. The working group Ethics and Law presented only an
interim report as they were unable to complete their work by that time. After further amendments, the working
group leaders posted their manuscripts in the section 'completed manuscripts' or, in the case of suggestions
which had not yet been voted upon, in the section 'Delphi round' of the password-protected home page, so that
the participants could once again review and comment upon the proposals. The final group consensus emerged
in this way from several rounds of proposals, reviews and amendments. During the process, the coordination
team met several times to review and edit all contributions. The English version of the guidelines was written
and updated during the period between the last quarter of 2007 and the first quarter of 2009.
Use and implementation of the guidelines
The aim of the current guidelines is to improve the quality of applying PN in practice. It must, however, be noted
that the guidelines are not mandatory directives or procedural regulations, but they are intended to provide
guidance to the medical and nursing profession on how to deal with specific situations. Special circumtances
pertaining to an individual patient, progress in medical knowledge, and development of new techniques may
justify a deviation from the recommendations included in these guidelines.
The implementation of guidelines is often difficult. It involves taking into consideration the infrastructure and the
personnel available, and the availability of experts in the field in one's own settings. Many times, although the
guidelines are available, it is not feasible to implement them either due to lack of resources or information.
The Leeds Castle conference on implementation of guidelines recommended against individual and isolated
methods of implementation [6]. It concluded that implementation must be carried out as a strategy with several
steps, with the aim of changing the attitudes and behaviour of those affected. Accordingly, it was important that
a plan which incorporated both dissemination of information as well as encouraged a change in bedside
practice, according to the guidelines, was formulated..
At the second consensus conference, the following steps for an implementation strategy were decided upon:

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





Publication in German language magazines like the 'Nutrition Medicine Today'.
Publication in English to enable dissemination in non-German-speaking countries.
Publication in an abbridged form - small enough to slip into the pocket of a doctor's white coat increasing the availability and the possibility of practical implementation of the guidelines, where they are
needed, i.e. at the bedside.
Dissemination at various meetings and congresses of medical specialists
Production and distribution of training CDs with practical examples.
Identification of nutrition support teams in hospitals and outpatient settings, and of the information they
might need.
Identification of hospitals that will commit themselves to implementation of the guidelines, and also will
give feedback regarding the implementation process (duplicator effect).
Awarding CME points to doctors within the framework of training activities.
Updating of the guidelines
The recommendations of the guidelines should be reviewed, and if necessary updated five years after
publication by the DGEM e.V.
Acknowledgements
The work involved in the preparation of the guidelines was financially supported by the German Society for
Nutritional Medicine e.V. as well as grants by the following companies provided to the University of Munich
Medical Center: Baxter Germany GmbH, Unterschleissheim, B. Braun Melsungen AG, Melsungen, and
Fresenius Kabi Germany GmbH, Bad Homburg.
References
7
1. Herbst B, Koller M. Methodology for developing guidelines for enteral nutrition. Akt Ernaehr Med (Nutritional
Medicine Today) 2003; 28 suppl. 1: pp 6-9
2. Koller M. Contributions to the social psychology for the analysis and solution of problems in the German health
system: the example of guidelines. Z Sozialpsych (Magazine for Social Psychology) 2005; 36: 47-60
3. Kopp A, Encke W, Lorenz W. Guidelines as an instrument for quality assurance in medicine. The guidelines
programme of the Joint Committee for Scientific Specialist Medical Association (AWMF).Bundesgesundheitsbl Gesundheitsforschung - Gesundheitsschutz (Federal health magazine - health research - health protection)
2002; 45: 223-233
4. Lorenz W, Ollenschlaeger G, Geraedts M et al. The guidelines manual of the AWMF and the AEZQ. ZaeFQ
2001; 95 suppl.1: 1-84
5. Miller J, Petrie J. Development of practice guidelines. Lancet 2000; 355: 82-83
6. Gross PA, Greenfield S, Cretin S et al. Optimal methods for guideline implementation: conclusions from Leeds
Castle meeting. Med Care 2001; 39: II85-II92
Koletzko B1, Jauch KW2, Verwied-Jorky S1, Krohn K1, Mittal R1 for the working group for developing the
guidelines for parenteral nutrition of The German Society for Nutritional Medicine.**
Working group members (WG):
Adolph M3 (WG 3, 6L, 14), Arends J4 (WG 19L), Bauer K5 (WG 13), Biesalski HK6 (WG 7L), Bischoff SC7 (WG
7L, 8L, 9, 12, 15), Blumenstein I8 (WG 4), Bockenheimer-Lucius G9 (WG 12), Boehles H-J5 (WG 4, 7, 13),
Bolder U10 (WG 5L), Braß P11 (WG 9), Celik I12 (WG 1), Dossett A4 (WG 19), Druml W13 (WG 14, 17L), Ebener
Ch14 (WG 5, 18), Fietkau R15 (WG 19), Franken Ch16 (WG 10), Frewer A17 (WG 12), Fusch Ch18 (WG 13L),
Goeters Ch19 (WG 4), Hartl W2 (WG 9, 11L), Hauner H20 (WG 5), Hausser L21 (WG 18), Heller AR22 (WG 6),
Holland-Cunz S23 (WG 18), Hug MJ24 (WG 19), Jauch KW2 (C, WG 1, 9L, 5, 11, 14, 18), Jochum F25 (WG 13),
Kemen M26 (WG 18), Kester L27 (WG 8), Kierdorf H28 (WG 17), Koch T22 (WG 6), Koletzko B1 (C, WG 1L, 6, 13,
15), Koller M29 (WG 1L), Kopp IB30 (WG 1), Kraehenbuehl L31 (WG 18), Krawinkel M32 (WG 13), Kreymann G33
(WG 3L, 5, 6, 14L), Krohn K1 (C, WG 6, 13), Kuse ER34 (WG 18), Laengle F35 (WG 18), Meier R36 (WG 8),
Muehlebach S37 (WG 9, 10L, 13), Muehlhoefer A38 (WG 7), Mueller MJ39 (WG 3), Ockenga J40 (WG 5),
Parhofer K41 (WG 11), Plauth M42 (WG 16L), Pscheidl E43 (WG 6, 9), Radziwill R44 (WG 8), Rittler P2 (WG 11),
Rothaermel S45 (WG 12L), Schmid I1 (WG 19), Schregel W46 (WG 9L), Schulz R-J47 (WG 4, 15L), Schuetz T48
(WG 16), Schwab D49 (WG 8), Senkal M50 (WG 6), Shang E51 (WG 19), Stanga Z52 (WG 9L, 10), Stein J8 (WG
4L), Thul P53 (WG 8, 9), Traeger K54 (WG 5), Verwied-Jorky S1 (C, WG 1), Volk O55 (WG 9), Wehkamp K-H56
(WG 12), Weimann A57 (WG 18L), Zander AR58 (WG 19), Zuercher G59 (WG 12, 19)
C = member of the coordinating team, WG= member of the working group, L= working group leader
WG of chapters: 1 Introduction and Methodology, 2 Nutritional status (see ESPEN Guidelines for Enteral
Nutrition), 3 Energy expenditure and Energy intake, 4 Amino acids, 5 Carbohydrates, 6 Lipid emulsions, 7
Water, Electrolytes, Vitamins and Trace elements, 8 Organisation, Regulations, Preparation and Logistics of
Parenteral Nutrition in Hospitals and Homes; the Role of the Nutrition support team, 9 Access Technique and its
Problems in Parenteral Nutrition, 10 Practical handling of AIO mixtures, 11 Complications and Monitoring, 12
Ethical and Legal Points of View in Parenteral Nutrition, 13 Neonatology/Paediatrics, 14 Intensive medicine, 15
Gastroenterology, 16 Hepatology, 17 Parenteral Nutrition in Patients with Renal Failure, 18 Surgery and
Transplantation, 19 Non-surgical Oncology.
1Dept.
Metabolic Diseases & Nutritional Medicine, Dr. von Hauner Children's Hospital, University of Munich;
Surgery Grosshadern, University Hospital, Munich; 3Dept. of Anaesthesiology and Intensive Medicine,
Eberhard-Karl University, Tuebingen; 4Dept of Oncology and Tumour Biology, University of Freiburg; 5Dept. of
Paediatrics, Johann-Wolfgang-Goethe University of Frankfurt; 6Institute for Biochemistry und Nutrition Science,
University of Stuttgart-Hohenheim; 7Dept Nutritional Medicine and Prevention, University Stuttgart-Hohenheim;
8Dept. Internal Medicine, University of Frankfurt; 9Senckenberg Institute for the History and Ethics of Medicine,
University of Frankfurt; 10Dept. of Surgery, University of Regensburg; 11Dept. of Anaesthesiology and Operative
Intensive Medicine, University of Cologne; 12Institute for Theoretical Surgery, Philipps University Hospital,
Marburg; 13Clinical Dept. of Nephrology and Dialysis, University of Vienna, Austria; 14Dept. of General, Visceral
and Children's Surgery, Heinrich-Heine-University of Dusseldorf; 15Depts. Paediatric Surgery and Radiation
Therapy, University of Rostock; 16Central Pharmacy, University of Dusseldorf; 17Dept. of History, Ethics and
Philosophy of Medicine, Medical University Hannover; 18Dept. of Pediatrics, McMaster University, Hamilton,
Canada; 19Dept of Anaesthesiology and Operative Intensive Medicine, University of Munster; 20Else-Kroener2Dept
8
Fresenius Centre for Nutritional Medicine, Technical University of Munich; 21Dept. of General and Visceral
Surgery, Augsburg; 22Dept. of Anaesthesiology and Intensive Therapy, University of Dresden; 23Dept. of
Paediatric Surgery, University of Tuebingen; 24Pharmacy, University Hospital Freiburg; 25Dept. of Paediatrics,
Spandau Hospital, Berlin; 26Dept. Surgery, Lutheran Hospital Herne; 27Dept. of Gastroenterology, Hepatology
and Endocrinology, Medical University of Hannover; 28Dept. Nephrology, Braunschweig; 29Centre for Clinical
Studies, University of Regensburg; 30Institute for Theoretical Surgery, Philipps University of Marburg; 31Dept. of
Surgery, Canton Hospital Fribourg, Switzerland; 32Institute for Nutritional Science and Centre for Paediatrics,
University of Giessen; 33Baxter S.A., Schaffhausenerstr., Zurich, Switzerland; 34Central Clinic for Anaesthetics,
Operative Intensive Medicine and Pain Therapy, Hospital of Salzgitter; 35Dept. General Surgery, University of
Vienna, Austria; 36Dept. of Gastroenterology, Hepatology and Nutrition, University of Basel, Switzerland; 37CSO
Vifor Pharma Ag, Villars-sur-Glâne, Switzerland; 38Dept. of Internal Medicine, Gastroenterology, Hepatology and
Infectiology, St. Catharine's Hospital, 70174 Stuttgart; 39Institute for Human Nutrition and Food Science,
Christian-Albrechts-University of Kiel; 40Medical Clinic II, Hospital Bremen Centre; 41Dept. Medicine II, University
of Munich; 42Dept. of Internal Medicine, Municipal Clinic Dessau; 43Dept. of Anaesthesiology, Intensive Medicine
and Special Pain Therapy, Landshut; 44Pharmacy und Patient Advice Centre, Clinic Fulda; 45Institute for
Biological, Health and Medical Law, University of Augsburg; 46Dept. of Anaesthetics, St. Joseph's Hospital
Krefeld-Uerdingen; 47Clinic for Geriatrics, St. Marien-Hospital, Cologne; 48Medical Department, Division of
Gastroenterologie, Hepatology and Endocrinology, Charité Universitätsmedizin Berlin;49Dept. Medicine II,
Martha-Maria Hospital, Nuremberg; 50Dept. Surgery I, St. Mary's Hospital Witten; 51Dept Surgery, University
Hospital of Mannheim; 52Polyclinic for Endocrinology, Diabetology and Clinical Nutrition, Clinic for General
Internal Medicine, University of Berne, Switzerland; 53Dept. of General, Visceral, Vascular and Thorax Surgery,
Humboldt University of Berlin; 54Dept. of Anaesthesiology, University of Ulm; 55Dept. of Internal Medicine
I/Cardiology, Krefeld; 56University for Applied Science, Hamburg; 57Dept. of General und Visceral Surgery, St.
George's Hospital, Leipzig; 58Dept. of Oncology and Haematology, University of Hamburg; 59Dept. of Internal
Medicine I, University of Freiburg.
Correspondence:
Berthold Koletzko, M.D., Professor of Paediatrics
Dr. von Hauner Children's Hospital
University of Munich
Medical Centre
Lindwurmstr. 4
D-80337 Muenchen, Germany
Phone +49 89 5160-3967, Fax +49 89 5160-3336
Email office.koletzko@med.uni-muenchen.de
Erstellungsdatum:
05/2007 (deutsche Fassung)
04/2009 (englische Fassung)
04/2014
Zurück zum Index Leitlinie Parenterale Ernährung / Guideline Parenteral Nutrition
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GMS German Medical Science 2009;7:Doc25. DOI: 10.3205/000084, URN: urn:nbn:de:0183-0000844
Chapter 3: Energy expenditure and Energy intake
Kapitel 3: Energieumsatz und Energiezufuhr
Key words: Energy requirements, sepsis, critically ill, intensive care
Schlüsselwörter: Energiebedarf, Sepsis, kritisch Kranke, Intensivtherapie
Abstract
The energy expenditure (24-h total energy expenditure, TEE) of a healthy individual or a patient is a vital
reference point for nutritional therapy to maintain body mass. TEE is usually determined by measuring resting
energy expenditure (REE) by indirect calorimetry or by estimation with the help of formulae like the formula of
Harris and Benedict with an accuracy of ± 20 %. Further components of TEE (PAL, DIT) are estimated
afterwards. TEE in intensive care patients is generally only 0 - 7 % higher than REE, due to a low PAL and lower
DIT. While diseases, like particularly sepsis, trauma and burns, cause a clinically relevant increase in REE
between 40 - 80 %, in many diseases, TEE is not markedly different from REE. A standard formula should not
be used in critically ill patients, since energy expenditure changes depending on the course and the severity of
disease. A clinical deterioration due to shock, severe sepsis or septic shock may lead to a drop of REE to a level
only slightly (20 %) above the normal REE of a healthy subject. Predominantly immobile patients should receive
an energy intake between 1.0-1.2 times the determined REE, while immobile malnourished patients should
receive a stepwise increased intake of 1.1-1.3 times the REE over a longer period. Critically ill patients in the
acute stage of disease should be supplied equal or lower to the current TEE, energy intake should be increased
stepwise up to 1.2 times (or up to 1.5 times in malnourished patients) thereafter.
Zusammenfassung
Der aktuelle Energieumsatz (24-Stunden-Gesamtenergieumsatz, TEE) eines Gesunden oder eines Patienten ist
für die Ernährungstherapie die entscheidende Bezugsgröße, um die Körpermassezu erhalten. Die Ermittlung
des TEE erfolgt entweder durch die Messung des Grundumsatzes (REE) mittels indirekter Kalorimetrie oder
durch Schätzung mit Hilfe von Formeln (z.B. Harris und Benedict) mit einer Genauigkeit von ± 20 % bei
Gesunden. Die anderen Komponenten (PAL, NIT) des TEE werden geschätzt. Der Gesamtenergieumsatz von
Intensivpatienten liegt in der Regel nur 0 % bis 7 % über dem Grundumsatz, aufgrund eines niedrigen PAL und
geringerer NIT. Während der Energieumsatz bei vielen Erkrankungen im Bereich des Standard-Grundumsatzes
bleibt, führen einige Erkrankungen (besonders Sepsis, Trauma, Verbrennungen) zu einer klinisch relevanten
Steigerung des REE von 40 % bis 80 %. Da die Steigerung des Energieumsatzes bei kritisch Kranken eine
dynamische Größe ist, abhängig vom Verlauf und vom Schweregrad der Erkrankung, sollte keine fixe Formel
angewandt werden. Eine klinische Verschlechterung (z.B. Schock, schwere Sepsis, septischer Schock) geht mit
einer relativen Abnahme des Energieumsatzes bis auf ungefähr 20 % des REE von Gesunden einher.
2
Überwiegend immobile Patienten sollten eine Energiezufuhr zwischen dem 1,0-1,2-fachen des ermittelten REE
erhalten, immobile Patienten nach Mangelernährung eine schrittweise Steigerung der Zufuhr auf das 1,1-1,3fache des REE über einen längeren Zeitraum. Die zugeführte Energie sollte bei kritisch Kranken im Akutstadium
im Bereich des aktuellen TEE oder leicht darunter liegen, danach sollte schrittweise auf das 1,2-fache (bei
gleichzeitiger Mangelernährung bis 1,5-fach) gesteigert werden.
Energy expenditure in healthy people
An understanding of energy expenditure in healthy individuals is essential for planning energy supply for
patients because:
1. it forms a basis for estimating the energy expenditure of the patient or
2. it may provide a reference when energy expenditure of a patient is measured to evaluate changes in
energy expenditure caused by disease.
Components of energy expenditure
The energy expenditure of a healthy individual or a patient is a vital reference point for nutritional therapy. Under
normal conditions this amount of energy must be provided to avoid a decrease or increase in body mass.
The total energy expenditure (TEE) consists of three main components:
 Resting energy expenditure, REE, or basal metabolic rate
 Energy expended during physical activity,
 Energy required for metabolism of the infused substrates (diet-induced thermogenesis, DIT)
Some illnesses such as sepsis, trauma, burns, hyperthyroidism and hypothyroidism, may result in a change in
energy metabolism and, therefore, in energy expenditure.
Measuring energy expenditure
Measurement of total energy expenditure over e.g. 24 hours or longer, is difficult to achieve and generally can
only be carried out under experimental conditions, usually with the doubly-labelled water method [1].
It is common practice to first measure the resting energy expenditure (REE), and then to estimate the other
components of total energy expenditure (TEE). In order to measure REE, a standardised protocol is followed
and various conditions (frequency of feeding, time of day, room temperature etc.) are strictly observed. The
method usually used for measurement of REE is indirect calorimetry [1]. In this method, the O2 and CO2
concentrations in the expired air are measured, and energy expenditure calculated, with the help of formulae, on
the basis of oxygen consumption and carbon dioxide production. This method can be used in both,
spontaneously breathing and mechanical ventilated individuals.
Estimation of the basal metabolic rate in healthy individuals from formulae



Harris and Benedict formula:
REE, men = 66.5 + 13.8 * weight (kg) + 5.0 * height (cm) - 6.8 * age (years)
REE, women = 655 + 9.6 * weight (kg) + 1.8 * height (cm) - 4.7 * age (years)
The basal metabolic rate of healthy people can be estimated by formulae with an accuracy of ± 20 % (I)
The following approximations can be used for estimating resting energy expenditure, when only weight is
available (C):
 20-30 years: 25 kcal/kg body weight/day
 30-70 years: 22.5 kcal/kg body weight/day
 > 70 years: 20 kcal/kg body weight/day
Commentary
If REE is not measured, REE or basal metabolic rate (BMR) can be estimated with the help of formulae.
Although many formulae have been developed to estimate the basal metabolic rate, the best known and used
among these is the formula by Harris and Benedict [2]. In this formula, BMR is estimated based on the height,
weight, age and gender of the individual. Although the formula was derived more than 90 years ago, using
indirect calorimetry on a small group of 239 mostly young normal subjects, it is as accurate as more recently
developed formulae, derived from larger groups. It is, therefore, still used as a guide to estimate energy
requirements. In all the formulae used, the calculated values for women, with all other factors being same, are
lower than for men. In addition, BMR decreases with increasing age.
The correlation coefficient squared (r2) between calculated and measured BMR is <0.75 for all formulae, i.e. only
75 % of the variance of BMR is predicted by weight, height, age and gender, with a 95 % confidence interval of
about ± 20 % in the samples where the respective formulae were developed.
Comparison of the basal metabolic rate values obtained by using the Harris and Benedict formula with
3
measured values in a German reference database demonstrated that the estimated values of 42.6 % of the
subjects were more than 10 % higher than the measured values, and for 18.0 % the estimates were more than
20 % higher [3]. In contrast, for 2.3 % the estimated values were more than 10 % lower than the measured
values, and for 0.7 % they were more than 20 % lower. Another study with 130 healthy subjects, using HarrisBenedict equation overestimated the basal metabolic rate by more than 10 % in 33 % of the subjects [4]. Both
studies show that the use of Harris-Benedict formula may lead to overestimation of basal metabolic rates in
certain individuals. Estimation of BMR can be improved slightly by using formulae also considering the lean body
mass and/or cell mass [4], which, however, must first be measured using an additional method. Use of body
weight only is a poor predictor of BMR, and is not recommended.
When only body weight is available, BMR can be roughly estimated as follows: BMR in individuals aged 30 to 70
years is approximately 22.5 kcal/kg body weight/day. In younger adults, the value is about 25 kcal/kg body
weight/day, and in older adults, 22 kcal/kg body weight/day. BMR of obese or malnourished subjects is
estimated from actual, and not from ideal body weight.
Estimating total energy expenditure in healthy people
Diet-induced thermogenesis (DIT) contributes to approximately 10 % of the estimated TEE. In healthy
individuals TEE is markedly dependent on energy expended during physical activity, and it can be estimated
from REE by multiplying the REE with a factor for physical activity level (PAL) [5]. If the TEE is not measured,
the amount of the physical activity may be estimated according to the degree of physical activity. Published
tables may be used for this [5]. For example, in an English study, the TEE of healthy women without any heavy
physical work was on an average 138 % of REE, i.e. the PAL was 1.38.
Energy metabolism in patients
Components of energy metabolism in patients

The total energy expenditure in patients is generally only 100 - 107 % of resting energy expenditure
(REE) (I).
Commentary
Most patients, especially those who are bedridden, have a low level of physical activity that has little effect on
TEE (except for patients undergoing intensive rehabilitation program). Furthermore, parenteral infusion of amino
acids or substrate administration by means of enteral feeding induces DIT to a much lesser extent than an oral
protein intake. Therefore, TEE of many parenterally fed patients is not significantly higher than REE.
Several studies studied the ratio of TEE to REE in intensive care patients and concluded that TEE is only 0-7 %
higher than REE [6-10]. In contrast, other studies reported a substantial increase of TEE up to 80% in critically ill
patients [11-13]. However, in these latter studies, TEE was not measured but calculated, using energy intake
and energy balance, i.e. the increase or decrease in individual body compartments.
In severely ill patients, energy expenditure may be altered due to several factors. Diseases that induce
metabolic changes by increasing or decreasing the release of hormones or cytokines, may cause a
corresponding increase as well as decrease in REE. Severe pain, psychological stress, shivering, and fever may
all increase REE.
Since the usual circadian variation in REE tends to be absent in critically ill patients, a valid estimate of their TEE
per day can be made from measuring energy expenditure during a 20 to 30 minute period at any time of the day.
REE determined in this way can be compared to normal REE for a healthy person of the same weight, height,
gender and age to assess the disease-induced change in REE.
Changes in the energy expenditure caused by illness


In many disease states, the TEE is not markedly different from REE (I).
Some illnesses, particularly sepsis, trauma and burns, cause a clinically relevant increase in REE
between 40-80 % (I).
Commentary
Not all diseases induce changes in REE. In most disorders, particularly in acute medicine, elective operations
etc., measured REE is within ± 10 % of the values predicted from formulae [14-16], which is within the range of
measurement error. Therefore, one of the formulae used for estimating REE can be applied in most patients,
e.g. the Harris und Benedict formula. TEE can be calculated as the estimated REE x 1.0 - 1.2 to accommodate
low levels of physical activity.
Some diseases, however, may cause a clinically significant change in REE, for example hypo- or
4
hyperthyroidism, sepsis, trauma and burns, that often result in a marked increase in REE of 40 to 80 % or more
[14-16].
These disease-induced changes in REE are difficult to estimate, because they depend both on the severity and
the duration of illness. A number of published studies show considerable differences between the estimated and
measured REE in critically ill patients, and the ratio between the two values can change very rapidly.
Time dependent changes in the course of disease


Energy expenditure in critically ill patients changes depending on the duration and the severity of disease.
Therefore, a standard formula should not be used for critically ill patients (I).
A clinical deterioration due to shock, severe sepsis or septic shock decreases energy expenditure of the
patient (I).
Commentary
The difficulty in assessing energy expenditure was highlighted by one study of 47 intensive care patients in
which the predictive values of five different formulae for estimating REE were investigated by measuring energy
expenditure [4]. The authors showed that REE could be estimated with one formula with an accuracy of ± 10%
in 72% of 130 intensive care patients, and concluded that this formula was preferable to the other four tested.
However, this result was based on assessments on day 19 of treatment on average, and different results might
have been obtained at other time points.
Studies assessing energy expenditure of critically ill patients on several consecutive days found considerable
day to day variation [15, 17, 18]: a continuous decrease from a peak value [19] or, in most cases, a pattern with
a rise, a peak and then a slow decrease [11-13, 20-23]. These studies indicate that no single formula can
reliably predict the energy expenditure for the total course of illness for a critically ill patient. It seems sensible to
assume that for most patients with sepsis, trauma or major operations, the course of energy expenditure
increases during the first days of disease, then rises continually, reaches a peak usually between day 4 and 10,
and then drops gradually over a period of weeks or even months. The peak value, the time at which the peak is
reached, and the total duration of metabolic changes, depends on the severity and course of the illness. Peak
values usually are about 40-80 % above normal REE.
In burns patients, a very rapid rise of REE to up to 90% above normal, followed by a gradual continual drop
returning to normal values only after more than 100 days was observed [19].
A deterioration in the patient's condition may reduce REE [24, 25] and thus may lead to an even more difficult
estimation of energy expenditure. Severe sepsis or septic shock may lead to a drop of REE to a level only
slightly (20%) above the normal REE or close to normal REE of a healthy subject. In case of clinical
deterioration, development of multi-organ failure and/or shock, if it is not feasible to measure REE, one should
assume that REE is either slightly above or close to normal REE.
Determination of parenteral energy supply based on total energy
expenditure
Energy metabolism and infusion

The measured or estimated energy expenditure is not necessarily the target value for parenteral energy
supply (C).
Commentary
An energy intake corresponding to the energy expended (isocaloric nutrition) results in energy balance, and the
preservation of status quo. In contrast, an energy intake below the energy expenditure (hypocaloric nutrition,
underfeeding) leads to a loss of body mass and weight. An energy intake above the energy expenditure
(hypercaloric nutrition, hyperalimentation) can compensate for preceding malnutrition.
It is often assumed that energy intake of patients, particularly of critically ill patients, should match the current
energy expenditure (measured or estimated), in order to maintain balance. This is not recommended, but rather
the amount of energy provided relative to energy expenditure should be a conscious therapeutic decision, taking
into account the objective of nutrition therapy in each case.
Determining energy intake

Patients who are largely immobile, with diseases not resulting in a significant change of REE, and who
show no signs of malnutrition, should initially receive an energy intake similar to their current measured or
estimated REE. The energy intake can be increased to about 1.2 times REE depending on individual
5
tolerance (C).
Commentary
In patients, as in healthy people, isocaloric nutrition leads to preservation of body mass. No controlled studies
are available on this issue; therefore, the above recommendation represents only an expert opinion (C).
Energy intake in malnourished patients

In predominantly immobile malnourished patients, energy intake should be increased stepwise over a
longer period to a target value of 1.1-1.3 times the REE (C).
Commentary
In malnourished patients, the lost endogenous stores have to be replenished. Therefore, energy intake should
be higher than current energy expenditure. To avoid a refeeding syndrome (cf. chapter "Complications and
Monitoring"), the energy intake should be gradually increased from a value close to REE to a higher value of
about 1.1-1.3 x REE. Thus in acute medical care, energy intake should be close to the current value of REE for
these patients.
Energy intake in critically ill patients
Assessment of energy intake in critically ill patients

In critically ill patients, hyperalimentation is not recommended in the acute stage of the disease (A).
Commentary
For a long time, nutrition therapy in critically ill patients was dominated by the concept of hyperalimentation, i.e.
the provision of a parenteral energy intake of 40-60 kcal/kg/day corresponding to 50-100 % above the increased
energy expenditure (even 33.5 kcal/kg/day corresponds to an energy intake of 50% above the normal REE).
The aim of hyperalimentation was to achieve a positive nitrogen balance.
There are no controlled trials comparing parenteral hyperalimentation with a nutritional regime providing a lower
energy intake. However, many studies comparing parenteral hyperalimentation with simple fluid therapy or
enteral nutrition showed no advantages or disadvantages between the two groups. A meta-analysis of 27
studies on PN patients revealed a higher mortality (risk ratio 1.78, 95% confidence interval 1.11 - 2.85) in a subgroup of critically ill patients receiving PN [26]. This higher mortality might have resulted from the
hyperalimentation used in many of these studies. A considerable proportion of energy supply in these studies
was provided as intravenous glucose, resulting in the risk of pronounced and lasting hyperglycaemia, which
could not be corrected even by large quantities of insulin. Hyperglycaemia may lead to adverse effects on the
immune system, and thereby affect the survival of critically ill patients [27] (I). In view of these adverse effects of
hyperglycemia and the associated higher mortality [26], it is recommended that hyperalimentation not be used in
critically ill patients.
Energy intake in acute stages of disease


In critically ill patients in the acute stage of disease, parenteral energy supply should be either lower than
or equal to the current TEE (B).
In critically ill patients who have survived the acute stage, energy intake should be increased stepwise to
1.2 times the current REE (or to 1.5 times REE in malnourished patients) (C).
Commentary
Animal studies revealed negative consequences of hyperalimentation, but also found.that in experimental
sepsis, lower parenteral energy provision (hypocaloric nutrition) resulted in improved survival [28, 29]. No
controlled clinical trials have assessed the impact of hypocaloric nutrition in critically ill patients. An observational
study [30] in patients treated for more than four days in intensive care showed that patients suffering from SIRS
who cumulative received only 33 - 65 % of the planned energy intake had a significantly higher survival (odds
ratio 1.22, 95 % confidence interval 1.15 - 1.29). A sub-group of these patients, who received only 25 % of
planned energy intake, had a significantly lower incidence of positive blood cultures [31].
Based on these data, it is concluded by the expert group that energy intake of critically ill patients, in the acute
6
stage of disease, should be less than or equal to the current TEE. In the initial phase, energy intake could be
even lower than energy expenditure, and then increased gradually over the course of several days until it
matches the current energy expenditure. Once the maximum value of energy expenditure is reached, energy
intake should be gradually reduced, over a longer period of time. At this time, patients should reenter an
anabolic state, in which the loss from the preceding catabolic state can be corrected. This can be achieved by a
stepwise increase of energy and substrate supply. Due to a lack of controlled trials, this recommendation
represents only an expert opinion (C).
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30. Krishnan JA, Parce PB, Martinez A, Diette GB, Brower RG. Caloric intake in medical ICU patients: consistency
of care with guidelines and relationship to clinical outcomes. Chest 2003; 124: 297-305
31. Rubinson L, Diette GB, Song X, Brower RG, Krishnan JA. Low caloric intake is associated with nosocomial
bloodstream infections in patients in the medical intensive care unit. Crit Care Med 2004; 32: 350-357
see Parenteral Nutrition Overview 073-018.htm and Chapter 1: Introduction and Methodology 073018e_01.htm
Kreymann G1, Adolph M2, Mueller MJ3 *
1Dept.
of Medicine, Univ. of Hamburg; currently Baxter S.A., Schaffhausenerstr., Zurich, Switzerland, 2Dept. of
Anaesthesiology and Intensive Medicine, Eberhard-Karl University, Tuebingen, 3Institute for Human Nutrition
and Food Science, Christian-Albrechts-University of Kiel for the working group for developing the guidelines for
parenteral nutrition of The German Association for Nutritional Medicine
Erstellungsdatum:
04/2014
AWMF online - Guidelines on Parenteral Nutrition: Amino Acids
1
AWMF online
Wissenschaftlichen
Medizinischen
Fachgesellschaften
Nr. 073-018e_04
Entwicklungsstufe:
3
Zitierbare Quelle:
Chapter 4: Amino Acids
Kapitel 4: Aminosäuren
Key words:Amino acids, branched-chain amino acids (BCAA), dipeptide, amino acid metabolism (first pass).
Schlüsselwörter: Aminosäuren, verzweigtkettige Aminosäuren, Dipeptide, Aminosäuremetabolismus
Abstract
Protein catabolism should be reduced and protein synthesis promoted with parenteral nutrion (PN). Amino acid
(AA) solutions should always be infused with PN. Standard AA solutions are generally used, whereas specially
adapted AA solutions may be required in certain conditions such as severe disorders of AA utilisation or in
inborn errors of AA metabolism. An AA intake of 0.8 g/kg/day is generally recommended for adult patients with a
normal metabolism, which may be increased to 1.2-1.5 g/kg/day, or to 2.0 or 2.5 g/kg/day in exceptional cases.
Sufficient non-nitrogen energy sources should be added in order to assure adequate utilisation of AA. A nitrogen
calorie ratio of 1:130 to 1:170 (g N/kcal) or 1:21 to 1:27 (g AA/kcal) is recommended under normal metabolic
conditions. In critically ill patients glutamine should be administered parenterally if indicated in the form of
peptides, for example 0.3-0.4 g glutamine dipeptide/kg body weight/day (= 0.2-0.26 g glutamine/kg body
weight/day). No recommendation can be made for glutamine supplementation in PN for patients with acute
pancreatitis or after bone marrow transplantation (BMT), and in newborns. The application of arginine is
currently not warranted as a supplement in PN in adults. N-acetyl AA are only of limited use as alternative AA
sources. There is currently no indication for use of AA solutions with an increased content of glycine, branchedchain AAs (BCAA) and ornithine-a-ketoglutarate (OKG) in all patients receiving PN. AA solutions with an
increased proportion of BCAA are recommended in the treatment of hepatic encephalopathy (III-IV).
Zusammenfassung
Ein Proteinkatabolismus soll bei parenteraler Ernährung (PE) vermindert und anabole Stoffwechselprozesse
gefördert werden. Standard-Aminosäure (AS) Lösungen werden empfohlen falls nicht in Sondersituationen z. B.
bei schweren AS-Verwertungsstörungen oder bei angeborenen Stoffwechselstörungen spezifisch adaptierte ASLösungen eingesetzt werden müssen. Für erwachsenen Patienten in ausgeglichenem Stoffwechselzustand wird
eine AS-Zufuhr von 0,8 g/kg/Tag empfohlen, die auf 1,2-1,5 g/kg/Tag oder in Ausnahmefällen auch auf 2,0-2,5
g/kg/Tag gesteigert werden kann. Zur Gewährleistung einer angemessenen Utilisation von AS sollten
ausreichend Nicht-Stickstoff-Energieträger zugegeben werden. Das angestrebte Verhältnis zwischen Stickstoffund Energiezufuhr (Stickstoff-Kalorien-Verhältnis) sollte unter Normalbedingungen 1:100-1:130 (g N:kcal) bzw.
1:16-1:21 (g AS:kcal) betragen. Glutamin sollte parenteral bei kritisch Kranken, sofern indiziert, in Form von
Peptiden verabreicht werden, wie z.B. 0,3-0,4 g Glutamin-Dipepetid/kg KG/Tag (entsprechend 0,2-0,26 g
Glutamin/kg KG/Tag). Für Patienten mit akuter Pankreatitis, nach Knochenmarkstransplantation sowie für
2
Neugeborene kann derzeit keine Empfehlung für eine Glutaminsupplementierung mit der PE ausgesprochen
werden. Der Einsatz von Arginin als Supplement in der PE beim Erwachsenen ist derzeit nicht gerechtfertigt.
Den N-azetylierten AS kommen als alternative Aminosäurenquellen zur Zeit nur eine begrenzte Bedeutung zu.
Für eine generelle Verwendung von AS-Lösungen mit einem erhöhten Gehalt von Glyzin und verzweigtkettigten
AS (VKAS) wie auch für Ornithin-α-Ketoglutarat (OKG) besteht keine gesicherte Indikation. Die Wirksamkeit von
AS-Lösungen mit erhöhtem Anteil an VKAS in der Behandlung der hepatischen Enzephalopathie (III-IV) wird
empfohlen.
Amino Acid Intake
Introduction
An important objective of parenteral nutrition (PN), in addition to meeting energy requirements, is to maintain
vital organ structure and function. Protein catabolism should be decreased and protein synthesis promoted.
Amino acids (AA), the building blocks in protein synthesis, are classified as dispensable, indispensable, and
conditionally dispensable AA and their precursors (Table 1). Recommended AA supplies with PN are generally
based on oral/enteral intake recommendations (Table 2), but data from animal studies [1-3] and clinical trials [4]
point to different AA needs with parenteral and enteral supply.
Table 1: Classification of Amino Acids in Adults and School Children
Dispensable AA Indispensable AA Conditionally dispensable AA
(precursors)
Isoleucine
Alanine
Arginine
(glutamate, aspartic acid)
Leucine
Aspartic acid
Cysteine
(methionine, serine)
Lysine
Asparagine
Glutamine
(glutamic acid, ammonia)
Methionine
Glutamic acid
Histidine
(serine, choline)
Phenylalanine
Glycine
Serine
(glutamate)
Threonine
Proline
Tyrosine
(phenylalanine)
Tryptophan
Valine
Table 2: Dietary Reference Values for Enteral Protein Intake [55]
Age
g/kg body weight/day g/day
m
f
m f
19 - < 25 years
0.8
59 48
25 - < 51 years
0.8
59 47
51 - < 65 years
0.8
58 46
≥ 65 years
0.8
54 44
Pregnant women (>4 months of pregnancy)
58
Breast-feeding women
63
Indications/Contraindications
Indication and Contraindication


AA should always be infused with PN (A).
Contraindications to the infusion of standard AA solutions are inborn errors of AA metabolism (e.g.
phenylketonuria, maple syrup urine disease, cystinuria) as well as severe disorders of AA utilisation (e.g.
severe liver dysfunction). Specially adapted AA solutions should be used when necessary (A).
Commentary
AA solutions are an essential part of complete PN for the maintenance of nitrogen homeostasis [5].
Contraindications to the infusion of standard AA solutions are inborn errors of AA metabolism (cf. chapter
"Neonatology/Paediatrics") as well as severe disorders of AA utilisation such as severe liver dysfunction (cf.
chapters "Gastroenterology" and "Hepatology") or renal disorders (cf. chapter "Parenteral nutrition in patients
3
with renal failure"). Specially adapted AA solutions should be used in these situations.
Compounding
Amino Acid Solutions

None of the presently available AA solutions meet all the physiological requirements of dispensable and
indispensable AA.
Commentary
Crystalline AA solutions used presently in PN contain between 3.5 and 15 % of weight as AAs (osmolarity 450 to
1450 mosmol/l) (Tables 3 and 4). None of the currently available solutions provide ideal quantities of
indispensable and dispensable AA [6] because of either poor solubility of individual AA (tyrosine, cysteine) or
instability in aqueous solutions (e.g. glutamine dissociates into pyroglutamate and ammoniac). Dipeptide
solutions, which have recently become available, allow for an improvement in the intravenous administration of
larger amounts of some AA (see below) in the form of complete solutions or supplements.
Table 3: Recommended Intakes for Indispensable Amino Acids (mg/kg body weight/day, [55])
≥19 years Pregnant Women Breast-feeding women
Histidine
14
18
19
Isoleucine
19
25
30
Leucine
42
56
62
Lysine
38
51
52
Methionine + Cysteine
19
25
26
Phenylalanine + Tyrosine 33
44
51
Threonine
20
26
30
Tryptophan
5
7
9
Valine
24
31
35
Table 4: Available Parenteral Amino Acid Solutions for Adults (g/L) (Version 05/2004)
Amino-plasmal® Aminoven® Intrafusin®
Parentamin® Synthamine V10 Thomaeamin® n
Amino Acid:
Concentration: 10 %/15 %
10 %/15 % 10 %/15 % 10 %/15 %
10 %
10 %/15 %
Tryptophan
1.8/2.1
2/1.6
1.4/2.1
1.8/2.1
1.8
1.2/1.8
Isoleucine
5.1/5.85
5/5.2
2.8/4.2
5.16/4.2
6
3.8/5.7
Leucine
8.9/11.4
7.4/8.9
3.8/5.7
8.88/5.7
7.3
6.6/9.9
Valine
4.8/7.2
6.2/5.5
3.1/4.7
4.8/4.7
5.8
4.1/6.15
Lysine
5.6/7.95
6.6/11.1
6.73/6.73
5.6/6.73
5.8
6.6/9.9
Methionine
3.8/5.7
4.3/3.8
3.6/5.5
3.8/5.5
4
2.8/4.2
Phenylalanine 5.1/5.7
5.1/5.5
2.7/4.1
5.16/4.1
5.6
4.1/6.15
Threonine
4.1/5.4
4.4/8.6
3.6/5.4
4.08/5.4
4.2
4.6/6.9
Arginine
9.2/16.05
12/20
9.3/14
9.2/14
11.5
9.2/13.8
Histidine
5.2/5.25
3/7.3
2.3/3.5
5.2/3.5
4.8
4.4/6.6
Glycine
7.9/19.2
11/18.5
10.4/15.6
10.4/15.6
10.3
7.7/11.55
Alanine
13.7/22.35
14/25
17.3/26
13.68/26
20.7
14.3/21.45
Amino Acid
4.6/16.2
-
16.97/22.07 9.2/22.07
-
9.9/14.85
L-asparagine
9.3/0
-
-
-
-
-
Aspartic acid
1.3/7.95
-
-
-
Proline
8.9/7.35
11.2/17
9.4/14.1
8.88/14.1
6.8
9.2/13.8
Serine
2.4/3
6.5/9.6
9.4/14.1
2.4/14.1
5
5.9/8.85
1.8/2.7
4
Tyrosine
1.3/0.5
0.4/0.4
1.22/1.83
1.28/1.827
0.4
0.3/0.3
Cysteine
0.5/0.37
-
0.52/0.52
-
-
0.7/1.05
Ornithine
2.5/0
-
-
Taurine
-
-
-
1/2
2.5/3.75
-
-
Requirement
Basic Adult Requirements


An AA intake of 0.8 g/kg/day is recommended for an adult patient on total PN with a normal metabolism
and normal organ functions, irrespective of age and sex (B). Depending on metabolic requirements, this
can be increased to 1.2-1.5 g/kg/day (A), or to 2.0 or 2.5 g/kg/day (C) in exceptional cases.
Sufficient non-nitrogen energy sources should be added in order to guarantee optimum utilisation of AA.
A nitrogen calorie ratio between 1 : 130 and 1 : 170 (g N/kcal) or 1 : 21 to 1 : 27 (g AA/kcal) is
recommended under normal metabolic conditions (A).
Commentary
A recently published meta-analysis of nitrogen balance studies, investigating the protein requirements of healthy
adults, has recommended an oral protein intake of 0.8 g/kg/day irrespective of age and sex [5].
As the objective of PN therapy in critically ill patients is to minimise the loss lean body cell mass, the abovementioned protein requirement for healthy adults should be adjusted according to the severity of the clinical
picture. For example, in non-hypercatabolic patients with acute kidney failure or during the polyuric recovery
phase after acute kidney failure, a protein intake of 1.0-1.3 g/kg /day is recommended to maintain nitrogen
balance [7]. An intake of 1.2-1.5 g/kg/day is recommended in patients with severe acute pancreatitis [8]. The
previously suggested upper limit of 1.5 g/kg/day may be exceeded in extremely catabolic, critically ill patients
depending on their energy requirements. An intake of up to 2.5 g/kg body weight/day is recommended by some
authors in order to achieve a positive nitrogen balance, particularly in burns patients with no kidney or liver
insufficiency, as well as in critically ill patients requiring dialysis due to renal insufficiency [9-11]. An adjustment
of the protein intake to >1.5 g/kg body weight/day is also recommended in malnourished patients [12]. The level
of intake should generally not exceed an amount allowing for a serum urea value near the upper end of the
reference range.
Sufficient non-nitrogen energy sources should be added in order to guarantee the optimum utilisation of AAs
[13]. A nitrogen calorie ratio between 1:130 and 1:170 (g N/kcal) or 1:21 to 1:27 (g AA/kcal) is recommended
under normal metabolic conditions (A). In contrast to data on oral/enteral protein intake, there are no sufficient
data to determine the optimal ratio of indispensable/total AA (E/T ratio) in PN.
Conditionally Indispensable Amino Acids
New studies are increasingly questioning the conventional classification of indispensable and dispensable AA in
clinical nutrition. Numerous data point out that some of the so-called dispensable AAs are conditionally
indispensable in adults under certain medical situations [14], and therefore, should be supplied [15].
Glutamine
In catabolic illnesses (e.g. elective surgery, trauma, pancreatitis, burns, high-dosage chemotherapy), massive
intracellular glutamine deficiency occurs in muscles. Many studies have highlighted the fact that in these
illnesses glutamine is released from muscle tissue and lungs and is made available for other organs (e.g.
intestines, kidney) and immune cells. Thus, glutamine is the most important AA for nitrogen transport between
organs and organ systems.



Critically ill patients receiving no enternal nutrition (including burns and trauma patients) should receive a
sufficient amount of glutamine dipeptides (0.3-0.4 g glutamine dipeptide/kg body weight/day = 0.2-0.26 g
glutamine/kg body weight/day) in PN (A).
No recommendation can be made for glutamine supplementation in patients with acute pancreatitis due
to the lack of data (C).
No recommendation can be made for glutamine supplementaion in PN for patients after bone marrow
transplantation (BMT), and in newborns, due to the availability of limited and inconsistent data (C).
Commentary
5
Twelve prospective randomised studies and 2 meta-analyses [16, 17] have established the efficacy of
glutamine-containing PN in both surgical [18-24] and other critically ill patients [25-28]. Administration of
glutamine resulted in a dose-dependent reduction in infection-related complications as well as length of hospital
stay in critically ill patients who had undergone surgery. Likewise, in medical intensive care patients there was a
significant reduction in complications and mortality.
Although, two randomised studies have been published [29, 30] on the effect of glutamine administration on
patients with acute pancreatitis, no recommendation can be made due to the small number of patients included
in the study. In patients after bone marrow transplantation, no consensus can be reached regarding the
administration of glutamine [31-33].

When indicated, glutamine should be administered parenterally, in the form of peptides (A).
Commentary
Commercially available AA solutions contain only small amounts of cysteine, tyrosine or glutamine due to their
low solubility or instability. These AAs are regarded as semi-essential in certain situations. Recently, di- and
tripeptides of cysteine, glutamine and tyrosine have been synthesised that are hydolysed rapidly to provide the
respective AA.
Glutamine-containing parenteral solutions must be freshly prepared, under strict aseptic conditions at 4°C due to
their low solubility in aqueous solutions and their tendency to be degraded to pyroglutamate, which involves a
release of ammonia. The concentration of glutamine in the aqueous parenteral solution should not exceed 1-1.5
% [w/v] in order to prevent precipitation. The amount of glutamine that can be administered is therefore limited,
as large amounts of fluid have to be infused to overcome the low solubility of glutamine.
Arginine

The application of arginine is not currently warranted as a supplement in PN in adults (C).
Commentary
There are only a few isolated studies on the parenteral use of arginine in patients. In critically ill patients,
arginine has a favourable effect on the function of immune cells and on the progression of wound healing [34,
35]. Arginine plays a key role in nitrogen homeostasis, in the formation of creatine and the polyamines, and is
the most important substrate in the formation of nitric oxide (NO). In burn patients, for example, a significant
drop in serum arginine concentration was observed due to an increased synthesis of ornithine (starting substrate
of polyamine synthesis) [34, 35]. An increase in arginine intake from 5 % to 7 % of total AA may result in
immunomodulatory effects [34-36]. Routine parenteral supplementation of arginine is not recommended due to
the insufficient data on safety and efficacy.
N-acetyl Amino Acids


N-acetyl AA are metabolised to a limited extent in humans and are, therefore, only of limited use as
alternative AA sources in clinical nutrition at the present time (B).
N-acetyl cysteine is recommended to prevent contrast agent (CA)-induced nephropathy (A).
Commentary
Initial studies on animals provided convincing data that the soluble and stable N-acetyl AA, i.e. acetyl cysteine,
acetyl tyrosine and acetyl glutamine, are effectively deacetylised in vivo and the released AA are well
metabolised [37]. Subsequent studies on humans, however, did not support this data. In humans, 50% of the
substrates are excreted unchanged in the urine. Compared to dipeptides, the half-life of acetyl cysteine after
intravenous administration is approximately 40 times higher [38, 39]. However, effectiveness of N-acetyl
cysteine (600 mg intravenously 12 hours before and 12 hours after administration of CA) in prevention of renal
failure after CA administration has been demonstrated in many studies [40, 41].
Glycine, Branched-chain Amino Acids, Ornithine-α-Ketoglutarate


There is currently no indication for use of AA solutions with an increased content of glycine, branchedchain AAs (BCAA) and ornithine-a-ketoglutarate (OKG) in all patients receiving PN (I).
AA solutions with an increased proportion of BCAA are recommended in the treatment of hepatic
encephalopathy (III-IV) as they are effective in alleviating the encephalopathy (A).
6
Commentary
The dispensable, soluble AA glycine is the only naturally occurring AA which is neither chirally nor optically
active. It is an essential part of scleroproteins as well as an intermediate in the biosynthesis of porphyrins,
purines, creatinine and glutathione. Glycine serves as a flexible bond for proteins, which is necessary for helix
formation, and acts as an extracellular signal protein. It is cytoprotective in ischemic insults, hypoxia and
reperfusion damage [42]. Orally administered glycine in conjunction with glutamine serves to repair cells, the
metabolic adaption, and protects intestinal mucosa after intestinal resection [43, 44]. Administration of high dose
glycine with glutamine resulted in a good compatibility and uptake in patients with polytrauma [45].
The use of parenteral AA solutions, which are concentrated with BCAA, is well-known. BCAA supplementation is
used in multiple conditions such as liver disorders (especially hepatic encephalopathy), sepsis, trauma,
disorders of gastric motility, and the prevention of failure of the respiratory musculature during artificial
respiration.
The effectiveness of BCAA in the treatment of hepatic encephalopathy was tested in seven controlled studies,
where the individual results were contradictory, but in meta-analysis showed an improvement in
encephalopathy. However, no benefit was observed in the survival rate [46].
Until to date, there are only small randomised studies that have investigated the use of AA solutions with an
increased proportion of BCAA in critically ill patients and demonstrated an improvement in clinical status [47-50].
The small number of patients in these studies does not justify a general recommendation.
OKG consists of one molecule of α-ketoglutarate (AKG) and 2 molecules of ornithine. After intravenous
administration, it dissociates into the two parts in blood [51]. OKG is well tolerated and is associated with the
stimulated release of insulin and growth hormone, and it serves as a substrate for polyamine synthesis. The
components of OKG participate in glutamine biosynthesis. In small studies, intravenous administration of OKG in
post-operative and critically ill patients results in protein conservation, stimulation of protein synthesis in the
muscles, and reduction in degradation of the muscular glutamine pool [52-54].
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35. Wu G, Meininger CJ, Knabe DA, Bazer FW, Rhoads JM. Arginine nutrition in development, health and disease.
Curr Opin Clin Nutr Metab Care 2000; 3: 59-66
36. Evoy D, Lieberman MD, Fahey TJ, III, Daly JM. Immunonutrition: the role of arginine. Nutrition 1998; 14: 611617
37. Neuhauser M, Bassler KH. [Biological availability of glutamine from N-acetyl-L-glutamine in intravenous
administration. Studies in the rat.] Article in German. Infusionsther Klin Ernahr 1986; 13: 292-296
38. Druml W, Lochs H, Roth E, Hubl W, Balcke P, Lenz K. Utilization of tyrosine dipeptides and acetyltyrosine in
normal and uremic humans. Am J Physiol 1991; 260: E280-E285
39. Magnusson I, Ekman L, Wangdahl M, Wahren J. N-acetyl-L-tyrosine and N-acetyl-L-cysteine as tyrosine and
cysteine precursors during intravenous infusion in humans. Metabolism 1989; 38: 957-961
40. Birck R, Krzossok S, Markowetz F, Schnulle P, van der Woude FJ, Braun C. Acetylcysteine for prevention of
contrast nephropathy: meta-analysis. Lancet 2003; 362: 598-603
41. Tepel M, van der Giel M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographic-contrastagent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000; 343: 180-184
42. Hall JC. Glycine. JPEN J Parenter Enteral Nutr 1998; 22: 393-398
43. Prabhu R, Thomas S, Balasubramanian KA. Oral glutamine attenuates surgical manipulation-induced alterations
in the intestinal brush border membrane. J Surg Res 2003; 115: 148-156
44. Weingartmann G, Fridrich P, Mauritz W et al. Safety and efficacy of increasing dosages of glycyl-glutamine for
total parenteral nutrition in polytrauma patients. Wien Klin Wochenschr 1996; 108: 683-688
45. Ziegler TR, Evans ME, Fernandez-Estivariz C, Jones DP. Trophic and cytoprotective nutrition for intestinal
adaptation, mucosal repair, and barrier function. Annu Rev Nutr 2003; 23: 229-261
46. Naylor CD, O'Rourke K, Detsky AS, Baker JP. Parenteral nutrition with branched-chain amino acids in hepatic
encephalopathy. A meta-analysis. Gastroenterology 1989; 97: 1033-1042
47. Freund HR, Hanani M. The metabolic role of branched-chain amino acids. Nutrition 2002; 18: 287-288
48. Fuerst P. New developments in glutamine delivery. J Nutr 2001; 131: 2562S-2568S
49. Garcia-de-Lorenzo A, Ortiz-Leyba C, Planas M et al. Parenteral administration of different amounts of branchchain amino acids in septic patients: clinical and metabolic aspects. Crit Care Med 1997; 25: 418-424
50. Wang XY, Li N, Gu J, Li WQ, Li JS. The effects of the formula of amino acids enriched BCAA on nutritional
8
support in traumatic patients. World J Gastroenterol 2003; 9: 599-602
51. Cynober L. Ornithine alpha-ketoglutarate in nutritional support. Nutrition 1991; 7: 313-322
52. Coudray-Lucas C, Le Bever H, Cynober L, De Bandt JP, Carsin H. Ornithine alpha-ketoglutarate improves
wound healing in severe burn patients: a prospective randomized double-blind trial versus isonitrogenous
controls. Crit Care Med 2000; 28: 1772-1776
53. Hammarqvist F, Wernerman J, von der Decken A, Vinnars E. Alpha-ketoglutarate preserves protein synthesis
and free glutamine in skeletal muscle after surgery. Surgery 1991; 109: 28-36
54. Wernerman J, Hammarkvist F, Ali MR, Vinnars E. Glutamine and ornithine-alpha-ketoglutarate but not
branched-chain amino acids reduce the loss of muscle glutamine after surgical trauma. Metabolism 1989; 38:
63-66
55. Deutsche Gesellschaft fuer Ernaehrung, OEsterreichische Gesellschaft fuer Ernaehrung, Schweizerische
Gesellschaft fuer Ernaehrungsforschung, Schweizerische Vereinigung fuer Ernaehrung (D-A-CH).
Referenzwerte fuer die Naehrstoffzufuhr. Frankfurt: Umschau Braus GmbH, 2000
Stein J1, Boehles HJ2, Blumenstein I1, Goeters C3, Schulz R4 *
1Dept.
Internal Medicine, University of Frankfurt, 2Dept. of Paediatrics, Johann-Wolfgang-Goethe University of
Frankfurt, 3Dept of Anaesthesiology and Operative Intensive Medicine, University of Munster, 4Clinic for
Geriatrics, St. Marien-Hospital, Cologne for the working group for developing the guidelines for parenteral
nutrition of The German Association for Nutritional Medicine
Erstellungsdatum:
04/2014
9
AWMF online - Guidelines on Parenteral Nutrition: Carbohydrates
1
AWMF online
Wissenschaftlichen
Medizinischen
Fachgesellschaften
Nr. 073-018e_05
Entwicklungsstufe:
3
Zitierbare Quelle:
Chapter 5: Carbohydrates
Kapitel 4: Kohlenhydrate
Key words: Glucose, fructose, non-protein calories, hyperglycaemia, insulin
Schlüsselwörter: Glukose, Fruktose, Nicht-Eiweiß-Kalorien, Hyperglykämie, Insulin
Abstract
The main role of carbohydrates in the human body is to provide energy. Carbohydrates should always be
infused with PN (parenteral nutrition) in combination with amino acids and lipid emulsions to improve nitrogen
balance. Glucose should be provided as a standard carbohydrate for PN, whereas the use of xylite is not
generally recommended. Fructose solutions should not be used for PN. Approximately 60 % of non-protein
energy should be supplied as glucose with an intake of 3.0-3.5 g/kg body weight/day (2.1-2.4 mg/kg body
weight/min). In patients with a high risk of hyperglycaemia (critically ill, diabetes, sepsis, or steroid therapy) an
lower initial carbohydrate infusion rate of 1-2 g/kg body weight/day is recommended to achieve normoglycaemia.
One should aim at reaching a blood glucose level of 80-110 mg/dL, and at least a glucose level <145 mg/dL
should be achieved to reduce morbidity and mortality. Hyperglycaemia may require addition of an insulin
infusion or a reduction (2.0-3.0 g/kg body weight/day) or even a temporary interruption of glucose infusion. Close
monitoring of blood glucose levels is highly important.
Zusammenfassung
Die wichtigste Rolle der Kohlenhydratzufuhr bei parenteraler Ernährung (PE) ist die Bereitstellung von Energie.
Bei jeder PE sollten Kohlenhydrate infundiert werden, zur Verbesserung der Stickstoffbilanz möglichst
gemeinsam mit Aminosäuren und Fettemulsionen. Während Glukose als Standardkohlenhydratlösung
eingesetzt wird, kann der Zuckeraustauschstoff Xylit nicht generell empfohlen werden. Fruktoselösungen sollten
keine Verwendung in der PE finden. In der Regel sollten etwa 60 % der Nichteiweiß-Energie als Kohlenhydrate
zugeführt werden mit einer Zufuhrrate von 3,0-3,5 g/kg KG/Tag (2,1-2,4 mg/kg KG/min). Patienten mit einem
hohem Hyperglykämierisiko (kritisch Kranke, Diabetes, Sepsis, Steroidtherapie) sollten eine niedrigere initiale
Kohlenhydratzufuhrrate von 1-2 g/kg KG/Tag erhalten. Die Einhaltung einer Normoglykämie ist anzustreben.
Der Zielbereich für die Blutglukosespiegel ist 80-110 mg/dl, aber zumindest sollten Werte unter 145 mg/dl
erreicht werden um Morbidität und Mortalität zu verminderen. Eine Hyperglykämie kann eine Insulingabe und
eine Reduktion der Kohlenhydratzufuhr mit der PE auf 2-3 g/kg KG/Tag oder auch eine zeitweilige
Unterbrechung der Kohlenhydratinfusion erfordern. Engmaschige Blutzuckerkontrollen sind unbedingt
erforderlich.
Physiology
2
Introduction - Basics
Knowledge of the biochemistry and physiology of carbohydrate metabolism is fundamental in understanding the
role of carbohydrates and their critical use. The main role of carbohydrates in the human body is to provide
energy. Carbohydrates also occur in the human body bound to proteins (proteoglycans), as amino sugars
(glucosamine) or in a complex form as components of matrix structures. Carbohydrates are comprised of carbon
(C) and water (H2O), hence their name.
The regulation of the serum glucose level plays a central role and is influenced by various factors: glucose
intake (enteral, parenteral); glucose oxidation in glycolysis or pentosephosphate cycle; gluconeogenesis mainly
in the liver (but also occasionally in the kidneys); glucose exchange with glycogen stores in the liver and
muscles.
Glycolysis
In aerobic conditions, glycolysis is the first step in the process of glucose oxidation. In this 2 moles of pyruvate
(C3) are generated in cytosol from one mole of glucose (C6) and 2 moles of adenosine triphosphate (ATP) are
released.
Under aerobic conditions, complete oxidation of the 2 moles of pyruvate through the Krebs cycle yields 30 moles
of ATP. Therefore, complete oxidation of one mole of glucose to water and CO2 yields 36 moles of ATP and 2
moles of guanosine triphosphate (GTP). However, under anaerobic conditions only 2 moles of ATP are
generated, and lactate is produced. Six moles of ATP are required to synthesize one mole of glucose from
lactate (Cori cycle), so there is a net consumption of 4 moles of ATP. Humans with normal metabolism utilise
approximately 4 - 5 g/kg body weight/day of glucose for glucose oxidation. Additional glucose intake results in
lipogenesis, with the synthesis of triglycerides.
Gluconeogenesis and Hepatic Glucose Production
Glucose can be synthesised in the liver or, to a lesser degree, in the kidneys. Substrates for gluconeogenesis
are lactate and pyruvate, which are derived from either anaerobic glycolysis or the degradation of glucogenic
amino acids (e.g. alanine, valine) from the muscles. Alanine can also be generated through the transfer of an
amino group from another amino acid (especially branched-chain amino acids), to pyruvate.
The hepatic glucose production in a healthy person amounts to a maximum of 2.2 mg/kg body weight/min which
is equivalent to 3.2 g of glucose/kg body weight/day. This amount equals approximately 220 g of glucose in a
person weighing 70 kg. Gluconeogenesis is an energy and oxygen consuming metabolic pathway, which
accounts for 50 % of the hepatic oxygen utilisation. Invivo, gluconeogenesis and glycolysis take place
simultaneously, and are arranged in a zonal fashion within the liver. The hormonal situation of the body
determines which of these metabolic pathways prevail.
Hormonal Regulation of Carbohydrate Metabolism
Under normal metabolic conditions, carbohydrate metabolism is regulated predominantly by the interaction
between insulin and glucagon. Other important factors in the regulation of carbohydrate metabolism are
hormones (epinephrine, cortisol) and cytokines (e.g. IL-6), particularly during post-aggression metabolism. In
certain tissues, glucose uptake into the cell is insulin-independent (e.g. erythrocytes, renal medulla, bone
marrow, leukocytes and brain).
Insulin lowers the intracellular concentration of glucose through genetic induction of key enzymes of glycolysis
and down-regulation of key enzymes involved in gluconeogenesis. Insulin/insulin+glucose have one effect, and
cAMP (acting as an intracellular agent for the glucagon) or cAMP and corticosteroids have the opposite effect in
carbohydrate metabolism. Insulin also ensures that the glycogen stores in the liver and muscle cells are
replenished. There is a simultaneous reduction in proteolysis in peripheral muscle cells, which provides the
precursors for gluconeogenesis. Insulin, therefore, acts as an anabolic hormone.
Supply of Carbohydrates
Carbohydrate application

Carbohydrates should always be infused with PN (A).
Commentary
Carbohydrates, a key substrate in PN, can improve the nitrogen balance by exerting a protein-saving effect [1-5]
3
(Ib). This can be promoted most effectively by combining the intake of amino acids with carbohydrates, or of
amino acids with carbohydrates and lipid emulsions [5-10]. Carbohydrate solutions are not only used for
nutritional purposes but also for fluid replacement [11].
Types of Carbohydrates to be administered



Glucose should be infused as a standard carbohydrate solution (C).
The use of xylite is not generally recommended due to controversial data (C).
Fructose solutions should not be used for parenteral nutrition (A).
Commentary
The standard parenteral carbohydrate solution is glucose. Glucose is easy to measure in blood and urine for the
purpose of monitoring, and prevention of overdosage.
Fructose, an important carbohydrate in a regular diet, can be partially metabolised in the body independent of
insulin. In the past, fructose was often used to provide high-calorie nutrition to critically ill patients or diabetics, to
prevent the complication of hyperglycaemia without insulin administration [12] (Ib). However, the use of fructose
to prevent complications is now less common due to a decrease in the recommended carbohydrate or energy
intake [12-15] (Ib). Life threatening complications may arise in the event of a undiagnosed hereditary fructose
intolerance [16].
Xylite, a sucrose substitute, can be metabolised independent of insulin in the pentosephosphate cycle. However,
xylite administration results in lower concentrations of glucose and insulin even during sustained endogenous
lipolysis due to its insulin-independent metabolism. The effects of xylite administration on functional proteins
have been described, although not substantiated by clinical outcome parameters. Xylite, therefore, is not
recommended in everyday use, due to dosage limitations and time-consuming monitoring [12-14].
Carbohydrates and Blood Glucose Level



As a rule approximately 60% of non-protein energy should be supplied as carbohydrates (C).
The aim is to maintain normoglycaemia (A).
The blood glucose level should be maintained between 80-110 mg/dL, if suitable to the overall clinical
situation (A). At least a glucose level of <145 mg/dL should be achieved, because levels above 145
mg/dL have been associated with higher morbidity and mortality (A).
Commentary
Hypoglycaemia can be prevented by intake of carbohydrates in situations with reduced gluconeogenesis (e.g.
restricted liver function). In order to maintain normoglycaemia, the exogenous intake should at least correspond
to the rate of the normal endogenous glucose production of 2-3 g/kg body weight/day (1.4-2.1 mg/kg/min). If a
higher amount of glucose is infused, the proportion of glucose utilised for oxidation decreases, whereas a higher
proportion of glucose is stored as fat [6, 17] (Ib).
Approximately 60% of non-protein energy should be supplied as carbohydrates, with 4 g/kg body weight/day
(2.8 mg/kg/min) being the upper limit of supply. An intake of 3.0 and 3.5 g/kg body weight/day (2.1-2.4 mg/kg
body weight/min) is preferable. The endogenous glucose production in critically ill patients is not reduced by a
higher infusion of exogenous carbohydrates or lipids [6, 18]. In these patients the risk of hyperglycaemia is
increased. Therefore, an initial low carbohydrate infusion rate of 1-2 g/kg body weight/day should be selected for
these or other patients with a high risk of hyperglycaemia (diabetes, sepsis, steroid therapy) [19]. It should also
be noted that glucose tolerance decreases in older patients [20].
The rate of glucose infusion should be monitored by monitoring the blood glucose level, as procedures to
measure glucose utilisation (indirect calorimetry) are not routinely used. In postoperative intensive care patients,
maintenance of blood glucose levels between 80 and 110 mg/dL (6.1 mmol/L) were shown to be beneficial with
regards to mortality and morbidity, compared to higher blood glucose levels [21-23]. A somewhat higher
threshold was set for blood glucose level (145 mg/dL; 8.0 mmol/L) in another patient population where the
outcome parameter was ICU mortality [24]. In a study of mixed surgical/medical patients, blood glucose levels
kept at approximately 140 mg/dL or lower by use of insulin resulted in a significant improvement in mortality and
morbidity as compared to a group where patients received insulin only after their blood glucose levels surpassed
200 mg/dL. A retrospective analysis of a subgroup of this population showed that the lowest mortality occurred
when the blood glucose levels were kept between 80 and 99 mg/dL (4.4-5.5 mmol/L) [25]. A decrease in
mortality with strict maintenance of normoglycaemia in critically ill patients only occurred when the intensive care
treatment period exceeded 3 days [26]. Lowering of blood glucose levels to between 80 and 110 mg/dL was
also associated with lower morbidity in critically ill patients [26]. In an analysis of surgical patients, a blood
glucose level of over 110 mg/dL was associated with increased mortality and morbidity, although this effect
seemed to be less marked in medical patients [22]. The positive effect on mortality and morbidity by
maintenance of blood glucose levels below 145 mg/dL is undisputed in all patients subjected to prospective
4
randomised studies. Hypoglycaemia, which occurs more often with the use of intensive insulin therapy, requires
frequent checks to determine the correct insulin dose, which should be implemented with the use of an
established algorithm.
Moreover, hyperglycaemia was also associated with deterioration in various acute disorders such as cerebral
ischemia [27-29] or myocardial infarction [30-32], irrespective of the presence of previously diagnosed diabetes.
It is likely that strict control of hyperglycaemia with insulin therapy will improve the outcome and short-term
morbidity in patients with such diseases. However, there are no prospective studies addressing this issue in
these patient groups.
Contraindication - Hyperglycaemia


Hyperglycaemia may in addition to insulin infusion require a reduction, or even a temporary interruption, of
carbohydrate infusion (C).
In order to avoid hyperglycaemia insulin administration may be necessary. This demands strict monitoring of
blood glucose levels (B).
Commentary
The only contraindication for carbohydrate intake is lasting hyperglycaemia with an insulin requirement of more
than 6 I.U./h Patients with pre-existing diabetes also require carbohydrates with simultaneous insulin infusion in
their PN. Insulin reduces blood glucose levels through increased cellular glucose intake and glucose turn-over.
The effects of insulin may be greatly reduced in certain disorders, such as diabetes mellitus, postoperative
insulin resistance, or sepsis. In hyperglycaemia, the amount of calories and carbohydrates should be restricted
(reduced to 2-3 g/kg body weight/day) and insulin should be administered. Continuous intravenous insulin
infusion is now preferred in intensive care patients. An intake of approximately 2-4 I.U./h is necessary as part of
PN after an initial bolus has been given. The higher the insulin intake and lower the hyperglycaemia, the more
frequently the blood glucose levels should be monitored. Initially, hourly to three-hourly checks are necessary
(cf. chapter "Complications and Monitoring").
References
1. Elwyn DH, Gump FE, Lles M, Long CL, Kinney JM. Protein and energy sparing of glucose added in hypocaloric
amounts to peripheral infusions of amino acids. Metabolism 1978; 27: 325-331
2. Humberstone DA, Koea J, Shaw JH. Relative importance of amino acid infusion as a means of sparing protein in
surgical patients. JPEN J Parenter Enteral Nutr 1989; 13: 223-227
3. Young GA, Hill GL. A controlled study of protein-sparing therapy after excision of the rectum: effects of
intravenous amino acids and hyperalimentation on body composition and plasma amino acids. Ann Surg 1980;
192: 183-191
4. Shaw JH, Holdaway CM. Protein-sparing effect of substrate infusion in surgical patients is governed by the
clinical state, and not by the individual substrate infused. JPEN J Parenter Enteral Nutr 1988; 12: 433-440
5. Long JM, III, Wilmore DW, Mason AD, Jr., Pruitt BA, Jr. Effect of carbohydrate and fat intake on nitrogen
excretion during total intravenous feeding. Ann Surg 1977; 185: 417-422
6. Tappy L, Schwarz JM, Schneiter P et al. Effects of isoenergetic glucose-based or lipid-based parenteral nutrition
on glucose metabolism, de novo lipogenesis, and respiratory gas exchanges in critically ill patients. Crit Care
Med 1998; 26: 860-867
7. Paluzzi M, Meguid MM. A prospective randomized study of the optimal source of nonprotein calories in total
parenteral nutrition. Surgery 1987; 102: 711-717
8. Baker JP, Detsky AS, Stewart S, Whitwell J, Marliss EB, Jeejeebhoy KN. Randomized trial of total parenteral
nutrition in critically ill patients: metabolic effects of varying glucose-lipid ratios as the energy source.
Gastroenterology 1984; 87: 53-59
9. Macfie J, Smith RC, Hill GL. Glucose or fat as a nonprotein energy source? A controlled clinical trial in
gastroenterological patients requiring intravenous nutrition. Gastroenterology 1981; 80: 103-107
10. de Chalain TM, Michell WL, O'Keefe SJ, Ogden JM. The effect of fuel source on amino acid metabolism in
critically ill patients. J Surg Res 1992; 52: 167-176
11. Lobo DN, Bostock KA, Neal KR, Perkins AC, Rowlands BJ, Allison SP. Effect of salt and water balance on
recovery of gastrointestinal function after elective colonic resection: a randomised controlled trial. Lancet 2002;
359: 1812-1818
12. Leutenegger AF, Goschke H, Stutz K et al. Comparison between glucose and a combination of glucose,
fructose, and xylitol as carbohydrates for total parenteral nutrition of surgical intensive care patients. Am J Surg
1977; 133: 199-205
13. Behrendt W, Raumanns J, Hanse J, Giani G. Glucose, fructose, and xylitol in postoperative hypocaloric
parenteral nutrition. Infusionstherapie 1988; 15: 170-175
5
14. Ladefoged K, Berthelsen P, Brockner-Nielsen J, Jarnum S, Larsen V. Fructose, xylitol and glucose in total
parenteral nutrition. Intensive Care Med 1982; 8: 19-23
15. Valero MA, Leon-Sanz M, Escobar I, Gomis P, Camara A de la, Moreno JM. Evaluation of nonglucose
carbohydrates in parenteral nutrition for diabetic patients. Eur J Clin Nutr 2001; 55: 1111-1116
16. Keller U. The sugar substitutes fructose and sorbite: an unnecessary risk in parenteral nutrition. Schweiz Med
Wochenschr 1989; 119: 101-106
17. Yamamoto T. Metabolic response to glucose overload in surgical stress: energy disposal in brown adipose
tissue. Surg Today 1996; 26: 151-157
18. Napolitano LM. Parenteral nutrition in trauma patients: glucose-based, lipid-based, or none? Crit Care Med
1998; 26: 813-814
19. Mizock BA. Blood glucose management during critical illness. Rev Endocr Metab Disord 2003; 4: 187-194
20. Al Jaouni R, Schneider SM, Rampal P, Hebuterne X. Effect of age on substrate oxidation during total parenteral
nutrition. Nutrition 2002; 18: 20-25
21. Van den Berghe G, Wouters P, Weekers F et al. Intensive insulin therapy in the critically ill patients. N Engl J
Med 2001; 345: 1359-1367
22. Van den Berghe G, Wouters PJ, Bouillon R et al. Outcome benefit of intensive insulin therapy in the critically ill:
Insulin dose versus glycemic control. Crit Care Med 2003; 31: 359-366
23. Mesotten D, Van den Berghe G. Clinical potential of insulin therapy in critically ill patients. Drugs 2003; 63: 625636
24. Finney SJ, Zekveld C, Elia A, Evans TW. Glucose control and mortality in critically ill patients. JAMA 2003; 290:
2041-2047
25. Krinsley JS. Association between hyperglycemia and increased hospital mortality in a heterogeneous population
of critically ill patients. Mayo Clin Proc 2003; 78: 1471-1478
26. Van den Berghe G, Wouters P, Weekers F et al. Intensive insulin therapy in the critically ill patients. N Engl J
Med 2001; 345: 1359-1367
27. Baird TA, Parsons MW, Phanh T et al. Persistent poststroke hyperglycemia is independently associated with
infarct expansion and worse clinical outcome. Stroke 2003; 34: 2208-2214
28. Bruno A, Biller J, Adams HP, Jr. et al. Acute blood glucose level and outcome from ischemic stroke. Trial of
ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Neurology 1999; 52: 280-284
29. Demchuk AM, Morgenstern LB, Krieger DW et al. Serum glucose level and diabetes predict tissue plasminogen
activator-related intracerebral hemorrhage in acute ischemic stroke. Stroke 1999; 30: 34-39
30. Bolk J, van der Ploeg T, Cornel JH, Arnold AE, Sepers J, Umans VA. Impaired glucose metabolism predicts
mortality after a myocardial infarction. Int J Cardiol 2001; 79: 207-214
31. Stranders I, Diamant M, van Gelder RE et al. Admission blood glucose level as risk indicator of death after
myocardial infarction in patients with and without diabetes mellitus. Arch Intern Med 2004; 164: 982-988
32. Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and prognosis of stroke in
nondiabetic and diabetic patients: a systematic overview. Stroke 2001; 32: 2426-2432
Bolder U1, Ebener C2, Hauner H3, Jauch KW4, Kreymann G5, Ockenga J6, Traeger K7 *
1Dept.
of Surgery, University of Regensburg, 2Dept. of General, Visceral and Children's Surgery, HeinrichHeine-University of Dusseldorf, 3Else-Kroener-Fresenius Centre for Nutritional Medicine, Technical University of
Munich, 4Dept Surgery Grosshadern, University Hospital, Munich, 5Dept. of Medicine, Univ. of Hamburg;
currently Baxter S.A., Schaffhausenerstr., Zurich, Switzerland, 6Medical Clinic II, Hospital Bremen Centre, 7Dept.
of Anaesthesiology, University of Ulm for the working group for developing the guidelines for parenteral nutrition
of The German Association for Nutritional Medicine
Erstellungsdatum:
6
04/2014
AWMF online - Guidelines on Parenteral Nutrition: Lipid emulsions
1
AWMF online
Wissenschaftlichen
Medizinischen
Fachgesellschaften
Nr. 073-018e_06
Entwicklungsstufe:
3
Zitierbare Quelle:
Chapter 6: Lipid emulsions
Kapitel 6: Lipidemulsionen
Key words: Lipid emulsions, α-tocopherol, hepatic steatosis, polyunsaturated fatty acids, critically ill
Schlüsselwörter: Fettemulsionen, α-Tocopherol, hepatische Steatose, mehrfach ungesättigte Fettsäuren,
kritisch Kranke
Abstract
The infusion of lipid emulsions allows a high energy supply, facilitates the prevention of high glucose infusion
rates and is indispensable for the supply with essential fatty acids. The administration of lipid emulsions is
recommended within ≤7 days after starting PN (parenteral nutrition) to avoid deficiency of essential fatty acids.
Low-fat PN with a high glucose intake increases the risk of hyperglycaemia. In parenterally fed patients with a
tendency to hyperglycaemia, an increase in the lipid-glucose ratio should be considered. In critically ill patients
the glucose infusion should not exceed 50% of energy intake. The use of lipid emulsions with a low
phospholipid/triglyceride ratio is recommended and should be provided with the usual PN to prevent depletion of
essential fatty acids, lower the risk of hyperglycaemia, and prevent hepatic steatosis. Biologically active vitamin
E (α-tocopherol) should continuously be administered along with lipid emulsions to reduce lipid peroxidation.
Parenteral lipids should provide about 25-40% of the parenteral non-protein energy supply. In certain situations
(i.e. critically ill, respiratory insufficiency) a lipid intake of up to 50 or 60% of non-protein energy may be
reasonable. The recommended daily dose for parenteral lipids in adults is 0.7-1.3 g triglycerides/kg body weight.
Serum triglyceride concentrations should be monitored regularly with dosage reduction at levels >400 mg/dl
(>4.6 mmol/l) and interruption of lipid infusion at levels >1000 mg/dl (>11.4 mmol/l). There is little evidence at
this time that the choice of different available lipid emulsions affects clinical endpoints.
Zusammenfassung
Die Infusion von Lipidemulsionen erlaubt die Zufuhr einer hohen Energiedichte, ermöglicht die Vermeidung
hoher Glukoseinfusionsraten und ist unverzichtbar für die Bedarfsdeckung mit essentiellen Fettsäuren. Zur
Vermeidung eines Mangels an essentiellen Fettsäuren ist die Gabe von Lipidemulsionen innerhalb ≤7 Tage
nach Beginn der PE (parenteralen Ernährung) erforderlich. Eine fettarme PE mit hoher Glukosezufuhr erhöht
das Risiko für eine Hyperglykämie. Bei parenteral ernährten Patienten mit Neigung zur Hyperglykämie sollte
eine Erhöhung des Verhältnisses zwischen Lipid- und Glukosezufuhr erwogen werden. Bei kritisch Kranken
sollte die Glukosezufuhr auf nicht mehr als etwa 50% der Energiezufuhr begrenzt werden. Lipidemulsionen mit
einer niedrigen Phospholipid/Triglyzerid-Ratio werden empfohlen und sollten mit der üblichen PE verabreicht
werden, um einer Verarmung an essentiellen Fettsäuren vorzubeugen, das Risiko stark erhöhter
Blutzuckerwerte zu vermindern und eine verstärkte Hepatosteatose zu vermeiden. Biologisch aktives Vitamin E
2
(α-Tocopherol) sollte regelmäßig zusammen mit Lipidemulsionen zugeführt werden, um einer Lipidperoxidation
vorzubeugen. Die parenterale Lipidzufuhr sollte in der Regel etwa 25-40% der parenteralen Nicht-ProteinEnergiezufuhr betragen. In bestimmten Situationen (z.B. bei kritisch Kranken, respiratorisch insuffizienten
Patienten) kann eine Fettzufuhr bis zu 50 oder 60% parenteraler Nicht-Protein-Energiezufuhr sinnvoll sein. Die
empfohlene Tagesdosis für die parenterale Gabe von Lipidemulsionen bei Erwachsenen liegt bei 0,7-1,3 g
Triglyzeride/kg KG. Die Serum Trigylzeridkonzentrationen sollten regelmäßig kontrolliert werden, um eine
Dosisreduktion bei Triglyzeridkonzentrationen >400 mg/dl (>4.6 mmol/l) und eine Unterbrechung der
Lipidinfusion bei >1000 mg/dl (>11.4 mmol/l) vornehmen zu können. Auswirkungen der Auswahl aus den
verschiedenen verfügbaren Lipidemulsionen sind derzeit nicht eindeutig belegt.
Background
The infusion of lipid emulsions allows for high energy supply with iso-osmolar solutions. In addition, an adequate
proportion of the energy intake as lipids facilitates the prevention of high glucose infusion rates and can,
therefore, contribute to the prevention of hyperglycaemia and hepatic steatosis. Lipid emulsions are also
indispensable for supplying the requirements of essential fatty acids.
The quantitatively dominant lipids in enteral and parenteral nutrition are triglycerides (triacylglycerols, neutral
lipids; gylcerol esterified with three fatty acids). The physical, chemical and metabolic properties of triglycerides
are determined by their fatty acid contents. Based on their chain length, fatty acids are considered as shortchain (<8 carbon atoms), medium-chain (8-10 carbon atoms), intermediate-chain (12-14 carbon atoms) and
long-chain (≥16 carbon atoms) fatty acids, which can either be saturated (without double bonds) or mono- or
polyunsaturated. Saturated, monounsaturated and polyunsaturated fatty acids differ in their metabolic and
physiological properties. While saturated fatty acids serve primarily as an energy source, polyunsaturated fatty
acids play an important role as components of structural lipids, for example in biological membranes.
Polyunsaturated fatty acids of the n-6 series (linoleic acid and metabolites), and polyunsaturated fatty acids of
the n-3 series (a-linolenic acid and metabolites) cannot be synthesised de novo by higher organisms and are,
thus, essential nutrients. For healthy adults the recommended dietary intake of linoleic acid is 2.5% and of alinolenic acid is 0.5% of the energy intake [1]. Long-chain polyunsaturated fatty acids formed from the essential
fatty acids, linoleic acid and a-linolenic acid, are important components of cell membrane and markedly affect
numerous membrane properties such as their fluidity, transport processes, and the activity of membraneanchored proteins and receptors. They also modify gene expression by binding to nuclear receptors like PPAR.
Certain polyunsaturated fatty acids (dihomo-gamma-linolenic acid, 20:3n-6; arachidonic acid, 20:4n-6;
eicosapentaenoic acid, 20:5n-3) serve as precursors in the synthesis of eicosanoids. The n-6 fatty acid
arachidonic acid is a precursor of pro-inflammatory mediators (such as leukotrienes of the n-4 series), and of
prostaglandins and thromboxanes of the n-2 series, which increase the vascular tone and promote platelet
aggregation. In contrast, prostaglandins and thromboxanes of the n-3 series and leukotrienes of the n-5 series,
formed from the n-3 fatty acid eicosapentaenoic acid, have many antagonistic effects such as a reduction in
platelet aggregation and vascular tone as well as anti-inflammatory effects.
More recently novel lipid mediators derived from poly-unsaturated fatty acids with pro-resolving activities on
inflammatory processes have been identified. They were identified in exsudates from resolving inflammation and
comprise the lipoxins, resolvins, and protectins [for review see [2,3]. Their synthesis is favored by the
transcriptional up-regulation of neutrophil 15-LO by PGE2 and PGD2, the so-called "eicosanoid switch" [4]. They
are highly stereospecific and act in the pico- to nanomolar range [5,6]. They affect PMN recruitment and
trafficking, expression of pro-inflammatory genes, reduce leukocyte-mediated tissue injury, and take part in
chemokine removal.
Lipoxins
Lipoxins are derived from AA and are generated through different biosynthetic pathways. Cells rich in 15lipoxygenase (15-LO) like airway epithelial cells, macrophages and basophils oxidize AA to 15S-HETE that is
further converted by neutrophil 5-LO to an epoxytetraene intermediate from which LXA4 and LXB4 are formed.
Alternatively, these lipoxins can also be generated from LTA4 by platelet 12-LO, most preferably under
conditions of hypoxia and diminished platelet glutathione content.
In addition, lipoxins can be generated from 15-HETE stored in membrane inositol-containing lipids. Upon
release, 15-HETE instead of AA is processed by neighbouring leukocytes resulting in decreased leukotriene and
increased lipoxin formation.
In the presence of aspirin, COX-1 is inhibited and COX-2 is acetylated. In vascular endothelial and in epithelial
cells, acetylated COX-2 metabolizes AA to 15R-HETE that is then processed by neutrophil 5-LOX to the aspirintriggered lipoxins (ATLs) 15-epi-LXA4 and 15-epi-LXB4. These epimers are more stable than the LXA4 and
LXB4 due to slower enzymatic degradation.
Both LXA4 and ATL bind to the ALX/FPRL1-receptor, which leads to reduced agonist-induced superoxide
production of PMNs and also inhibits their migration [7]. In addition, lipoxins regulate CD11/CD18 expression
and L-selectin shedding [8]. On the other hand, they increase monocyte recruitment and uptake of apoptotic
PMNs by macrophages [9].
3
Resolvins and protectins
The resolvins and protectins are derived from the omega-3 fatty acids EPA and DHA by different biosynthetic
pathways (Fig. 2). Only resolvins of the E1-series are generated from EPA through the tandem transcellular
conversion of EPA by acetylated COX II in vascular endothelial and epithelial cells and LOX in activated
neutrophils. Alternatively, resolvin E1 (RvE1) can be synthesized independent from aspirin by cytochrome P450
monooxygenase [10].
Resolvins of the D-series (RvD1) and protectins (PD1, NPD1) are derived from DHA by biosynthetic pathways
involving LOX. In addition, via aspirin-acetylated COX II, aspirin-triggered RvD1 (AT-RvD1) can be generated.
RvE1 is a ligand of the orphan receptor ChemR23 acting and inhibits NF-?B activation [11]. In addition, RvE1 is
a partial agonist at the LTB4-receptor BLT1 on PMNs and dampens LTB4-dependent activation of PMNs as
shown by reduced mobilization of intracellular calcium by RvE1 compared to LTB4 [12]. In addition, RvE1 dosedependently inhibited LTB4-induced calcium mobilization.
RvE1 dramatically reduced neutrophil infiltration in zymosan-induced peritonitis in mice that was BLT1dependent at low but independent at high RvE1 concentrations [12]. Furthermore, RvE1 blocked PMN
superoxide generation [13] and reduced the expression of proinflammatory genes.
Also, resolvins of the D-series block production of pro-inflammatory mediators as shown in the case of TNF-αinduced generation of IL-1ß in microglial cells [14]. Furthermore, they regulate PMN infiltration into inflamed
tissues [14-16].
Like resolvins, protectins regulate PMN infiltration as demonstrated by reduced peritoneal PMN recruitment in a
mouse model [6]. PD1 exerts its actions also when administered after the initiation of inflammation and was
shown to act in an additive fashion together with RvE1. Furthermore, PD1/NPD1 has profound neuroprotective
actions as evidenced by the limitation of brain injury after stroke. In this context, Lukiw and coworkers
demonstrated that protection by NPD1 from oxidative stress-mediated injury mainly occurs through the
modulation of apoptotic signaling pathways [17].
PD1 exerts immunoregulatory effects as it blocks T-cell migration, secretion of TNFa and IFN-g, and promotes
T-cell apoptosis via clustering of lipid rafts [18,19]. Furthermore, in concert with lipoxins and resolvins, it
increases CCR5 expression on apoptotic PMNs thereby promoting removal of CCR5L and termination of the
inflammatory reaction [20].
Fig. 2: Eicosanoids synthesis pathways. Depending on the fatty acid content of cellular membranes lipid
mediators with different pro-inflammatory potency or pro-resolving properties are generated from omega-3 or
omega-6 polyunsaturated fatty acids via the cyclooxygenase or lipoxygenase pathway. Pro-inflammatory
arachidonic acid (AA) -derived 5-series leukotrienes, 2-series prostanoids, and thromboxane A2 and
eicosapentaenoic acid derived 3-series prostanoids and 5-series leukotrienes with largely reduced inflammatory
properties. Pro-resloving lipoxins derive from AA while resolvins and protectins are generated from EPA.
Characteristics of lipid metabolism in critically ill patients
Endogenous lipid stores are the main energy source for critically ill patients with an inadequate food intake. In
such situations, adipose tissue triglycerides are hydrolyzed to release free fatty acids and glycerol into the
circulation [21]. The markedly increased mobilisation of free fatty acids results in a decrease in intracellular
4
triglyceride storage. This increased lipid catabolism is not countered by parenteral administration of
carbohydrates. Usually, the released free fatty acids are rapidly utilised in peripheral tissues. Depending on the
overall metabolic situation, there is either ketone body formation or re-esterification and triglyceride formation in
the liver, subsequently released into the circulation as very low density lipoproteins (VLDL). The increase in
plasma levels of free fatty acids is proportional to the severity of the trauma, and the extent to which the
production of free fatty acids surpasses their utilisation.


Fat-free parenteral nutrition can result in subnormal serum levels of essential fatty acids within one week
(IIb)
Administration of lipid emulsions is required within no more than one week after starting PN (C).
Commentary
Total PN with carbohydrate and amino acid solutions but without lipid emulsions results in a biochemically
detectable deficiency of essential fatty acids, with a drop in linoleic acid and a rise in the trien/tetraen ratio, within
only one week ([22]; IIb). These deficiencies can be corrected by parenteral administration of lipid emulsions
[23]. In infants, not only biochemical but also clinical signs of essential fatty acid deficiency, such as scaly
dermatitis, can be seen after just one week of fat-free PN ([24-26]; Ib).


Low-fat PN with a high glucose intake increases the risk of hyperglycaemia (Ia)
In parenterally fed patients with a tendency to hyperglycaemia, an increase in the lipid-glucose ratio
should be considered (C).
Commentary
Tappy et al. [27] randomised critically ill patients to either PN with 75% glucose, 15% amino acids and 10% lipid
energy intake or PN with 70% lipid, 15% glucose and 15% amino acid energy intake. The low lipid intake was
associated with increased blood glucose levels (Ia).
The typical metabolic changes resulting from the systemic inflammatory reaction is characterized by reduced
carbohydrate and increased lipid oxidation. Therefore, an increased exogenous carbohydrate intake enhances
the risk of hyperglycaemia.
In a randomised study of polytrauma patients, there was a significantly higher rate of infection in patients
administered parenteral soybean oil emulsion with an extremely high non-protein energy intake of 28 kcal/kg
compared to patients who received no intravenous lipids over the first few days [28]. However, it is noteworthy
that the energy intake in patients given fat-free nutrition was 25% lower, hence complications might also have
resulted from excessive overall substrate supply. In contrast, a meta-analysis of studies in surgical patients
showed no differences in the course of the illness and rate of complications with PN either with or without lipid
emulsions administered [29].
Effects of parenteral lipid administration on glucose metabolism
In healthy patients, both the plasma glucose concentration and the glucose uptake by tissues remained
unaffected by simultaneous parenteral infusion of glucose (4 mg/kg/min, using the glucose-clamp technique)
and lipid emulsions (20 % soybean oil or 20 % soybean oil/medium-chain triglycerides [MCT]) at an infusion rate
of 0.07 g/kg/h). However, both lipid emulsions reduced glucose oxidation as compared to the control group ([30],
IIa).
In critically ill patients, oxidative and non-oxidative glucose utilisation (continuous glucose administration, 2
mg/kg/min, plus amino acid administration, 0.15 g N/kg/day) is not influenced by the simultaneous administration
of lipid emulsions (1 mg/kg/day, 20 % soybean oil emulsion) (indirect calorimetry, (1-13C)-glucose, (6.6-2H2)glucose) ([31], IIa). An increase in glucose intake (4 mg/kg/min) does not result in a decrease in endogenous
glucose production or gluconeogenesis in critically ill patients. As compared to lipid-dominated PN (only 15% of
the total calories are administered as glucose, rest as 20% soybean oil emulsion) no decrease in net protein loss
was achieved by a glucose intake of 4 mg/kg/min. Tappy et al. [27] suggested that in critically ill patients glucose
should not exceed 50% of the parenteral energy intake due to the potential detrimental effects of predominantly
glucose-based PN, such as enhanced insulin secretion, potential insulin resistance, and high CO2 production
resulting from the stimulation of the de-novo lipogenesis.
Liver damage
In adult patients with gastrointestinal disorders, administration of PN containing soybean oil, which provided
either 2.5% or 30% of non-protein energy over a two-week period, did not result in significant differences in ALT
(alanine transferase), AST (aspartate transferase) and alkaline phosphatase between the two groups ([32]; Ib).
In critically ill patients, an excessive intake of glucose increases hepatic lipogenesis [33-36], whereas
5
intravenous lipids reduce the dependency on glucose as an energy source. A case study showed that
intravenous lipid administration lowered hepatic steatosis [37]. Animals receiving lipid-free PN demonstrated an
increase in hepatic steatosis, and in ALT and AST as compared to PN with lipids [38].
The impact of PN with or without lipids on hepatic steatosis was tested in a randomised controlled study on 37
patients (22 men). The patients received their non-protein energy intake either from glucose only or from
glucose and a lipid emulsion; a third group received an extremely high amino-acid low-carbohydrate intake [39].
Over a period of 11-13 days of PN, the liver fat content, measured in repeated biopsies, increased from 5% to
35% in the glucose group (p < 0.001) and from 7% to 23% (p < 0.001) in the amino acid group, whereas the
group receiving lipid emulsions showed no increase in steatosis. The accumulation of fat in the liver was
associated with raised levels of serum ALT and AST, but no cholestatic changes.
Development of cholestatic liver disease associated with PN has been frequently observed in premature infants
with septic infections [38]. Case studies suggest that PN-associated cholestasis in children receiving long-term
PN can be improved by reducing or interrupting the parenteral lipid intake [40]. However, in adults receiving
long-term nutrition (>6 months) the degree of cholestasis correlated with the energy supply, and not with the
proportion of fat to energy provided ([41], IIb). In a pilot study carried out on 14 patients, a slight increase in liver
size, and in the sonographically detected echodensity of the liver was detected in patients receiving soybean oil
emulsion for one week, whilst no significant changes were observed in patients given soybean oil/MCT
emulsion. General conclusions can not be deduced as there were methodological limitations of this study.
The occurrence of cholestasis has been associated with increased serum concentrations of phytosterols that are
found in vegetable oils and in lipid emulsions [42,43]. In newborn pigs, phytosterols reduced bile flow [44].
However, it remains controversial whether the increased phytosterol serum levels in cholestatic PN patients are
a cause or an effect of cholestasis [42,43].
Osmolarity/peripheral venous application

Lipid emulsions can be infused via peripheral veins over a number of days (C).
Commentary
Due to their low osmolarity (20% lipid emulsions: 270-345 mosm/l; 350-410 mosm/kg), lipid emulsions can be
infused via peripheral venous access if needed.

The infusion of lipid emulsions presents no independent, clinically relevant risk of infection (IV).
Commentary
In vitro studies suggested that the infusion only of 10% lipid emulsions resulted in significantly larger bacterial
proliferation within 6-24 hours than the use of mixed PN solutions with or without lipids, after experimental
inoculation with Staph. aureus, Strept. pyogens, Str. faecalis, Escherichia coli, Pseudomonas aeruginosa,
Klebsiella pneumonia [45-48]. In contrast, a clinical study in newborns found bacterial contamination of the
infusion solution to occur after 24 or 48 hours, irrespective of whether mixtures contain lipids or not [49].
Although the in vitro multiplication of Candida albicans was similar in all infusion solutions [45,46], in a clinical
study contamination in lipid emulsions was higher after 24 hours than after 48 hours ([49]; IIb). A case-control
study, however, showed that post-operative infections or febrile episodes associated with the infusion of lipidbased hypnotic propofol were due to insufficient aseptic techniques during the administration of the infusion [50].
A lower risk of contamination has been reported in complete mixtures used for PN than in the infusion of
individual components with added lipid solutions [46,51]. A meta-analysis of studies in surgical patients showed
no association of infectious complications with the administration of parenteral lipid emulsions [29].
Lipid infusion, lipid peroxidation and anti-oxidants

Biologically active vitamin E (α-tocopherol) should continuously be administered along with parenteral
lipid emulsions (B).
Commentary
Administration of polyunsaturated fatty acids results in an increase in lipid peroxidation markers
(malonyldialdehyde, TBARS), with a corresponding drop in the concentration of α-tocopherol in patients
receiving PN containing soybean oil emulsion ([52]; IIb; [53]; Ib). In patients receiving home PN, an
administration of 500 ml of 20% soybean oil emulsion plus 10 IU α-tocopherol (two to three times a week)
resulted in stable plasma a-tocopherol levels, whereas tissue levels of α-tocopherol dropped steadily ([54], IIa).
Daily supplementation of PN containing a soybean oil/MCT mixed emulsion with 100 mg DL-α-tocopherol
6
resulted in higher vitamin E serum concentrations and lower in vitro peroxidation of VLDL and LDL particles
([55]; Ib). Current soybean oil/MCT emulsions contain 0.85 mg α-tocopherol/g triglyceride. PN with an olive
oil/soybean oil emulsion resulted in lower concentrations of lipid peroxidation markers and higher vitamin E
serum levels than with a soybean oil emulsion ([56]; Ib; [53]; Ib).

Intravenous lipids should usually be provided with PN (C).
Commentary
A lipid emulsion should usually be provided with PN to prevent depletion of essential fatty acids, lower the risk of
hyperglycaemia, and prevent hepatic steatosis. If PN is indicated, lipid emulsions should commence after
hemodynamic stability has been established or achieved.

Parenteral lipids should provide about 25-40% of the parenteral non-protein energy supply (C).
Commentary
Based on the recommendations of food intake for healthy persons [1] and by clinical experience, it is
recommended that parenteral lipids should usually provide about 25-40% of non-protein calories, depending on
the individual patient's tolerance to carbohydrates and lipids. In critically ill patients, a higher lipid intake of up to
50% of the non-protein calories may be advisable, in view of frequently altering metabolic state and glucose
intolerance. In intensive care patients with respiratory insufficiency, up to 60% of non-protein energy is
administered as lipid to patients with good lipid tolerance during the acute phase, with the objective to reduce
the intensity of mechanical ventilation caused by diminished carbon dioxide production (RQ <0.8).
Huschak et al. [57] observed a significant reduction in CO2 production, and in the duration of mechanical
ventilation in mechanically ventilated poly-trauma patients, when given 60% of overall energy intake as
intravenous lipids as compared to the control group that received only 30% of energy as lipids (Ib).

The recommended daily dose for parenteral lipids in adults is between 0.7 and 1.3 g triglycerides/kg body
weight, but this can be increased to 1.5 g/kg body weight in case of high energy requirements (C).
Commentary
Fatty acids are oxidised in hepatocytes, myocardium, skeletal muscles, and other tissues. A lipid supply greater
than the maximum rate of lipid oxidation, estimated between 1.2 and 1.7 mg/kg/min in adults, is not
recommended. 'Fat Overload Syndrome' may result when lipid infusion rate is too high relative to the rate of
utilisation. Non-utilised lipid particles can be taken up by the mononuclear phagocyte system (MPS), and the
immune defence might deteriorate, as a result of inadequate chronic activation of the MPS [58,59]. The clinical
symptoms of 'Fat Overload Syndrome' are similar to systemic inflammatory response syndrome (SIRS) or
sepsis: fever, hepatosplenomegaly, icterus, acute lung injury (ALI/ARDS), thrombocytopenia, bleeding,
disseminated intravascular coagulation, metabolic acidosis and hypoalbuminaemia.

In patients receiving parenteral lipids, a serum triglyceride concentration >400 mg/dl (>4.6 mmol/l) should
result in a dosage reduction, and a serum triglyceride concentration >1000 mg/dl (>11.4 mmol/l) should
lead to an interruption of lipid infusion (C).
Commentary
While a fasting serum triglycerides <200 mg/dl is desirable in healthy individuals, serum triglyceride levels of
approximately 4.6 mmol/l (400 mg/dl) can be reached postprandially and are considered acceptable during
infusion of lipid emulsions (C).
Hypertriglyceridemia induced by lipid infusion can usually be controlled by reducing the dose [60]; IIb). If
hypertriglyceridemia (TG >4.6 mmol/l or >400 mg/dl) occurs with continuous infusion, the lipid emulsion dose
should be reduced, and in cases of severe hypertriglyceridemia (TG > 11.4 mmol/l or >1000 mg/dl) the dose
should be interrupted [61,62]. During the first days of infusion, plasma triglyceride levels should be monitored so
that the dose can be modified, if necessary. When lipid utilisation is impaired, e.g. in severe illness, insulin
resistance or liver failure, the lipid dose should be adapted based on plasma triglyceride concentrations.
Determination of serum opacity in the supernatant after centrifugation of whole blood is not considered useful.

Lipid infusion with PN is not indicated in severe hyperlipidemia (e.g. hereditary or acquired disorders of
triglyceride hydrolysis), in severe metabolic acidosis with impaired lipid utilisation, and in severe
coagulopathy (DIC stage III or higher) (C).
7
Commentary
Organ failure, disturbances in microcirculation after blood transfusions, or disturbances in coagulation present
no absolute contraindication for parenteral lipid administration. Parenteral supply of 20 % soybean oil emulsions
(35 % of an overall energy supply of 35-40 kcal/kg/day) resulted in no impairment in pulmonary hemodynamics,
gas exchange and diffusion capacity in patients after major upper abdominal surgery ([63]; Ib).

In acutely ill patients, lipid infusion should be administered over at least 12 hours/day. With a more critical
metabolic situation, slower infusion rates such as continuous infusion over approximately 24 hours are
recommended. Shorter infusion times may be chosen in stable patients, particularly those receiving longterm or home PN (C).
Commentary
In ARDS patients, a randomised study comparing intake of 1.3 g lipid emulsion/kg body weight over either 6 or
24 hours showed a disadvantage with the rapid infusion rate as evaluated by pulmonary prostaglandin
metabolism, pulmonary shunt and oxygenation index ([64]; Ib).

The use of lipid emulsions with a low phospholipid/triglyceride ratio is recommended (B).
Commentary
Emulsions with low a phospholipid/triglyceride ratio, usually in 20 % lipid emulsions, result in less hyperlipidemia
than emulsions with a higher phospholipid/triglyceride ratio (classic 10 % emulsions) ([65-68]; Ib)
Available lipid emulsions
Soybean oil emulsions
Parenteral lipid emulsions based on soybean oil have been widely used for several decades. Soybean oil
contains high concentrations of polyunsaturated fatty acids (PUFA, around 60 % of the total fatty acids; ratio of
linoleic acid α-linolenic acid (n-3) approximately 8:1). The administration of soybean oil emulsions resulted in
high serum PUFA concentrations. However, due to the low content of biologically active vitamin E (αtocopherol), serum vitamin E levels are lower without added supplements than with an olive oil-based emulsion,
which has a higher vitamin E/ PUFA ratio ([56]; Ib; [53]; Ib).
Clinical, ex-vivo and animal studies suggested that the type of parenterally administered fatty acids may
influence immune functions, and high PUFA containing lipid emulsions are associated with immunosuppressive
effects ([69-72]; Ib). Higher post-operative concentrations of IL6 and CRP were seen after administration of
soybean oil emulsion (20 % of the energy intake in extremely high NPE intake of 40 kcal/kg daily) as compared
to lipid-free PN, in patients after resection of gastric colorectal tumours ([73]; IIa). Many authors advise not to
administer 100 % soybean oil emulsions to critically ill patients ([64,73-75]).
Emulsions based on a physical mix of soybean oil and medium-chain triglycerides
(MCT)
An emulsion based on a physical mix of equal parts of soybean oil and MCT-oil (from coconut oil) supplies only
half the PUFA as compared to 100% soybean oil emulsions, with a similar ratio of linoleic acid (n-6) to αlinolenic acid (n-3) of approximately 8:1. This lower essential fatty acid supply is adequate for meeting the needs
of adults and infants ([22,76-78]) (Ib). Although in vitro hydrolysis of medium-chain triglycerides by lipoprotein
lipase is faster than that of long-chain triglycerides, clinical studies do not demonstrate uniform results. Some
studies also report slower plasma elimination or increased serum triglycerides with soybean/MCT than with
100% soybean oil emulsions [79,80], probably due to differences in rate of lipid particle clearance in vivo [81].
Compared to LCT, MCT are rapidly taken up by mitochondria, largely independent of carnitine, and are oxidised
faster and to a greater proportion, but the energy content per g MCT fat is lower than of LCT. In an ex vivo test
with cross-over design, neutrophils showed reduced bactericidal activity after infusion of soybean oil emulsions
but not after a mixed soybean oil/MCT emulsion [71]. The administration of mixed soybean oil/MCT emulsion led
to a slight improvement in nitrogen balance of intensive care patients after 6 and 9 days of PN ([82]; IIb), and in
septic patients after 10 days of PN ([83]; Ib) as compared to 100% soybean oil emulsion. In patients after stem
cell transplantations for malignant haematological disorders, the use of the mixed soybean oil/MCT emulsion
(n=18) resulted in a higher number of days with pyrexia (10 versus 7, p=0.01), and days on antibiotics (12
versus 8, p=0.04) as compared to a 100% soybean oil emulsion (n=18). Other end points, such as the
occurrence of Graft versus Host Disease (GVHD) and mortality, were not different ([84]; Ib). The use of an
8
experimental soybean oil/MCT emulsion in a 25/75 ratio resulted in significantly higher resting energy
consumption, oxygen consumption and carbon dioxide production, as a result of higher thermogenetic effect of
MCT as compared to a 100 % soybean oil emulsion [85]. The MCT/LCT emulsion available for clinical use has a
lower proportion of MCT and thus a lower thermogenic effect is expected.
Randomly interesterified MCT/soybean oil emulsions
These emulsions contain triglyceride particles with reesterification of medium-chain fatty acids (made of coconut
oil) and long-chain fatty acids (made of soybean oil) in random distribution within the molecule. The fatty acid
composition is comparable to that of the physical mix of soybean oil and MCT. These randomly interesterified
emulsions are often called "structured lipids", although they actually do not contain true structured lipids with
defined positions of specific fatty acids in the triglyceride molecule [86]. Lindgren et al. [87], reported a slightly
higher positive nitrogen balance in intensive care patients within the first three days of receiving an infusion of a
randomly interesterified MCT/soybean oil emulsion as compared to a 100% soybean oil emulsion (II). Randomly
interesterified lipids (1.0 or 1.5 g/kg/day) resulted in a higher overall lipid oxidation rate (indirect calorimetry) in
post-operative patients without an increase in ketogenesis or a difference in serum triglyceride levels when
compared to a soybean oil emulsion ([88], Ib). Although Chambrier et al. [89] found no difference in nitrogen
balance and 3-methyl histidine excretion in post-operative patients who received the physical mix or the
randomly interesterified mix of soybean oil and MCT, Kruimel et al. [90] reported an improved nitrogen balance
over the first 5 post-operative days and a slight increase in the serum triglycerides and non-esterified fatty acids
in patients who were operated for an aortic aneurysm. Rubin et al. [91] reported similar safety and compatibility
parameters, but with faster normalisation of raised transaminases with randomly interesterified soybean oil/MCT
emulsion in patients receiving home PN (Ib).
Olive oil/soybean oil
The available olive oil based lipid emulsion contains olive oil and soybean oil in a ratio of 4:1, and shows a high
content of the monounsaturated oleic acid and of biologically active vitamin E (α-tocopherol). The ratio between
linoleic acid (n-6) and α-linolenic acid (n-3) is 9:1. The olive oil/soybean oil emulsion is comparable to soybean
oil emulsion in terms of observed numbers of catheter infections, thromboses, and unplanned stays in hospital
during long-term administration of over 6 months ([92]; IIb). In an in vitro test of peripheral white blood cells from
healthy persons, olive oil showed less influence on the proliferation of lymphocyte subpopulations and their
receptor expression than soybean oil emulsions [93], and similar effects were shown in monocytes and
neutrophils [94,95]. A small group of 2 x 11 burns patients showed an improvement in liver function when given
parenteral olive oil emulsions as compared to a soybean oil/MCT group ([96]; Ib). In randomised controlled
studies in children and infants, the olive oil based emulsion showed comparable tolerance and safety to a
soybean oil emulsion, but resulted in more favourable fatty acid levels in serum, reduced markers of lipid
peroxidation, and higher serum vitamin E levels ([56]; Ib; [53]; Ib).
Fish-oil based emulsions
In critically ill patients, the generation of pro-inflammatory lipid mediators can be reduced with the use of fish oil
emulsions, which may prevent the escalation of SIRS to sepsis or even septic shock [97,98]. An infusion of fish
oil emulsion in healthy volunteers resulted in a reduction in the in vitro release of endotoxin-induced proinflammatory mediators like TNF-α, IL1, IL6 and IL8 from monocytes ([75]; Ib). Morlion et al. [99] and Koeller et
al. [100] found a lower ratio of leukotriene B5 to leukotriene B4 in post-operative patients a fish oil emulsion, with
possible anti-inflammatory effects (Ib). Schauder et al. [101] reported no immunosuppressive effects but an
increase in IFN-γ, TNF-α and IL-2 synthesis (Ib) after 0.2 g/kg/day of parenteral fish oil in the post-operative
phase (Ib).
Parenteral supplementation with fish oil emulsion in post-operative patients results in a rapid increase in the ratio
of eicosapentaenoic acid (20:5n-3; EPA) to arachidonic acid (20:4n-6; AA) in thrombocyte phospholipids ([102],
Ib). A delay in collagen-induced, but not ADP-induced platelet aggregation did not result in altered bleeding
times or bleeding complications following oesophagus resections. Patients after major abdominal surgery, who
received either a soybean oil emulsion or a mixture of 20% fish oil emulsion and 80% soybean oil emulsion,
showed no clinically significant difference in coagulation or bleeding times ([103]; Ib). Lower mortality, shorter
mechanical ventilation times, and shorter stays in intensive care units and hospitals were reported in postoperative patients, especially if the fish oil infusion had been administered prior to surgery ([104]; Ib). The stable
HLA-DR expression patterns observed when receiving fish oil were associated with less severe infections [104].
Lower levels of ALT/AST, bilirubin, LDH and lipase were also reported in cancer patients after elective
abdominal surgery when a mixture of 20% fish oil emulsion and 80% soybean oil emulsion was used as
compared to 100% soybean oil emulsion ([105]; Ib).
The use of fish oil emulsion in 56 patients with abdominal sepsis was associated with lower rates of re-operation
and shorter length of stay in the intensive care units and total hospital stay ([106], abstract only). In an open
case analysis of 661 patients, increasing fish oil dosage was advantageous for survival in 276 patients with
sepsis and 118, 80 and 17 patients with either 1, 2 or 3 organ failures respectively ([107]; IIb). Parenteral fish-oil
9
enriched lipid emulsion did not effect platelet function in critically ill patients ([108]; Ib).
The high unsaturated fatty acid content in fish oil tends undergo peroxidation, both during storage and in the
patient after infusion. Apart from the direct effects of released oxygen radicals, lipid peroxidation products have a
pro-inflammatory effect. Peroxidation of the high unsaturated fatty acids in the fish oil emulsions should be
prevented by addition of vitamin E (15-29.6 mg/100ml).
MCT, soybean and fish oil based emulsion
An emulsion of MCT-oil (coconut)/soybean oil/fish oil (weight ratio 5:4:1) administered to patients after elective
major abdominal surgery for a 5-day duration reduced the ratio of leukotriene B4/B5 in leukocytes stimulated ex
vivo as compared to a soybean oil emulsion [100]. A post-hoc analysis on a subgroup of 256 patients after
abdominal surgery in a multicentre trial reported a 5-day reduction in the postoperative length of hospital stay
with MCT/soybean/fish oil (5:4:1) as compared to soybean oil emulsion, although the rate of clinically relevant
complications were similar ([109]). In a very small group of 8 kidney donors and transplant recipients, infusion of
this lipid emulsion induced no differences in coagulation, liver or renal functions or serum creatinine in transplant
recipients [110]. The currently available published clinical data on the use of this emulsion is still limited.
Emulsion of soybean oil, MCT, olive oil and fish oil
A soybean/MCT/olive/fish oil emulsion in a weight ratio of 30: 30: 25: 15 in healthy volunteers (20% emulsion,
0.125 g/kg/h), after 6 hours of parenteral infusion, resulted in a slight rise in serum triglycerides and respectively
quicker clearance after discontinuing the appropriate lipid emulsion as compared to a 20% soybean oil emulsion
[111]. A published study of 249 postoperative patients showed that the rise in serum triglyceride levels, when
receiving this mixed lipid emulsion, is the same as with a soybean oil emulsion [112]. In an interim evaluation of
a small number of surgical patients who received 5-days of postoperative PN, a reduction in hospital stay of 7
days was recorded in patients after a mixed emulsion (13.4 +/- 2.0 days, n=19) than after a soybean oil emulsion
(20.4 +/- 10 days, n=14) [113]. Recent publication of the data of all 249 patients in this study, however, did not
show any significant difference in the biochemical and clinical parameters or in LOS (length of stay), in either the
intention-to-treat analysis or the per-protocol analysis [112]. Furthermore, there was an increased ex vivo
release of leukotriene B5 and reduced leukotriene B4-release from leukocytes [114]. In a small group of intensive
care patients (a total of 20 patients), it was found that there was an increase in ALT in both groups after 5 days
of PN in a comparison between mixed emulsions and soybean oil emulsions. There was, however, less
tendency towards an increase in the mixed emulsion group (n.s.) ([115]; Ib). The currently available published
clinical data on the use of this emulsion is still limited.
Conclusions
Soybean oil-based emulsions meet energy and essential fatty acid requirements. There are indications that
mixture of soybean oil with other oils such as MCT or olive oil result in more favourable metabolic parameters
and a more desirable, lower PUFA supply. Emulsions containing fish-oil may provide anti-inflammatory effects
and offer the potential for a targeted approach in specific disease states. Further research is needed on relevant
clinical end points, and clear recommendations on clinical use of different emulsions cannot be given at this
time.
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Adolph M1, Heller AR2, Koch T2, Koletzko B3, Kreymann KG4, Krohn K3, Pscheidl E5, Senkal M6 *
1Dept.
of Anaesthesiology and Intensive Medicine, Eberhard-Karl University, Tuebingen, 2Dept. of
Anaesthesiology and Intensive Therapy, University of Dresden, 3Dept. Metabolic Diseases & Nutritional
Medicine, Dr. von Hauner Children's Hospital, University of Munich, 4Dept. of Medicine, Univ. of Hamburg;
currently at Baxter Schweiz AG, Zuerich, Switzerland, 5Dept. of Anaesthesiology, Intensive Medicine and
Special Pain Therapy, Landshut, 6Dept. Surgery I, St. Mary's Hospital Witten for the working group for
developing the guidelines for parenteral nutrition of The German Association for Nutritional Medicine
14
Erstellungsdatum:
04/2014
AWMF online - Guidelines on Parenteral Nutrition: Water, Electrolytes, Vitamins and Trace Elements
1
AWMF online
Wissenschaftlichen
Medizinischen
Fachgesellschaften
Nr. 073-018e_07
Entwicklungsstufe:
3
Zitierbare Quelle:
Chapter 7: Water, Electrolytes, Vitamins and Trace
Elements
Kapitel 7: Wasser, Elektrolyte, Vitamine und Spurenelemente
Key words: Fluid intake, trace elements, zinc, selenium, vitamins
Schlüsselwörter: Flüssigkeitsaufnahme, Spurenelemente, Zink, Selen, Vitamine
Abstract
A close cooperation between medical teams is necessary when calculating the fluid intake of parenterally fed
patients. Fluids supplied parenterally, orally and enterally, other infusions, and additional fluid losses (e.g. diarrhea)
must be considered. Targeted diagnostic monitoring (volume status) is required in patients with disturbed water or
electrolyte balance. Fluid requirements of adults with normal hydration status is approximately 30-40 ml/kg body
weight/d, but fluid needs usually increase during fever. Serum electrolyte concentrations should be determined
prior to PN, and patients with normal fluid and electrolyte balance should receive intakes follwing standard
recommendations with PN. Additional requirements should usually be administered via separate infusion pumps.
Concentrated potassium (1 mval/ml) or 20% NaCl solutions should be infused via a central venous catheter.
Electrolyte intake should be adjusted according to the results of regular laboratory analyses. Individual
determination of electrolyte intake is required when electrolyte balance is initially altered (e.g. due to chronic
diarrhea, recurring vomiting, renal insufficiency etc.). Vitamins and trace elements should be generally substituted
in PN, unless there are contraindications. The supplementation of vitamins and trace elements is obligatory after a
PN of >1 week. A standard dosage of vitamins and trace elements based on current dietary reference intakes for
oral feeding is generally recommended unless certain clinical situations require other intakes.
Zusammenfassung
Für die Berechnung der Flüssigkeitszufuhr bei parenteral ernährten Patienten ist eine enge Absprache zwischen
den betreuenden ärztlichen Teams notwendig. Neben der PE muss auch die oral und enteral zugeführte
Flüssigkeit sowie ggf. eine weitere Infusionstherapie und außergewöhnliche Flüssigkeitsverluste (z.B. Diarrhöe)
berücksichtigt werden. Für Patienten mit gestörtem Wasser- oder Elektrolythaushalt ist eine gezielte Diagnostik
(Volumenstatus) zur Ermittlung des individuellen Flüssigkeitsbedarfs erforderlich. Während der Flüssigkeitsbedarf
für Erwachsene mit normalem Volumenstatus bei ca. 30-40 ml/kg KG/d liegt, ist der Flüssigkeitsbedarf bei Fieber
üblicherweise erhöht. Bei normalem Flüssigkeits- und Elektrolythaushalt erfolgt die Zufuhr von Elektrolyten initial
standardisiert nach allgemeinen Empfehlungen. Die Serumelektrolytkonzentrationen sollten vor Beginn einer PE
bestimmt werden. Eine Elektrolytzufuhr im Bereich des normalen Bedarfs wird mit der appliziert. Bei deutlich
gesteigertem Bedarf sind zusätzliche Zufuhrwege (z.B. über separate Infusionspumpen) sinnvoll. Die isolierte
Zufuhr von hochdosierten Kalium- (1mval/ml) bzw. NaCl 20%-Lösungen sollte über einen zentralen Venenkatheter
2
erfolgen. Die Elektrolytzufuhr muss im Verlauf der PE nach regelmäßig durchgeführten Laborkontrollen angepasst
werden. Bei initial verändertem Elektrolythaushalt (z.B. bedingt durch chronische Diarrhöe, rezidivierendes
Erbrechen, Niereninsuffizienz etc.) ist eine individuelle angepasste Elektrolytzufuhr erforderlich. Vitamine und
Spurenelemente sollten bei PE grundsätzlich substituiert werden, sofern keine Kontraindikationen bestehen. Ab
einer PE-Dauer >1 Woche ist die Supplementation von Vitaminen und Spurenelementen obligat. Die Zufuhr von
Vitaminen und Spurenelementen in Anlehnung an Dosisempfehlungen für die orale Ernährung wird generell
empfohlen falls nicht spezielle Krankheitssituationen andere Zufuhren erfordern.
Preliminary Remarks
Fluid and electrolyte requirements, of patients receiving PN are administered by means of parenteral infusions,
oral and/or enteral intake. A close cooperation is, therefore, necessary between medical teams, involved in the
overall care of the patient and the team prescribing the PN intakes of the patient, especially if the teams are
mutually exclusive.
Many of the practices involved in providing fluid and electrolyte requirements of the patients, particularly the
substitution of vitamins and trace elements, are clinically established practices that are not based on randomized
studies. Some recent clinical studies evaluating high-dosage vitamins or trace elements are mostly prospective,
controlled and randomised studies. Although these studies have the highest level of evidence (A), general
recommendations cannot not always derived from these studies, because they usually included small patient
numbers only.
Fluid Intake in Parenteral Nutrition




The fluid requirement in adults with normal hydration status is approximately 30 - 40 ml/kg body weight/d.
Depending on their age, children have a much higher fluid intake per kg body weight (cf. chapter
"Neonatology/Paediatrics") (C).
In the event of fever, fluid needs usually increase by approximately 10 ml/kg body weight/d per 1°C rise in
temperature above 37°C (C).
Targeted diagnostic monitoring is required in patients with disturbed water or electrolyte balance (e.g. shock,
sepsis, renal insufficiency) to determine individual fluid needs (C).
When calculating the fluid intake of parenterally fed patients, fluids supplied parenterally, orally and enterally, other
infusions, and additional fluid losses (e.g. diarrhea) must be considered (C).
Commentary
The recommended daily fluid supplies are not based on systematic studies, but on clinical experience and
recommendations by experts and medical societies [1-5]. There is no conclusive literature on fluid requirements in
patients with fever, or in patients with disturbed water or electrolyte balances. The recommendations made here
are, therefore, based on expert opinion (C).
The determination of the hydration of a patient is a prerequisite for calculating parenteral fluid requirements,
especially when a disturbance in fluid balance is clinically suspected. In such patients, transitions between
hypovolaemia, euvolaemia and hypervolaemia are frequent. The current fluid volume status may be evaluated by
clinical symptoms (change of body weight, skin turgor, central venous pressure [CVP], sonographic evidence of
vena cava filling) and laboratory parameters (haematocrit, serum sodium, serum and urine osmolarity).
Hypovolaemia is characterised by weight loss, reduced skin turgor, dry mucous membranes, reduced arterial and
central venous pressure (collapsed jugular vein, CVP <4 cm H2O, collapsed vena cava in sonography),
tachycardia, and where applicable increased serum sodium and increased serum osmolarity as well as increased
urine osmolarity (>450 mosmol/kg). Symptoms of hypervolaemia are typically the formation of edema, in the legs
or on the coccyx in bedridden patients, pulmonary edema, ascites, a tendency towards arterial hypertension, and
increased filling pressure in the large veins. Laboratory tests may also show reduced plasma osmolarity and
hematocrit levels [6]. These criteria usually allow for estimates of the current fluid volume status, both at the
beginning of and during PN. Treatment of the underlying illness causing a fluid imbalance should also be initiated.
Fluid imbalance can be symptomatically treated by means of individually adapted PN, for example, in critically ill
patients and patients with acute or chronic renal, liver, heart or lung insufficiency. Strict monitoring of and
appropriate changes in fluid and electrolyte intake are necessary in patients at-risk for disturbances in fluid and
electrolyte balance, especially in critically ill patients and in patients with renal failure or chronic renal insufficiency
(cf. chapter "Parenteral nutrition in patients with renal failure").
Electrolyte Intake in Parenteral Nutrition


Electrolyte intake in patients with normal fluid and electrolyte balance should follow general recommendations
(Table 1). Serum electrolyte concentrations (Na, K, Ca, Mg, phosphate) should generally be determined prior to
commencing PN (C).
Electrolyte supplies in the normal range may be administered with the glucose-amino acid solution (C). Additional

3
requirements should be administered by other methods (i.e. via separate infusion pumps), to avoid compatibility
problems (C). Isolated potassium (1 mval/ml) or 20% NaCl should be infused via a central venous catheter (C).
Electrolyte intake should be adjusted according to the results of regular laboratory analyses performed during PN.
Individual determination of electrolyte intake is required when electrolyte balance is initially altered (e.g. due to
chronic diarrhea, recurring vomiting, renal insufficiency etc.) (A).
Table 1: Standard daily doses of parenterally administered electrolytes in PN in adult patients (adapted from [5])
Sodium
60 - 150 mmol
Potassium
40 - 100 mmol
Magnesium
4 - 12 mmol
Calcium
2.5 - 7.5 mmol
Phosphate
10 - 30 mmol
Commentary
Electrolyte supply with PN is closely linked to fluid intake. The values for standard electrolyte intake (Table 1) have
been adapted from the guidelines of the American Gastroenterological Association (AGA) [5], which are based on
the "FDA Requirements for Marketing" published in 2000 [7]. These values should be seen as general guidelines
and may be used in patients with normal renal and liver functions as well as normal electrolyte concentrations in
the blood. Restrictions may be necessary in disorders where limited intake is recommended, e.g. of sodium in
hypertension and cardiac insufficiency. Currently available recommendations for standard electrolyte intake are
based on oral intake and have been extrapolated for the parenteral situation. The requirement of laboratory checks
at the beginning of PN is an expert opinion. When determining the electrolyte intake in PN, it should be taken into
consideration that many commercially available multi-chamber bags and amino acid solutions contain electrolytes
in various doses, which do not always meet patients' requirements in the long run. These quantities need to be
taken into account when calculation additional needs that may need to be added to the PN bag.
In case of a standard electrolyte intake, this should be administered via the PN bag (C). Higher doses may be
required in the event of large fluid losses (e.g. vomiting, diarrhea, large wounds, high-output fistulae, renal
illnesses). Such additional electrolytes should generally be given as a separate infusion, e.g. via infusion pumps, if
requirements exceed the upper end of the ranges shown in Table 1. Compatibility problems are thus prevented,
and short-term adjustments in electrolyte levels are possible.
There are no studies evaluating the adequate frequency of laboratory monitoring of serum electrolytes during PN.
A check every 24 hours was found beneficial in intensive care patients at the beginning of PN (week 1-2), whilst
twice weekly testing for ward patients was considered adequate as long as there were no special risk factors (8).
The time intervals between tests might be extended with longer duration of PN, provided the electrolyte values
were stable; checks every 1-2 weeks in the first three months, and then every month in the following three months
generally are sufficient in stable patients on at-home parenteral nutrition [8]. This recommendation is in agreement
with the Mayo scheme, which is presented in more detail in the chapter on "Complications and Monitoring".
Supply of vitamins and trace elements during parenteral nutrition under
standard conditions



Parenteral vitamins and trace element supplies should be provided to patients receiving total PN (C).
Vitamins and trace elements should be generally substituted in PN, unless there are contraindications. The
supplementation of vitamins and trace elements is obligatory after a PN duration of >1 week.
A standard dosage of vitamins and trace elements is generally recommended because individual requirements
cannot be easily determined. Preferably, all vitamins and trace elements supplied with a normal diet should also be
substituted with PN as available (C). The quantities of daily parenteral vitamin and trace element supplies are
based on current dietary reference intakes for oral feeding (A).
Commentary
Vitamins and trace elements must be administered as essential nutrients to parenterally fed patients to prevent
deficiency syndromes [9-11]. There is a lack of studies clearly indicating when it is necessary to substitute vitamins
and trace elements with PN. In patients who receive home PN, deficits have been shown to occur without
substitution, and they can be completely or partially corrected with standard supplies [9-11]. The supply of vitamin
E reduces the formation of lipid peroxides during PN [12].
The recommended standard supplies of vitamins and trace elements in adults (Table 2) have been adapted from
the guidelines for electrolytes by the American Gastroenterological Association (AGA) and should be regarded as
4
estimated requirements [5], which are based on the "FDA Requirements for Marketing" from 2000 [7]. They do not
completely correspond to the reference intake values for healthy, orally fed subjects [3]. Recommendations for
parenteral trace element supply in children are provided (Table 3) [13, 14]. While standardised vitamin
supplementation does not result in desirable blood or tissue concentrations for all vitamins [15, 16], it is not
possible to determine individual requirements of vitamin and trace elements with clinical routine care.
Vitamins and trace elements should be added to the parenteral solutions. Vitamins should be added just before
using the nutrition bag. Loss of activity can be minimized by dissolving the vitamins in a lipid solution or by using a
light protection covering [17] (cf. chapter "Practical Handling of AIO Admixtures").
Table 2: Estimated daily requirements of parenterally administered vitamins and trace elements in adult patients
(adapted from [5, 7])
Vitamin B1 (thiamine)
6 mg
Vitamin B2 (riboflavin)
3.6 mg
Vitamin B6 (pyridoxine)
6 mg
Vitamin B12 (cobalamine) 5 µg
pantothenic acid
15 mg
niacine
40 mg
biotin
60 µg
folic acid
600 µg
Vitamin C (ascorbic acid)
200 mg
Vitamin A
3300 I.U. (= 1 mg)
Vitamin D
200 I.U.
Vitamin E
10 I.U. (= 9.1 mg)
Vitamin K
150 µg
chromium
10 - 20 µg (= 0.05-0.10 µmol)
copper
0.3 - 1.2 mg (= 4.7-18.8 µmol)
iodine
70 - 140 µg (= 0.54-1.08 µmol)
iron
1 - 1.5 mg (= 18-27 µmol)
manganese
0.2 - 0.8 mg (= 3.6-14.6 µmol)
selenium
20 - 80 µg (= 0.25-1.0 µmol)
zinc
2.5 - 4 mg (= 38-61 µmol)
NB: the values given here reflect recommendations of the American Gastroenterological Association [5]. The
values for certain vitamins and trace elements deviate considerably from the dietary reference values by the
German-speaking nutrition societies (D-A-CH) [3].#
Table 3: Estimated daily requirements of parenterally administered vitamins and trace elements in infants and
children (according to [13, 14])
Element
Infants
Children
(µg/kg body weight/d)
(µg/kg body weight/d or
[maximum µg/d])
preterm term
Zinc
400
250 < 3 Mo 50
100 > 3 Mo
[5000]
Copper*
Selenium**
20
2.0
20
2.0
20
2.0
[300]
[30]
Chromium**
0.2
0.2 -
0.2
[5.0]
1.0
1.0
[50]
Manganese** 1.0
Molybdenum** 0.25
0.25
Iodine
1.0
1.0
* not in cholestasis
** not in renal dysfunction
0.25
1.0
5
[5.0]
[1.0]
Guidelines on the Deviation from Standard Conditions in the Substitution of Vitamins
and Trace Elements

A deviation from the standard intake of vitamins and trace elements may be indicated under certain clinical
situations (C).
Commentary
A standard supplementation of micronutrients may not be sufficient for certain medical situations, for instance, in
bone marrow transplants [18] and in dialysis patients (cf. chapter "Parenteral nutrition in patients with renal
failure"). There are studies where pharmacological doses of certain vitamins and trace elements were used. It was
shown that low plasma concentrations of vitamin C could be normalised after administration of high doses of
vitamin C in perioperative intensive care patients [19]. The use of pharmacological doses of specific micronutrients
exceeds the requirements of PN and therefore, will not be discussed here (Table 4).
An up-to-date overview of the vitamins and trace elements supplements presently available for parenteral use in
Germany is provided (Table 5 and 6). These supplements can be used in daily clinical practice, even though the
composition of these supplements does not correspond exactly to the estimated vitamin requirements (Table 2).
Table 4: Risk constellations for potentially increased requirements of vitamins and trace elements
Illness
Postulated affected micro nutrients [ref. in brackets]
Trauma
Vitamins C and E, zinc [20-22]
Sepsis
Selenium, Vitamins C and E? [20, 23-26]
Burns
Vitamin C, zinc, copper and selenium [27-30]
ARDS
Vitamin C? [21]
n-Acetyl cysteine? [31]
Renal insufficiency
Water-soluble vitamins like Vitamin C? Cave at: Risk in oxalate formation [32]
Wernicke's
encephalopathy
Thiamine (when there is a risk constellation of alcoholism, dialysis, malabsorption)
[8, 33-35]
Liver disease
Cholestatic liver disease: in particular fat-soluble vitamins A, D, E, K
Alcoholic liver disease: risk of general micronutrient deficiency caused by
malnutrition
Advanced liver cirrhosis:
Electrolyte disturbances (Na+, K+, Ca, Mg) as well as a lack of zinc
Table 5: Vitamin supplements for parenteral administration, available in Germany
A. Vitamin Supplements
Supplements
A
[I.U.]
D
E
K
C
B1
B2
B6
B12 Folic
[I.U.] [I.U.] [µg] [mg] [mg] [mg] [mg] [µg] acid
[mg]
Cernevit®*
3500 220
11.2
---
Frekavit®
fat-soluble
3300 200
10
Frekavit®*
water-soluble
---
---
Multibionta®N* 3000 --for infusions
125
Pantothenic
acid
[mg]
Biotin Niacine
[mg] [mg]
3.5
4.14 4.53 6
0.41
17.25
0.07
46
150 ---
---
---
---
---
---
---
---
---
---
---
100
3
3.6
4
5
0.40
15
0.06
40
5.5
---
100
10
7.3
15
---
---
25
---
40
Soluvit®*
---
Vitalipid®
3300 200
---
---
---
100
10
150 ---
6
2.5
3.6
4
5
0.4
15
0.06
40
---
---
---
---
---
---
---
---
* Vitamin K is recommended during long-term PN use, i.e. 1 x per week
Table 6: Trace element supplements for parenteral application available in Germany
B. Trace Element Supplements
Zn
Mn
Cu
Fe
Mo
Se
I
F
Cr
[µmol] [µmol] [µmol] [µmol] [µmol] [µmol] [µmol] [µmol] [µmol]
Addel®N
100
5
20
20
0.2
0.4
1
50
0.2
Tracitrans®plus 100
5
20
20
0.2
0.4
1
50
0.2
Tracutil®
10
12
35
0.1
0.3
1
30
0.2
50
All specifications refer to a packaging unit (10 ml or 1 ampule). See reference [8] for comparison with the USA.
References
1. ASPEN Board of Directors and the Clinical Guidelines Task Force. Guidelines for the use of parenteral and enteral
nutrition in adult and pediatric patients. JPEN J Parenter Enteral Nutr 2002; 26: 1SA-138SA
2. Bischoff SC, Ockenga J, Manns MP. [Artificial nutrition in intensive internal medicine. Chances and problems.]
Article in German. Internist (Berl) 2000; 41: 1041-1061
3. German Nutrition Society. [Reference Values for Nutrient Intake.] Article in German. Frankfurt am Main, Germany:
Umschau Braus GmbH, 2000
4. Filston HC. Fluid and electrolyte management in the pediatric surgical patient. Surg Clin North Am 1992; 72: 11891205
5. Koretz RL, Lipman TO, Klein S. AGA technical review on parenteral nutrition. Gastroenterology 2001; 121: 9701001
6. Rose B, Post T. Clinical Physiology of acid-base and electrolyte disorders. New York: McGraw-Hill, 2001
7. Food and Drug Administration (FDA). Parenteral Multivitamin Products; Drugs for Human Use; Drug Efficacy Study
Implementation; Amendment. Federal Register 2000; 65: 21200-21201
8. Kelly DG. Guidelines and available products for parenteral vitamins and trace elements. JPEN J Parenter Enteral
Nutr 2002; 26: S34-S36
9. Davis AT, Franz FP, Courtnay DA, Ullrey DE, Scholten DJ, Dean RE. Plasma vitamin and mineral status in home
parenteral nutrition patients. JPEN J Parenter Enteral Nutr 1987; 11: 480-485
10. Labadarios D, O'Keefe SJ, Dicker J et al. Plasma vitamin levels in patients on prolonged total parenteral nutrition.
JPEN J Parenter Enteral Nutr 1988; 12: 205-211
11. Marinier E, Gorski AM, de Courcy GP et al. Blood levels of water-soluble vitamins in pediatric patients on total
parenteral nutrition using a multiple vitamin preparation. JPEN J Parenter Enteral Nutr 1989; 13: 176-184
12. Silvers KM, Sluis KB, Darlow BA, McGill F, Stocker R, Winterbourn CC. Limiting light-induced lipid peroxidation
and vitamin loss in infant parenteral nutrition by adding multivitamin preparations to Intralipid. Acta Paediatr 2001;
90: 242-249
13. No authors listed. Guidelines for essential trace element preparations for parenteral use. A statement by an expert
panel. AMA Department of Foods and Nutrition. JAMA 1979; 241: 2051-2054
14. Greene HL, Hambidge KM, Schanler R, Tsang RC. Guidelines for the use of vitamins, trace elements, calcium,
magnesium, and phosphorus in infants and children receiving total parenteral nutrition: report of the Subcommittee
on Pediatric Parenteral Nutrient Requirements from the Committee on Clinical Practice Issues of the American
Society for Clinical Nutrition. Am J Clin Nutr 1988; 48: 1324-1342
15. Mikalunas V, Fitzgerald K, Rubin H, McCarthy R, Craig RM. Abnormal vitamin levels in patients receiving home
total parenteral nutrition. J Clin Gastroenterol 2001; 33: 393-396
16. Steephen AC, Traber MG, Ito Y, Lewis LH, Kayden HJ, Shike M. Vitamin E status of patients receiving long-term
parenteral nutrition: is vitamin E supplementation adequate? JPEN J Parenter Enteral Nutr 1991; 15: 647-652
17. Smith JL, Canham JE, Kirkland WD, Wells PA. Effect of Intralipid, amino acids, container, temperature, and
duration of storage on vitamin stability in total parenteral nutrition admixtures. JPEN J Parenter Enteral Nutr 1988;
12: 478-483
18. Jonas CR, Puckett AB, Jones DP et al. Plasma antioxidant status after high-dose chemotherapy: a randomized
trial of parenteral nutrition in bone marrow transplantation patients. Am J Clin Nutr 2000; 72: 181-189
19. Vollbracht C, McGregor P. [Vitamin C - an essential micro nutrient for the intensive care medicine.] Book chapter in
German. In: Hartig W, Biesalski HK, Druml W, Fuerst P, Weimann A (Hrsg.). Ernaehrung und Infusionstherapie.
Standards fuer Klinik, Intensivtherapie und Ambulanz. Stuttgart: Thieme, 2004: 37-48
20. Berger MM, Chiolero RL. Key vitamins and trace elements in the critically ill. Nestle Nutr Workshop Ser Clin
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Perform Programme 2003; 99-111
21. Nathens AB, Neff MJ, Jurkovich GJ et al. Randomized, prospective trial of antioxidant supplementation in critically
ill surgical patients. Ann Surg 2002; 236: 814-822
22. Young B, Ott L, Kasarskis E et al. Zinc supplementation is associated with improved neurologic recovery rate and
visceral protein levels of patients with severe closed head injury. J Neurotrauma 1996; 13: 25-34
23. Angstwurm MW, Schottdorf J, Schopohl J, Gaertner R. Selenium replacement in patients with severe systemic
inflammatory response syndrome improves clinical outcome. Crit Care Med 1999; 27: 1807-1813
24. Berger MM, Reymond MJ, Shenkin A et al. Influence of selenium supplements on the post-traumatic alterations of
the thyroid axis: a placebo-controlled trial. Intensive Care Med 2001; 27: 91-100
25. Galley HF, Davies MJ, Webster NR. Ascorbyl radical formation in patients with sepsis: effect of ascorbate loading.
Free Radic Biol Med 1996; 20: 139-143
26. Galley HF, Howdle PD, Walker BE, Webster NR. The effects of intravenous antioxidants in patients with septic
shock. Free Radic Biol Med 1997; 23: 768-774
27. Berger MM, Cavadini C, Chiolero R, Guinchard S, Krupp S, Dirren H. Influence of large intakes of trace elements
on recovery after major burns. Nutrition 1994; 10: 327-334
28. Berger MM, Spertini F, Shenkin A et al. Trace element supplementation modulates pulmonary infection rates after
major burns: a double-blind, placebo-controlled trial. Am J Clin Nutr 1998; 68: 365-371
29. Bertin-Maghit M, Goudable J, Dalmas E et al. Time course of oxidative stress after major burns. Intensive Care
Med 2000; 26: 800-803
30. Ritter C, Andrades M, Guerreiro M et al. Plasma oxidative parameters and mortality in patients with severe burn
injury. Intensive Care Med 2003; 29: 1380-1383
31. Laurent T, Markert M, Feihl F, Schaller MD, Perret C. Oxidant-antioxidant balance in granulocytes during ARDS.
Effect of N-acetylcysteine. Chest 1996; 109: 163-166
32. Cross JM, Donald AE, Nuttall SL, Deanfield JE, Woolfson RG, MacAllister RJ. Vitamin C improves resistance but
not conduit artery endothelial function in patients with chronic renal failure. Kidney Int 2003; 63: 1433-1442
33. Ambrose ML, Bowden SC, Whelan G. Working memory impairments in alcohol-dependent participants without
clinical amnesia. Alcohol Clin Exp Res 2001; 25: 185-191
34. Hung SC, Hung SH, Tarng DC, Yang WC, Chen TW, Huang TP. Thiamine deficiency and unexplained
encephalopathy in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis 2001; 38: 941-947
35. Thomson AD, Cook CC, Touquet R, Henry JA. The Royal College of Physicians report on alcohol: guidelines for
managing Wernicke's encephalopathy in the accident and Emergency Department. Alcohol Alcohol 2002; 37: 513521
Biesalski HK1, Bischoff SC2, Boehles HJ3, Muehlhoefer A4 *
1Institute
for Biochemistry und Nutrition Science, University of Stuttgart-Hohenheim, 2Dept Nutritional Medicine and
Prevention, University Stuttgart-Hohenheim, 3Dept. of Paediatrics, Johann-Wolfgang-Goethe University of
Frankfurt, 4Dept. of Internal Medicine, Gastroenterology, Hepatology and Infectiology, St. Catharine's Hospital,
Stuttgart for the working group for developing the guidelines for parenteral nutrition of The German Association for
Nutritional Medicine
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04/2014
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Zitierbare Quelle:
Chapter 8: Organisation, Regulations, Preparation
and Logistics of Parenteral Nutrition in Hospitals
and Homes; the Role of the Nutrition support
team
Kapitel 8: Organisation, Verordnung, Zubereitung und Logistik der
parenteralen Ernährung im Krankenhaus und zu Hause; die Rolle von
Ernährungsteams
Key words: Nutrition support team, organisation of PN, compounding, multi-chamber bags, home parenteral
nutrition
Schlüsselwörter: Ernährungsteam, individuelle Rezeptur, Compounding, Mehrkammerbeutel, heimparenterale
Ernährung
Abstract
PN (parenteral nutrition) should be standardised to ensure quality and to reduce complications, and it should be
carried out in consultation with a specialised nutrition support team whenever possible. Interdisciplinary nutrition
support teams should be established in all hospitals because effectiveness and efficiency in the implementation
of PN are increased. The tasks of the team include improvements of quality of care as well as enhancing the
benefit to cost ratio. Therapeutic decisions must be taken by attending physicians, who should collaborate with
the nutrition support team. "All-in-One" bags are generally preferred for PN in hospitals and may be industrially
manufactured, industrially manufactured with the necessity to add micronutrients, or be prepared "on-demand"
within or outside the hospital according to a standardised or individual composition and under consideration of
sterile and aseptic conditions. A standardised procedure should be established for introduction and
advancement of enteral or oral nutrition. Home PN may be indicated if the expected duration of when PN
exceeds 4 weeks. Home PN is a well established method for providing long-term PN, which should be indicated
by the attending physician and be reviewed by the nutrition support team. The care of home PN patients should
be standardised whenever possible. The indication for home PN should be regularly reviewed during the course
of PN.
Zusammenfassung
2
Die parenterale Ernährung (PE) im Krankenhaus sollte standardisiert werden um die Qualität zu erhöhen und
die Komplikationsraten zu reduzieren. PN sollte soweit möglich in Konsultation mit einem spezialisierten
Ernährungsteam durchgeführt werden. Ein interdisziplinär arbeitendes Ernährungsteam sollte in allen
Krankenhäusern etabliert werden, um die Effektivität und die Effizienz der Durchführung der Ernährungstherapie
zu verbessern. Die Aufgaben des Teams sind vielseitig und beinhalten u.a. die Verbesserung der
ernährungsmedizinischen Qualität sowie der Wirtschaftlichkeit. Die Indikation zu medizinischen Maßnahmen
einschließlich der PE muss durch den behandelten Arzt gestellte werden und sollte unter Einbezug des
Ernährungsteams erfolgen. "All-in-One"-Beutel werden generell für die PE im Krankenhaus bevorzugt und
können entweder vollständig industriell hergestellt, industriell hergestellt mit der Notwendigkeit individueller
Zugaben von Mikrosubstraten, oder innerhalb bzw. außerhalb des Krankenhauses nach standardisierter bzw.
individueller Rezeptur "on demand" unter Berücksichtigung von sterilen und aseptischen Bedingungen
zubereitet werden. Im Laufe einer PE sollte generell ein enteraler oder oraler Kostaufbau nach standardisiertem
Schema angestrebt werden. Eine Indikation für eine Heim-PE kann gestellt werden wenn eine PE-Dauer von
mindestens vier Wochen erwartet wird. Heim-PE ist ein medizinisch etabliertes Verfahren zur langfristigen PE,
die durch den behandelnden Arzt indiziert wird und durch ein Ernährungsteam begleitet werden sollte. Die
Betreuung des heimparenteralen Patienten sollte möglichst standardisiert erfolgen. Die Indikation zur Heim-PE
ist im Verlauf regelmäßig zu überprüfen.
Nutrition Support Team
Organisation of Parenteral Nutrition in Hospitals



PN in hospitals should be standardised and carried out in consultation with a specialised nutrition support
team whenever possible (C).
Nutrition support teams should be established in hospitals, because effectiveness and efficiency in the
implementation of PN are increased (A).
The nutrition support team should work in close consultation with the medical and nursing staff (C).
Commentary
The practical implementation of artificial nutrition often does not correspond with current scientific evidence,
mainly due to a lack of specialist knowledge and insufficient organisation. This particularly applies to the
intensive care sector where nutrition support is often required [1]. Less than 5 % of hospitals in Germany have
established nutrition support teams, which is a far lower rate than in some other European countries such as the
UK [2,3]. The impact of nutrition support teams has been evaluated in various studies. With nutrition support
teams, patients' energy requirements are more likely to be met and mechanical as well as metabolic
complications of nutritional therapy are reduced [4-9]. The authors of a meta-analysis of all studies published
between 1970 and 1993 [10] concluded that nutrition support teams reduce the rate of catheter sepsis and
metabolic complications, improve documentation, and probably also lower costs, although the personnel costs of
the team were not taken into consideration in all studies. The economic benefits of setting up a nutrition support
team, and even of only a dedicated nutrition nurse, have been extensively documented [11-14]. Standardisation
of product selection and of prescribing can result in significant savings [15].
If it is not possible to establish a nutrition support team, then at least a physician dedicated to nutrition support
should be available, with support by other staff such as nursing staff and dieticians, wherever possible.
Establishing a Nutrition Support Team



A nutrition support team should be established in all hospitals and should include physicians, nurses and
dieticians and/or nutritionists trained in clinical nutrition; pharmacists, technical assistants and
administrative assistants should also be available if possible (C).
The appropriate size of the team depends on the size of the hospital, the scope of the hospital, the
number of patients cared for, the budget and other activities of the team (C).
The tasks of the team include reviewing the indications for PN, documenting the patient's nutritional state
and metabolic situation both at the beginning and during PN, developing and adapting the PN
composition or selecting the commercially available bags as well as monitoring sterility, compatibility and
stability of the nutrition bag. The team should also be involved in helping to identify when PN is no longer
required, in collaboration with the attending physician, in planning the introduction and advancement of
enteral or oral nutrition, and in helping organising home PN when necessary. The team should pay
particular attention to implementing PN according to current scientific knowledge and guidelines. The
tasks of the team also include training personnel, patients and their relatives (C).
Commentary
3
The nutrition support team should advise the ward on the choice of standard or individual PN solutions, how they
should be prepared in individual cases, which hygiene and compatibility aspects must be observed, how PN
should be administered (e.g. selection of access, tubes, pumps) and how possible complications may be
prevented (cf. chapter "Access Technique and its Problems in Parenteral Nutrition"). The monitoring of PN
comprises laboratory, clinical and anthropometrical parameters (cf. chapter "Complications and Monitoring").
The team's task is to improve the medical quality and at the same time optimise the benefit to cost ratio of this
expensive form of nutrition. This can be achieved by monitoring indication and composition of PN, by providing
suitable quantities and selection of substrates, as well as suggesting alternatives as appropriate.
Indication for PN

Therapeutic decisions, including those on using PN, must be taken by the attending physicians. The
nutrition support team should be involved in decisions on PN (C).
Commentary
Legal regulations indicate the physician's responsibility for decisions on PN, whereas the role of the nutrition
support team is based on expert opinion because there is no published data. Involving a nutrition support team's
expertise can provide benefits, e.g. if it results in an increase in efficacy of PN [1-15].
Preparation of PN solutions




"All-in-One" bags are generally preferred for PN in hospitals (B).
"All-in-One" bags may be industrially manufactured, industrially manufactured with the necessity to add
micronutrients, or be prepared "on-demand" within or outside the hospital according to a standardised or
individual composition. There is no general preference for any one of these three concepts (C). Industrially
manufactured multi-chamber bags may be more economical than the preparation of a bag in hospital, if one
considers the added personnel cost for the later choice (B).
In hospitals PN bags should be prepared at the hospital pharmacy under sterile conditions according to agreed
quality assurance guidelines (B).
Additions of micronutrients or other components to PN bags must be performed under aseptic conditions, and
they should preferably be added under a Lamina Airflow according to good manufacturing practice (GMP)
standards (C).
Commentary
Providing PN from multiple bottles should be avoided because it is often more expensive than the multi-chamber
bag and it carries a higher risk for error [16, 17]. The choice between commercial multi-chamber bags and
individually prepared PN bags depends on the type and structural conditions of the hospital as well as patient
needs. Individual PN compositions are usually preferred for long-term and home PN, as well as for a number of
paediatric patients [18].
Prerequisites for preparing individually composed PN solution include the need for a sterile workplace, regular
microbiological checks, and monitoring of compatibility and stability [19, 20]. Further details are laid down in
guidelines of the Federal Chamber of Pharmacists [21]. In Germany PN solutions used in hospitals must be
prepared under the responsibility of a pharmacist [22]. Manufacture is defined in the German Drug Law:
manufacture is the extraction, production, preparation, processing, working, filling, packing and labelling of drugs
which includes PN [22]. Manufacturing permits, know-how and authorisation with exceptions particularly
regarding the pharmacy are regulated in the German Drug Law. PN can only be manufactured in pharmacies
and without a special license. The preparation of nutrition bags for immediate use (within no more than 24h) may
be carried out by a physician or assistant staff.
The nutrition support team should advise the pharmacy on the completion of its tasks, since otherwise
recommendations are not met to a satisfactory extent [23, 24].
Sterility of PN bags aseptically prepared in the hospital pharmacy may be guaranteed for up to 7 days at room
temperature [25]. However, this expert group recommends that such solutions should be used within 24h after
preparation if stored at room temperature, or within 7 days if stored at 4 °C. This recommendation is based on
the known risk of microbiological contamination and physicochemical changes, which are expected to increase
with storage time. Industrially-manufactured multi-chamber bags can be stored for periods of months to years as
specified by the manufacturer. Attention should be paid to the preparation of the multi-chamber bag for use,
since the stability of added components such as vitamins is limited and often does not exceed 24h at room
temperature [26].
4
In hospitals pumps should always be used for PN administration to ensure a controlled flow rate and to help
prevent metabolic and osmotic complications.
Advancement of enteral and oral nutrition



A standardised schedule should be established for introduction and advancement of enteral or oral nutrition (C).
Individual advancement of enteral and oral nutrition may be necessary in patients with gastroenterological
diseases such as pancreatitis, Crohn's disease, Colitis Ulcerosa, hepatic cirrhosis, or after long-term PN for
more than 14 days (C).
The advancement of oral nutrition results in a progressive supply of both macro- and micronutrients (C).
Commentary
Some studies have associated PN with altered morphology and intestinal function, for example with reduced
mucosa thickness, a reduced number of villi in the small intestine and increased intestinal permeability [27-30],
while other trials do not show such alterations [31, 32]. If such effects occur, they depend on the duration of PN
and are usually reversible.
In general a standardised advancement of enteral and oral nutrition is recommended after PN, because clinical
practice has shown that incompatibilities may occur, particularly in the adaptation phase, regardless of whether
enteral or oral nutrition. A standardised schedule should be established for the advancement of enteral and oral
nutrition in the hospital. The speed of PN reduction depends on the tolerance of enteral or oral nutrition. Based
on expert opinion, nutrition consultation during the phase of advancing enteral and oral nutrition is useful,
particularly in patients who received PN for more than 14 days and in patients with gastroenterological disease.
Advancement of enteral and oral nutrition must be adapted to the patient's tolerance, particularly in pancreatitis,
where nutrition-related pain is well documented. Consideration should also be dedicated to the type and amount
of protein given to patients with liver cirrhotic patients and imminent encephalopathy. Small meals and the use of
medium chain triglycerides may be useful after gastrointestinal operations and in patients with dumping
syndrome.
Supplying PN
Standardisation of Procedures

Standardisation of procedures for supplying PN is recommended to ensure quality and to reduce
complications (B).
Commentary
Standardisation includes a clear process for defining PN indications, which is provided by the attending
physician and preferably checked by a nutrition support team (or a physician dedicated to nutrition support). PN
is only indicated when sufficient oral or enteral nutrition is not achievable. Criteria for the choice of central
venous catheters (individual or tunnelled catheters or PORT systems) should be laid down. The choice of
macro- and micronutrient intakes depends on energy requirements, the patient's metabolic situation, illness and
other aspects of therapeutic strategies. Energy requirements can be estimated with the help of established
formulas (i.e. Harris-Benedict formula). A limited number of products should be selected for PN, which can be
decided on by the nutrition support team jointly with the drugs committee and the hospital pharmacy. If
individually prescribed PN solutions are considered necessary the attending physician and the nutrition support
team, these should be prepared by trained personnel under the guidance of a pharmacist following standardised
procedures under sterile conditions. The application of PN must be monitored and documented, for example by
the nutrition support team. The roles of the nutrition support team contribute greatly to establishing standardised
implementation of PN, because the team is involved in most steps and hence can take over main coordination
tasks. Documented reductions of medical complications and of unnecessary costs by inadequate PN are
arguably the result of the work of nutrition support teams [33-38].
Cost Aspects of PN

The adequate calculation of PN costs in hospital requires internal accounting (C). Home PN is usually available
on prescription and is financed by health insurance funds, although additional payments by the patient may be
necessary.
5
Commentary
Hospital accounting is needed to secure funding for central hospital services such as PN services [39-41], and
the multidisciplinary nutrition support team jointly with the hospital pharmacy should aim at being involved in the
evaluation of cost aspects of PN. The nutrition support team should be funded by the health care funds and not
by industrial sponsorship to avoid potential conflicts of interests.
Home PN





Home PN is a well established method for providing long-term PN (A).
Home PN is indicated if
(I) the patient cannot obtain adequate oral or enteral feeding
(II) there are no other reasons for not discharging the patient from hospital,
(III) home PN is expected to last for a period of at least 4 weeks,
(IV) the patient requests or is (presumably) in agreement with home PN, and
(V) it is expected that disease state or quality of life remains stable or is improved with home PN (C).
The attending physician should decide on the indication for home PN, which should also be reviewed by the
nutrition support team (B).
The patient or its legal representative should receive extensive information on home PN and the need for
providing a suitable catheter system (tunnelled central venous catheter or PORT). The nutrition support team
should be involved in all aspects of comprehensive planning and organisation of home PN
Home PN must be monitored considering complications (i.e. catheter complications, metabolic complications,
organisational deficiencies) and success rate (i.e. improvement in nutritional status and quality of life); and the
nutrient supply must be adapted if necessary, which can be done either by a dedicated nutrition support team or
by an outpatient physician experienced in this area. The care of home PN patients should be standardised
whenever possible. The indication for home PN should be regularly reviewed during the course of PN.
Commentary
Complication rates during home PN are generally low. The most frequently occurring complications are catheter
sepsis (0.34 occurrences per year), catheter occlusions (0.071/year), catheter-associated central venous
thromboses (0.027/year), fluid and electrolyte disturbances (0.12-0.61/year), liver and bile duct problems
(0.42/year) and other metabolic complications (osteopeny, hyperglycaemia, hypertriglyceridemia etc.) [42-44].
According to a European study, catheter complications occur in approx. 0.25% of patients over the course of
home PN, 50 % of these complications being infections (equals 0.37/year) [45]. Comparable results have been
reported for children [46]. Validated methods for reducing complications such as catheter infections or
thrombosis have not been reported [42]. For patients with short bowel syndrome or other forms of intestinal
failure, the only alternative to long term PN is intestinal transplantation, which is still associated with high rates of
complication despite impressive progress in this area [47].
Home PN is carried out in tumour patients with peritoneal carcinosis or (sub)ileus, in patients with intestinal
failure, such as short bowel due to Crohn's disease, after intestinal ischaemia with short gut infarction (e.g.
superior mesenteric artery or venous thromboses), radioenteritis and in severe colonic motility disorders [42].
Tumour patients receiving home PN contribute a smaller number to the home PN population in some other
countries (e.g. Denmark, UK) [48].
Many of the underlying principles for supplying PN also apply to home PN and depend on general or organrelated considerations (see appropriate chapters). Some additional aspects must be considered with home PN.
For example, it is important to estimation the patient's prognosis and possible duration of home PN. Although
there is no scientifically agreed lower limit of duration, a minimal duration of home PN of at least one month is
consistently recommended. In adult patients the duration of home PN is usually shorter than one year, because
patients either die (99% of tumour patients) or oral or enteral nutrition can be established [49, 50]. There is
expert consensus that patients bound to die usually benefit do not from (home) PN, which should be checked
even more critically in the case of home PN than in hospital where there is usually a defined therapy objective.
This question is difficult since definitions are imprecise and decisions often need to be taken on an individual
basis, taking into account the (presumed) wishes of the patient and effects on quality of life, which should be
given high priority. Home PN can positively influence in tumour patients if patients survive at least three months
after commencing home PN [51]. However, quality of life of patients on home PN was lower than in patients
without home PN, which may in part be due to a more severe underlying illness in patients who require home
PN [52, 53]. The quality of life after small intestinal transplants is comparably higher in patients without rejection
[54, 55].
Which catheter system is optimal for home PN remains controversial. Based on comparative studies we assume
that tunnelled central venous catheter (i.e. BroviacÒ catheter) may present slight advantages over port systems
6
with respect to infections and catheter sepsis [45, 56]. Conventional non-tunnelled central venous catheters
should not be used outside the hospital [57]. The costs and particularly the long-term costs of consumables are
significantly lower with the use of Broviac®-catheters than with implanted port systems, which require special
needles for injection. Individual factors such as daily infusions or infusions with larger time intervals and
cosmetic aspects should also to be considered selecting access catheters. Hence, the choice of catheter is
influenced by many factors which have not been fully explored in comparative studies.
Preparation and organisation of Home PN is usually carried out prior to patient discharge from hospital and
requires approx. 2-3 working days by the nutrition support team and other hospital departments. Tasks include:
(I)
review of indication,
(II)
detailed information, clarification and consent of patient and their relatives,
(III) preparation of individual composition,
(IV) authorisation of a qualified pharmacy , or a specialised home care company, for preparation of PN
solutions, home delivery of the materials, and implementation of home PN, potentially in collaboration
with a home care nursing service,
(V)
(VI)
individual instruction of the patient and its relatives - depending on the wishes and degree of
independence of the patient - by the nutrition support team or the home care service organisation.
setting up a plan for monitoring, which may by implemented by a general practitioner and/or a
specialised clinic.
These standards have generally been developed empirically, but have also been tried-and-tested in various
practical settings [33, 58, 59]. There is no standard strategy to document complications and monitor home PN.
We recommend controls of clinical and laboratory parameters every one to two weeks in the first three months,
followed by monthly checks over the next three months, as recommended also in the Mayo Clinic schedule (cf.
chapter "Complications and Monitoring ").
Assuring stability and compatibility of the PN solutions is extremely important in Home PN, because the bags
are often delivered only once a week or so to the patient and then are stored in the refrigerator at 4°C until
utilised after hours of being warmed up to room temperature. The micronutrients (vitamins, trace elements) show
a particularly limited storage time and should be added just prior to using the PN bag [60]. The electrolyte and
mineral concentrations should be taken into consideration in bags containing lipids, because they may result in
the emulsion breaking (i.e. a separation of lipid and water components) (cf. chapter "Practical Handling of AIO
Admixtures") [61]. The stability should be checked with the manufacturer whenever the composition is modified.
The administration of home PN should be employed by specially trained carers, or in individual cases by the
patient, if the patient requests this and has been appropriately trained [59]. It is important that measures
associated with home PN are standardised by means of a suitable standard of care. The contents of these
standards of care are usually established by empirical measures rather than hard scientific data, but they have
been tried and tested and should form the basis of standard operating procedures until scientifically accountable
guidance is available.
In conclusion, home PN is an area for which many standards have been established, but which have rarely been
backed up by controlled, randomised trials. Thus, there is a great need for studies in this area which might
contribute to improved quality of care and reducing the burdening of in-patient departments.
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contamination of total parenteral nutrition. 2. Effect of storage duration and temperature. JPEN J Parenter
Enteral Nutr 1999; 23: 228-232
61. Weissenborn U, Bollinger W. Stabilität von Mischlösungen. In: ADKA-Ausschuß für Klinische Pharmazie (Hrsg.).
Mischlösungen zur parenteralen Ernährung. Praxis der Klinischen Pharmazie, Band 2. Stuttgart: Deutscher
Apotheker Verlag, 1993: 55-62
Bischoff SC1, Kester L2, Meier R3, Radziwill R4, Schwab D5, Thul P6 *
1Dept.
Nutritional Medicine and Prevention, University Stuttgart-Hohenheim, 2Dept. of Gastroenterology,
Hepatology and Endocrinology, Medical University of Hannover, 3Dept. of Gastroenterology, Hepatology and
Nutrition, University of Basel, Switzerland, 4Pharmacy und Patient Advice Centre, Clinic Fulda, 5Dept. Medicine
II, Martha-Maria Hospital, Nuremberg, 6Dept. of General, Visceral, Vascular and Thorax Surgery, Humboldt
University of Berlin for the working group for developing the guidelines for parenteral nutrition of The German
Association for Nutritional Medicine
9
Erstellungsdatum:
04/2014
AWMF online - Guidelines on Parenteral Nutrition: Access Technique and its Problems in Parenteral Nutrition
1
AWMF online
Wissenschaftlichen
Medizinischen
Fachgesellschaften
Nr. 073-018e_09
Entwicklungsstufe:
3
Zitierbare Quelle:
Chapter 9: Access Technique and its Problems in
Kapitel 9: Technik und Probleme der Zugänge in der parenteralen Ernährung
Key words: Intravenous access, central venous catheter, handling of central catheter, catheter-related infections, in-line
filter
Schlüsselwörter: Intravenöse Zugänge, zentralvenöse Katheter, Handhabung zentraler Katheter, katheterassoziierte
Infekte, In-line-Filter
Abstract
Catheter type, access technique, and the catheter position should be selected considering to the anticipated duration of
PN aiming at the lowest complication risks (infectious and non-infectious). Long-term (>7-10 days) parenteral nutrition
(PN) requires central venous access whereas for PN <3 weeks percutaneously inserted catheters and for PN >3 weeks
subcutaneous tunnelled catheters or port systems are appropriate. CVC (central venous catheter) should be flushed with
isotonic NaCl solution before and after PN application and during CVC occlusions. Strict indications are required for
central venous access placement and the catheter should be removed as soon as possible if not required any more.
Blood samples should not to be taken from the CVC. If catheter infection is suspected, peripheral blood-culture samples
and culture samples from each catheter lumen should be taken simultaneously. Removal of the CVC should be carried
out immediately if there are pronounced signs of local infection at the insertion site and/or clinical suspicion of catheterinduced sepsis. In case PN is indicated for a short period (max. 7-10 days), a peripheral venous access can be used if no
hyperosmolar solutions (>800 mosm/L) or solutions with a high titration acidity or alkalinity are used. A peripheral venous
catheter (PVC) can remain in situ for as long as it is clinically required unless there are signs of inflammation at the
insertion site.
Zusammenfassung
Abhängig von der voraussichtlichen Dauer der PE sollte der Kathetertyp, die Zugangstechnik und die Katheterposition mit
dem geringsten Komplikationsrisiko (infektiös und nicht-infektiös) gewählt werden. Eine langfristige (>7-10 Tage),
bedarfsadaptierte parenterale Ernährung (PE) ist auf einen suffizienten zentralvenösen Zugangsweg angewiesen, wobei
für eine PE <3 Wochen perkutan eingelegte Katheter und für eine PE >3 Wochen subkutan tunnelierte Katheter oder
implantierte Portsysteme zur Anwendung kommen. Der zentralvenöse Katheter (ZVK) sollte vor und nach der PEApplikation und bei ZVK-Okklusion mit physiologischer NaCl-Lösung gespült werden. Die Indikationsstellung zur Anlage
eines venösen Zugangs muss streng erfolgen und der Katheter sollte schnellst möglich wieder entfernt werden, wenn er
nicht mehr benötigt wird. Zur Reduktion des Infektionsrisikos sollten Blutentnahmen aus dem ZVK vermieden werden. Bei
Verdacht auf Katheterinfektion sollten gleichzeitig Blutkulturen peripher und aus jedem Katheterlumen entnommen
werden. Bei ausgeprägten lokalen Infektzeichen der Insertionsstelle und klinischem Verdacht auf Katheter-induzierte
Blutstrom-Infektion ist die ZVK-Neuanlage vorzunehmen. Im Falle einer kurzzeitig indizierten PE (max. 7-10 Tage) kann
eine periphervenöse Zufuhr durchgeführt werden, wenn keine hyperosmolaren Lösungen (> 800 mosm/l) und keine
Lösungen mit einer hohen Titrationsazidität bzw. -alkalität (Bikarbonat, Trispuffer) appliziert werden. Die periphere Kanüle
(PVK) kann so lange liegen bleiben wie sie benötigt wird wenn an der Einstichstelle keine Entzündungszeichen auftreten.
2
Central Venous Access



Long-term (> 7-10 days) parenteral nutrition (PN) requires central venous access (A).
Strict indications are required for central venous access placement, and the catheter should be removed as soon as
possible (A).
Catheter type, access technique, and the catheter position should be selected considering to the anticipated duration of
PN aiming at the lowest complication risks (infectious and non-infectious) (A).
Commentary
PN solutions are administered either via a central venous catheter or over short term via peripheral venous cannulae,
depending on the condition of the patient (type of illness, current state of health etc.), composition of the infused solution,
amount of energy to be administered, and duration of PN. Accessibility of the venous system needs to be evaluated
considering vascular status, anatomy, and coagulation status. PN associated complications such as infections and
mechanical problems result in significantly increased morbidity and mortality [1, 2]. Regular monitoring of metabolic
response to PN is also required [3]. Any venous access that is no longer required should be immediately removed [4, 5].
PN is usually administered via a central venous catheter because of the high osmolarity of nutrient admixtures. The
objective of a central venous catheter (CVC) is to get access to the vena (V) cava. The tip of the CVCs is often placed in
the superior vena cava.. Peripheral and central venous access sites are available for this placement.
When using central venous access sites, the CVC is inserted directly into a large vein close to the heart. The location of
the catheter tip should generally be radiologically documented; ECG-controlled position monitoring is possible.
An alternative to central venous cannulation is a peripherally inserted central catheter (PICC) using an ultrasound-guided
cannulation of a peripheral vein in the upper arm [6]. A technically simpler method is the placement of a PICC-line in an
elbow vein without ultrasound control, and advancement of this peripheral catheter to the superior vena cava. The
advantages of these peripheral access sites are lower rates of acute complications such as pneumothorax, lifethreatening bleedings, etc. The disadvantage is that local complications (phlebitis etc.),[7] and late complications,
especially thromboses and infections, occur more frequently [8] (see also section on peripheral venous access [below]
under peripheral venous PN].
Selection of catheters for central venous access

Central venous catheters inserted by percutaneous cannulation are favoured for short-term administration of PN (A).
Commentary
The estimated duration of PN is extremely important when selecting the type of catheter. If less than three weeks of PN
are anticipated, then percutaneously inserted catheters (e.g. by means of Seldinger technique) are appropriate [9]. The
Seldinger method is favoured as it offers significant advantages when compared to other techniques: lower risk of injury
with cannulation, lower risk of air embolism [10, 11] and higher success rate [12].
Infusion pumps


High-caloric PN should preferably be administered with infusion pumps (C).
PN should always be administered by an infusion pump in neonatal and paediatric patients (C).
Commentary
The supply rate of infusion solutions can be set, with a high degree of accuracy by using infusion pumps, or by employing
the effects of gravity and setting the infusion speed via a drop counter. All-in-one solutions should preferably be
administered via an infusion pump. The advantage of such devices is a precise control of the flow rate, which may
enhance PN tolerance.
The drop speed, when using gravity infusions, cannot be regulated as precisely as with the use of infusion pumps,
resulting in potentially excessive infusion rates. The use of infusion pumps is generally recommended for infants and
children, to secure a controlled flow rate.
Infectious CVC complications


CVC cannulation predisposes patients to infectious complications (A).
Blood samples should not to be taken from the CVC to reduce the risk of infection (B).
Commentary
3
There is close correlation between length of hospital stay (LOS) and risk of infection [13-15]. Thrombotic complications
also depend on LOS [15, 16].
Difficult cannulations, severe infectious underlying illnesses, immune deficiency or cannulations carried out under
emergency conditions or by inexperienced doctors, predispose patients to infectious CVC complications in PE [17-19].
Blood sampling from a CVC increase the risk of catheter-associated infections [20-24].
Patients with structural heart disease and associated risk factors should receive endocarditis prophylaxis prior to
cannulation.
Used catheter/flush system




Subcutaneous tunnelled catheters or port systems should be implanted and used for long-term PN, especially for home
PN (A).
Port needles should be replaced every three to seven days (B).
Routine flushing of non-utilised CVCs or port systems with heparin is not recommended (A).
CVC should be flushed with isotonic NaCl solution before and after PN application (A).
Commentary
Tunnelled or implanted permanent devices (Broviac® or Hickman®/Groshong® catheters, port systems) are suitable for
long-term PN (> 3 weeks) [1]. Broviac® and Hickman®/Groshong® catheters are implantable, percutaneously inserted
venous silicone catheters. The majority of tunnelled devices have a short polyester cuff attached to the catheter that
encourages fibrosis, and therefore anchorage within the subcutaneous tissues, and thus can prevent bacteria from
penetrating [25].
If the CVC is temporarily not in use, it should be flushed daily with isotonic NaCl solution [26]. A heparin flush solution is
not recommended as no benefits are known [26], but there is a risk of heparin-induced thrombocytopenia (HIT) and
incompatibilities.
In 1993, Raad et al. [27] described the non-tunnelled silastic catheter as a safe and economical alternative to the
surgically implanted systems (tunnelled and port catheters). Port systems are totally implantable venous silicone or
polyurethane catheters with subcutaneous reservoir chambers made of titanium or ceramic. The port membrane is made
of silicone, and is only punctured with special port cannulae (non-coring port needles). It is recommended that the port
needle be replaced every third to seventh day in patients receiving home PN with cyclical nutritional application. The
transparent dressing should be replaced at similar intervals [28-32]. If no nutrient solution and only drugs (cytostatic) are
administered via the port, the port needle can be left in situ for 2 weeks [33-35]. Extremely good long-term usability and
high patient acceptance have been observed with correct handling [36]. Numerous prospective, non-randomised studies
show a drop in the infection rate when using subcutaneous port systems [37, 38]. The tunnelled CVC (Broviac/Hickman)
should be preferred over the port system for long-term PN administration in children and teenagers because relatively
large flush volumes are required to flush the infusion chamber.
In a prospective cohort study, the instillation of minocycline ethylene diamine tetraacetate (M-EDTA) (port lock)
significantly reduced rate of infections and thrombosis in children [39].
Access sites/catheter position



In adults, the subclavian vein is preferred over the internal jugular vein or any other access site with respect to infection
risk (A).
In paediatric patients, access through the groin results in comparable infection rates that other access sites (B).
PN solutions should be administered through a CVC with its tip positioned in the superior vena cava (C).
Commentary
Clinical research data are still limited with regard to the insertion site [40, 41]. Percutaneously inserted catheters should
usually be placed in the superior vena cava. In adults, femoral catheters correlate with an increased risk of thrombosis
and catheter-related sepsis and are, therefore, inappropriate for the administration of PN solutions [42-52]. Access to the
superior vena cava can be achieved through the internal jugular vein, subclavian vein or a peripheral vein in the arm.
Catheters placed through the jugular vein are associated with an increased rate of local haematomas, arterial damage
and catheter-associated infections as compared to subclavian and femoral catheters [53-58]. On the other hand,
subclavian catheters are associated with an increased risk of pneumothorax as compared to jugular catheters [13, 14, 54,
59-61].
It has not been conclusively determined whether the tip of the catheter is better positioned in the superior vena cava or in
the right atrium [62-65]. However, pericardial tamponades, cardiac arrhythmia, heart lesions and thromboses have been
described when the catheter tip has been positioned in the atrium, rendering this an obsolete position.
The prospective randomised study by Cowl et al. [65] compared 102 patients receiving PN through a subclavian catheter
compared to peripherally inserted CVCs. The study concluded that peripherally inserted CVCs are associated with a
significantly higher rate of thrombophlebitis and placement problems. No differences have been recorded regarding rate
of infection, catheter dislocation and occlusions. These results are in line with those of other authors [66-68].
Studies in paediatric patients have shown a lower incidence of mechanical complications with access through the groin,
and the rate of infection is similar to that of non-femoral access [69-71].
Control of catheter position



4
An x-ray examination should be carried out after every CVC placement, if the subclavian venous access route is used, or
if there were any complications with regard to implantation, or if no alternative procedure can be used to verify the
catheter position (B).
Ultrasound-controlled catheter positioning significantly reduces the rate of complications associated with cannulation (A).
ECG-controlled CVC placement represents a safe method (A).
Commentary
Fluoroscopic control permits immediate correction of the catheter position in the superior vena cava [72], but is no longer
recommended due to the relatively high radiation exposure. A radiological confirmation to ensure correct position of a
CVC is recommended, by some authors, before commencing PN [73-75].
Various meta analyses have shown that ultrasound-guided CVC insertion via venous cannulation is clearly superior to
conventional standard catheter placement, which uses fixed anatomical reference points, with regard to the rate of
success and complications [76-81]. Another method for confirming the position of the catheter tip in the superior vena
cava or the right atrium is to use electrocardiographically guided placement [82, 83], in which a fluid-filled catheter or the
retracted guide wire [83, 84] are used as an electrode for intravascular ECG-guidance [85-87]. Prerequisites are a sinus
rhythm and an ECG device authorised for intracardial ECG-guidance. The procedure is not recommended limited for use
in left-sided internal jugular vein cannulation because of limited accuracy [88].
Watters et al. [89] compared 1,236 ECG-controlled placements with 586 fluoroscopically-controlled CVC placements.
Radiological thorax monitoring resulted in an optimum catheter position in both groups [89]. Other studies (partly
randomised, prospective) show that ECG-guided CVC placement is a safe method [90-93].
Material-related issues

Catheter material, catheter design, mechanical properties and anti-infectious potential correlate with the rate of
complications (A).
Commentary
There are strict requirements regarding the materials used for venous catheters. Catheters must be manufactured from
tissue-friendly material, must have a length classification and be X-ray opaque. Generally, every CVC represents a
foreign body that can result in inflammation, formation of thromboses, and infections.
The catheter material may increase thrombogenicity which can result in catheter colonisation and catheter-associated
infections [94, 95]. Special attention should be paid to potential reactions of incompatibility to the material or coatings.
The associated thrombogenicity and contamination rate, due to physicochemical reactions, is high in catheters made of
PVC, polypropylene or polyethylene but low in coated polyurethane catheters [62, 96-99]. Catheters with a rough surface
make it easier for microorganisms to attach themselves (especially coagulase-negative staphylococci, Pseudomonas
aeruginosa and Acinetobacter calcoaceticus) [62, 94, 100, 101]. Some candida species can produce mucous in the
presence of glucose-based solutions which enables fungal pathogens to attach themselves easily, and explains the high
rate of infection [102]. More recent data on heparin-coated CVCs show positive results regarding the reduction of CVC
colonisation by microorganisms [102-105]. A few isolated cases of heparin-induced thrombocytopenia (HIT) using
heparin-coated pulmonary catheters and CVCs have been described in literature [106, 107].
The catheter used for central venous access should be as thin as possible and the lumen of the analogous vein should
be as large as possible. The rate of infection with CVC was reported increases with the number of CVC lumina [108-112],
but there are also studies showing no increased infection risks with multi-lumen catheters, especially if PN is administered
through a separate lumen and no blood samples are taken via the CVC [52, 113-115]. As short intravascular length of the
CVC catheter and limited venous wall contact appear preferable.
Hygiene measures



Rigorous asepis must be applied during CVC insertion (use of mask, cap, sterile gown, sterile gloves).
Prior to the CVC insertion, the insertion site should be disinfected, preferably with chlorhexidine (B).
Antibiotic prophylaxis and the use of antibiotic-containing creams are not recommended for CVC insertion (B).
Commentary
Evidence-based measures for the prevention of catheter-related infections in PN have been reviewed by Attar et al. [116]
and O'Grady et al. [13]. Their recommendations are to wear a sterile cap, mask, gown and gloves after hand disinfection,
to sufficiently disinfect the skin at the insertion site (at least for 30 seconds with 2 % chlorhexidine) as well as to use a
sufficiently large, sterile drape for the cannulation site [117, 118]. The importance of team training in CVC handling is
emphasised [13, 119, 120].
Skin disinfection with a 2 % chlorhexidine gluconate aqueous solution reduced the colonisation rate by microorganisms
compared to 10 % polyvidon-iodine solution or 70 % alcohol (residual effect of chlorhexidine) [118]. A randomised,
prospective study showed that other chlorhexidine preparations (e.g. 0.5 % tincture) are not more effective than the 10 %
polyvidon-iodine solution with regards to catheter colonisation [121]. In a study on newborns, a 0.5 % chlorhexidine
reduced the catheter colonisation rate more effectively than polyvidon-iodine solutions [122]. A multicentric study
5
confirmed that a chlorhexidine-impregnated polyurethane foam over the catheter exit site reduces the risk of CVC
colonisation and infection [123].
Antibiotic prophylaxis during catheter insertion, for prevention of line-induced infections, is not useful [61, 124-126]. The
prophylactic use of antibiotic-containing creams promote resistant flora and fauna, and should, therefore, not be used [20,
127]. No difference has been observed in catheter-associated infections when it was covered with gauze or transparent
film [20].
Covering the catheter insertion site

Sterile gauzes or sterile, transparent, semi-permeable films should be used to cover the catheter insertion site (A).
Commentary
A large-scale study has compared gauze dressings and transparent film dressings in peripheral venous access. The
results showed a comparable incidence of phlebitis and catheter colonisation [98]. This data indicates that transparent
film dressings can remain on the insertion site throughout the duration of the intravenous therapy, without the risk of
increasing thrombophlebitis [98]. A meta-analysis confirmed similar results for gauze and film dressing with regards to
catheter-associated risk of infection in CVC. Film dressings could, however, result in damp patches and theoretically
promote infections [128].
Well-healed insertion sites from tunnelled catheters require no dressing. A gauze dressing should, preferably, be used if
the catheter insertion site is bleeding or oozing [20, 129-132]. Dressings that have become wet/damp or loosened should
be immediately replaced [61, 129, 130].
The recommendation for preferentially using alcohol-based skin disinfectants (fast-acting, positive effect) when changing
the dressing has to be evaluated against the warnings of numerous catheter manufacturers regarding potential damage
to catheter materials and induction of breaks by such disinfectants..
Catheter care

Catheter care in patients with PN should be carried out by specially trained staff, according to define standards of care
(B).
Commentary
A reduction in catheter-associated infections can be achieved by specifically trained personnel (training on indications,
insertion and care), and by minimising manipulation of the catheter [61, 119, 133-136]. Disinfection must be carried out in
accordance with standards of hygiene prior to any manipulation of the catheter cuff or catheter [20, 21, 137-142].
CVC changes

CVC changes should not be performed routinely, and if an infection is suspected, no guide wire should be used for
changing a CVC (A).
Commentary
Prophylactic catheter changes over the guide wire do not result in a drop in the risk of catheter-associated infections
[143], but in an increase [110]. A CVC should not be routinely changed [13,114], except for a CVC inserted under
emergency conditions which should be reinserted after the patient's condition has been stabilised. A CVC should be
replaced when a local infection occurs at the insertion site, or if a catheter-associated bloodstream infection is suspected,
but under such conditions a guide wire technique should not used [13].
Special catheters

Antibiotic or silver-coated catheters should only be used in at-risk patients and high-risk care situations (A).
Commentary
The rate of catheter-associated infections is reduced when using CVCs impregnated with chlorhexidine and silver
sulfadiazine or with minocycline and rifampicin as compared to untreated catheters [20, 118, 144, 145]. A meta analysis
outlines the infection-related benefits of a CVC impregnated with chlorhexidine-silver sulfadiazine on the exterior [103,
146-148]. Catheters coated with minocycline/rifampicin on the inside and outside performed even better in a randomised
study [146, 149-153]. There are also positive results with silver-impregnated catheter systems [154-156].
Coated catheters should be used if the CVC is required for more than 5 days, and there is also a high risk of infection
[13]. The slightly higher costs no longer presents a plausible argument against general use in at-risk patients [150, 157].
There is an indication for coated catheters in these at-risk patient groups: critically-ill patients, patients with compromised
immune systems, newborns, infants and children [154].
6
Anticoagulation

A low-dosed oral prophylactic anticoagulant should be administered to patients with home PN (B).
Commentary
Clinically relevant catheter-associated thromboses are late complications of long-term PN [63-65]. Catheter occlusions
can occur because of the generation of fibrin or thrombin build-up or partial or total parietal thrombosis [158]. Two studies
indicated that heparin-coated CVCs showed disadvantages regarding the potential for developing thrombosis [159, 160].
Prophylaxis with low-dosage warfarin showed a drop in the risk of thrombosis [161, 162], but not in oncology patients
[163]. The favourable effect of warfarin (dose:1 mg/day) is confirmed in the systematic review by Klerk et al. [164], but it is
not confirmed for heparin [165].
Filters

The use of in-line filters for removing particles is recommended for at-risk groups (children, immune-suppressed patients)
but controversial in patients who are not at increased risk (B).
Commentary
Infusion solutions can be contaminated with particles through the manufacturing process, from the container, or during
the transportation or storage process. Mixing macronutrients with electrolytes, trace elements and vitamins can result in
further particle contamination (incompatibility problems). Patients receiving PN are exposed to potential contamination
through container materials and administration equipment (e.g. plastic particles) as well as the unintentional introduction
of bacteria and precipitates. The use of filters during PN administration is effective for the mechanical removal of larger
particles, precipitates, bacteria, fungi, larger lipid particles and air [166]. However, there has not been an adequate study
to date which confirms that the use of in-line filters significantly reduces the rates of catheter-associated infection [20].
The greatest concern regarding particles introduction relates to AIO admixtures containing calcium phosphate
precipitates, which can cause diffuse microvascular lung embolisms [167]. Precipitates are usually not visible due to the
lipid content. Calcium hydrogen phosphate is often highly-concentrated, having better solubility at 2 - 8°C than at 37°C,
which questions the reliability of filtration. Ball et al. analysed particle contamination in "ready to use" application systems.
Two admixture samples were taken from the infusion set immediately before being administered to the patient and one
sample was then filtered. Both samples were evaluated microscopically. The results showed that the unfiltered sample
contained significantly more particles [168].
Bethune et al. [166] recommend the use of filters in the administration of PN to the following at-risk patient groups:
patients with total and/or prolonged PN, patients with weak immune systems, newborns and children. In the paper of Ball
et al. [168] in-line filters are recommended for all patients receiving PN. The in-line filter should be placed as close to the
patient as is practical. A 1.2 mm filter is used for lipid-containing AIO admixtures and should be changed every 24 hours.
A 0.2 mm filter can only be used for non-lipid-containing infusion solutions and should only be replaced after 96 hours
[169]. Filters themselves can, however, also cause problems (e.g. occlusions, adsorption of PN components like micro
elements and drugs, cost of filters).
Currently, there is no proof that in-line filters have any significant influence on the rate of catheter-associated septicaemia
[170]. Therefore, no recommendation can be made on their routine use for infection prevention.
There are no legally binding rules for using in-line filters in PN. Guidance by the Robert Koch Institute [61] on using in-line
filters argues against the routine use of such filters for infection prevention purposes, but it does not refer in any detail to
particle infiltration.
Occlusions of the CVC or port system: Measures


CVC occlusions can be caused by blood clots, precipitations and/or residues of PN solution components, or drugs
administered (A).
Isotonic NaCl solution should be instilled as an initial measure (A).
Commentary
Catheter occlusion is the most frequent non-infectious complication. Understanding and correctly identifying the potential
aetiologies leading to occlusion is extremely important for the treatment strategy [171].
Occlusions can occur in the form of blood clots or due to fibrin residues, especially after blood samples have been taken
via the catheter or port systems. As an initial measure in CVC occlusions, NaCl (0.9 %) should be injected after first
aspirating the contents of CVC applying slight pressure. This procedure should be repeated if not initially successful. If
the catheter remains blocked, it should be flushed with urokinase or RTPase (5,000 IE/mL) (and left to work for 30-60
minutes), especially if there is a suspicion of a blood clot [172-174]. The catheter should be replaced if none of these
measures are successful.
In individual cases, it is possible that tiny amounts of blood stick to the catheter wall and cannot be removed even through
intensive flushing. This is an ideal breeding ground for bacteria and can result in the colonisation of the catheter system
[175, 176].
If no blood sample had been taken from the occluded system, then it must be assumed that an occlusion has probably
7
occurred due to residue from the nutrient solution components. Lipid residues can result in CVC occlusions. These
usually take a few days to form [177]. In these cases, it may be effective to instil sodium hydroxide (NaOH: 0.1 mmol/ml,
0.1 M, pH 13) [178]. Flushing with alcohol (ethanol 96 %) should not be carried out, as according to silicone catheter
manufacturers, alcohol immediately changes the surface of such catheters.
Insoluble precipitates develop with the administration of drugs and electrolytes like calcium or phosphates. Precipitates
can be caused by incompatibilities between these components e.g. by the formation of insoluble crystals [179]. Calcium
phosphate precipitates are of special significance, and are influenced by various factors in the admixture like amino acid
composition, relative calcium and phosphate content, pH etc. [180, 181]. A subcutaneously implanted permanent
catheter, which is occluded due to insoluble precipitates, can be potentially re-utilised by pH changes in the PN solution
[182-185]. Bicarbonate is very incompatible, and should not be added.
Infection of the CVC or port system:
See Figure 1. Flow diagram on suspicion of catheter-induced bloodstream infection [186-189].
Figure 1: Procedure in case of suspected central venous catheter related systemic infection

8
If catheter infection is suspected peripheral blood-culture samples, and culture samples from each catheter lumen

9
should be taken simultaneously (A).
Removal of the CVC should be carried out immediately when there are pronounced signs of local infection at the
insertion site and/or clinical suspicion of catheter-induced sepsis (A).
Commentary
Bacterial or fungal colonisation of a CVC is a potentially life threatening complication of PN as an infection of the vascular
bed with the risk of complications such as septic thrombosis, infectious colonisation of other organs and endocarditis
[190]. Catheter-related sepsis occurs in 5-8 of 1,000 patient days and is associated with increased morbidity, mortality
and medical costs [20, 127, 191, 192].
If catheter infection is suspected and any resulting complications, the guidelines for antimicrobial therapy for catheter
infections, which have been drawn up by the Paul Ehrlich society, should be observed.
It is not always easy to diagnose a catheter-associated infection by using only clinical parameters. In order to substantiate
the suspected diagnosis, CVC blood cultures (in multi-lumen catheters, two blood-culture samples drawn from each
catheter lumen) [193] and peripherally drawn blood cultures (collected from two separate venous cannulation sites) must
be obtained (Figure 1); They should be taken at a maximum of 2 hours apart. However, the decision to remove the
catheter (with the exception of subcutaneously implanted permanent catheters [195]) should be taken according to
clinical criteria, and does not depend exclusively on the results of the microbiological tests.
The catheter must be removed if there are clear and definitive signs of local infection (e.g. purulent secretion at the exit
site). Although, the removed catheter tip can become contaminated by this procedure, a routine microbiological test
should still be carried out. Systemic antibiotic treatment (AB) should be started and adapted, if necessary, after receiving
the culture and antibiotic sensitivity results. In exceptional cases, and in the absence of an immediate threat (subclinical
infection), treatment with systemic antibiotics can be attempted without removing the catheter, especially if the removal of
the catheter (special subcutaneously implanted permanent catheter) or the resulting consequences are likely to be
problematic [20]. Potential advantages or disadvantages of catheter removal should be considered in decision-making in
individual patients, e.g. those on long-term home PN [196, 197].
In the absence of local signs of infection and in clinically stable patients (subclinical infection), the catheter is left in situ
temporarily. Systemic antibiotic therapy should be provided and PN continued. In patients with signs of acute sepsis
(acute rise in temperature with new clinical symptoms), organ dysfunction and/or haemodynamic instability (e.g. systolic
blood pressure <90 mmHg or drop in systolic blood pressure of ≥40 mmHg relative to initial value, or a mean arterial
pressure <60 mmHg, or the need for blood pressure lowering drugs), the catheter must be removed. The tip should be
sent for microbiological tests and a new catheter inserted at another appropriate site [198]. In these cases, a systemic
antibiotic therapy must be commenced. Guidelines are available regarding further adjuvant therapy for sepsis (diagnostic
and therapy of sepsis -no. 079/001- http://leitlinien.net/)
Evaluation of blood culture results
If peripheral blood cultures are negative with subclinical signs of infection, but blood cultures from the CVC are positive,
and if other sources of inflammation can be excluded or are unlikely from a clinical point of view, the CVC should be
removed and the patient treated with antibiotics. If blood cultures drawn from both the peripheral veins and CVC are
positive, or there are subclinical signs of infection, a temporary (non-tunnelled) CVC should always be removed. This
particularly applies to patients with artificial heart valves [199-201] and to infections with Staphylococcus aureus or
candida species. Systemic antibiotic therapy should also be commenced [202-204]. If there are only subclinical signs of
infection in patients with tunnelled CVCs, as in port systems, the situation should be monitored. However, a
supplementary antibiotic lock treatment and systemic antibiotic therapy should be started [205, 206]. Surgical removal of
the port system must be considered if these measures have no effect. Complicated infections with acute symptoms
present high-risk situations regardless of blood culture results [207-210]. In such cases the catheter must be removed as
quickly as possible and systemic antibiotic therapy started, even before the blood culture results are received [202, 208211]. This particularly applies to secondary complications (septic thrombosis, septic embolisms or endocarditis), and also
inpatients with tunnel or port system infections or with artificial heart valves [202, 207].
In addition to the systemic antibiotics and within the framework of an anticipative strategy, a further antibiotic lock
treatment can be applied to tunnelled CVCs or port systems and intraluminal catheter colonisation with staphylococci,
enterobacteriaceae, gram-negative bacteria or fungi in the absence of blood culture infection [212-214]. A series of
studies have shown that aminoglycosides or penicillin can have a favourable effect, similar to expensive third generation
cephalosporins, leading to a drop in bacterial colonisation [215-218]. Positive clinical experiences have been observed
with the administration of vancomycin (3 ml: 2 mg/ml) or a mixture of garamycin (0.5 mg/ml) and vancomycin (1.0 mg/ml)
[219, 220].
Henrickson et al. randomised 126 paediatric oncological patients with tunnelled CVCs to a prophylactic lock treatment
using three substances [221]. The first patient group received heparin (10 U/ml), the second group received heparin and
vancomycin (25 µg/ml), and the third group received heparin, vancomycin and ciprofloxacin (2 µg/ml). The use of
vancomycin-ciprofloxacin significantly reduced catheter-associated infections relative to the group receiving only heparin
(p=0.005). A similar beneficial effect was observed by using vancomycin lock treatment (p=0.004).
An antibiotic lock solution does not represent a routine procedure, but makes sense in patients requiring long-term
access, and if there are potential problems regarding CVC reinsertion [212, 218].
Peripheral venous access


10
In adult patients, PN through periperal venous access can be carried out if the PN is indicated for a short period (max. 710 days) of time and no hyperosmolar solutions (>800 mosm/L) or solutions with a high titration acidity or alkalinity
(bicarbonate, TRIS-buffer) are used (B).
A peripheral venous catheter (PVC) in adults can remain in situ for as long as it is clinically required unless there are
signs of inflammation at the insertion site (A).
Commentary
Peripheral venous access (PVC) is associated with less complications than central venous access [222, 223]. PN
administered via PVCs can only be used as additional nutritional support or as a temporary measure, as large volumes
are required to deliver the required nutrients. Peripheral administration of PN should last for no more than 7 (-10) days as
the rate of complications increases after this time period [224-227]. There is no general consensus regarding the optimum
PN-composition, infusion technique or pharmacological supplements, best suited to PVCs, in peripheral PN. In the
absence of lipids, a limit of 800 mosm/L including potential electrolyte supplements should be adhered to. The vein
quality of the patient also has to be taken into consideration.
Thrombophlebitis is one of the most significant complications limiting peripheral PN. There are many factors involved in
its pathogenesis. The incidence of thrombophlebitis depends on osmolarity, pH value and infusion speed of the PN
solution [228-230]. Problematic substrates are glucose, amino acids and electrolytes. Earlier studies have shown that
infusion solutions containing glucose and crystalline amino acids rarely resulted in phlebitis despite an osmolarity of >600
mosmol/L [231, 232]. The glucose concentration should not exceed 125 g/L [233]. A maximum osmolarity of 800-1000
mosmol/L is recommended.
No link between hyperosmolality and phlebitis has been observed in lipid-based mixtures. Kane et al. [234] randomised
36 patients for the peripheral intake of nutrient solutions with an osmolarity of between 1200 and 1700 mosm/L. They
found no difference in the incidence of phlebitis, although this either could be related to the catheter diameter and/or the
flow rate. Williams et al. [235] documented similar results for lipid-based solutions with 650 mosm/kg or 860 mosm/kg. A
phlebitis rate of 7-26 % was recorded by McMahon et al. [225, 227, 236, 237] when lipid-based nutrient solutions with an
osmolarity over 1100 mosm/L were administered.
The pH value of commercial nutrient solutions is approximately 5 to 6. The acidity is caused by the amino acids and
glucose degradation products which are produced during sterilisation [238].
The frequently used PN bags made of ethylene-vinyl-acetate (EVA) are permeable to air; this allows for the oxidation of
nutrients, for example, of glucose to gluconic acid [239]. Experimental studies showed a significant correlation between
increased acidity and an incidence of phlebitis in different infusion solutions [229, 240, 241]. Adding a neutralising buffer
to infusion solutions with crystalloids (normal pH 4.0-6.5) resulted in a reduction in the rate of phlebitis [238]. There are,
however, no significant clinical studies supporting the routine use of buffer supplements in peripheral PN. Furthermore,
the effects of these supplements on the stability of PN would be difficult to assess. In addition, the amino acid mixtures
themselves have a buffer effect (pK values).
While an increased rate of phlebitis and infection at a LOS of over 3 days was postulated earlier [99, 242], more recent
studies show that the time-specific risk of an obstruction, phlebitis and catheter colonisation remains the same even in
longer LOS [243-245]. Peripheral venous catheters can, therefore, remain in place as long as they are clinically required
[61,243]. In children, peripheral access may be left for the total duration of intravenous administration and only be
changed if complications arise [245-248]. The risk of phlebitis is lower when the cannula is placed on the back of the
hand compared to venous access sites in the wrist or upper arm [249].
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Shimandle RB, Johnson D, Baker M, Stotland N, Karrison T, Arnow PM. Safety of peripheral intravenous catheters in children. Infect Control Hosp Epidemiol
1999; 20: 736-740
Garland JS, Dunne WM, Jr., Havens P, Hintermeyer M, Bozzette MA, Wincek J et al. Peripheral intravenous catheter complications in critically ill children: a
prospective study. Pediatrics 1992; 89: 1145-1150
Garland JS, Nelson DB, Cheah TE, Hennes HH, Johnson TM. Infectious complications during peripheral intravenous therapy with Teflon catheters: a prospective
study. Pediatr Infect Dis J 1987; 6: 918-921
Nelson DB, Garland JS. The natural history of Teflon catheter-associated phlebitis in children. Am J Dis Child 1987; 141: 1090-1092
Maki DG, Mermel LA. Infections due to infusion therapy. In: Bennett JV, Brachman PS, eds. Hospital infections. Philadelphia: Lippencott-Raven; 1998: 689-724
see Parenteral Nutrition Overview 073-018.htm and Chapter 1: Introduction and Methodology 073-018e_01.htm
Jauch KW1, Schregel W2, Stanga Z3, Bischoff SC4, Braß P5, Hartl W1, Muehlebach S6, Pscheidl E7, Thul P8, Volk
O9 *
1Dept.
Surgery Grosshadern, University Hospital, Munich, 2Dept. of Anaesthetics, St. Joseph's Hospital KrefeldUerdingen, 3Polyclinic for Endocrinology, Diabetology and Clinical Nutrition, Clinic for General Internal Medicine,
University of Bern, Switzerland, 4Polyclinic for Endocrinology, Diabetology and Clinical Nutrition, Clinic for General
Internal Medicine, University of Berne, Switzerland, 5Dept. of Anaesthesiology and Operative Intensive Medicine,
University of Cologne, 6CSO Vifor Pharma Ag, Villars-sur-Glâne, Switzerland, 7Dept. of Anaesthesiology, Intensive
Medicine and Special Pain Therapy, Landshut, 8Dept. of General, Visceral, Vascular and Thorax Surgery, Humboldt
University of Berlin, 9Dept. of Internal Medicine I/Cardiology, Krefeld for the working group for developing the guidelines
for parenteral nutrition of The German Association for Nutritional Medicine
* English version edited by Sabine Verwied-Jorky, Rashmi Mittal and Berthold Koletzko, Univ. of Munich Medical Centre,
Munich, Germany
Erstellungsdatum:
04/2014
AWMF online - Guidelines on Parenteral Nutrition: Practical Handling of AIO Admixtures
1
AWMF online
Wissenschaftlichen
Medizinischen
Fachgesellschaften
Nr. 073-018e_10
Entwicklungsstufe:
3
Zitierbare Quelle:
Chapter 10: Practical Handling of AIO Admixtures
Kapitel 10: Praktische Handhabung von AIO-Mischungen
Key words: Infusion systems, compounding, industrial parenteral nutrition systems, stability, quality assurance
Schlüsselwörter: Infusionssysteme, Compounding, industrielle PE-Systeme, Stabilität, Qualitätssicherung
Abstract
All-in-one admixtures (AIO-admixtures) provide safe, effective and low-risk PN (parenteral nutrition) for
practically all indications and applications. Water, energy (carbohydrates and lipids), amino acids, vitamins and
trace elements are infused together with PN either as industrially-manufactured AIO admixtures provided as
two- or three-chamber bags (shelf life usually more than 12 months) completed with electrolytes and
micronutrients where appropriate or as individually compounded ready-to-use AIO admixtures (compounding,
usually prepared by a pharmacy on either a daily or weekly basis and stored at 2-8°C). Physico-chemical and
microbial stability of an AIO admixture is essential for the safety and effectiveness of patient-specific PN, and its
assurance requires specialist pharmaceutical knowledge. The stability should be documented for an application
period of 24 (-48) hours. It is advisable to offer a limited selection of different PN regimes in each hospital. For
reasons of drug and medication safety, PN admixtures prepared for individual patients must be correctly labelled
and specifications for storage conditions must also be followed during transport. Monitoring is required where
applicable. Micronutrients are usually administered separately to AIO admixtures. In case compatibility and
stability have been well documented trace elements and/or combination preparations including water-soluble or
water-soluble/fat soluble vitamin supplements can be added to PN admixtures under strict aseptic conditions.
AIO admixtures are usually not used as vehicles for drugs (incompatibilities).
Zusammenfassung
Eine sichere, effektive und risikoreduzierte parenterale Ernährung (PE) hat sich in Form der All-In-OneErnährung (AIO-Ernährung) für praktisch alle Indikationen und Anwendungen etabliert. Bei PE werden Wasser,
Energie (Kohlenhydrate und Fett), Aminosäuren, Vitamine und Spurenelementen gemeinsam infundiert,
entweder mit industriell gefertigten Standard-AIO-Zwei- oder Dreikammerbeuteln (Haltbarkeit ist in der Regel >
12 Monate) komplettiert mit Elektrolyten oder Mikronährstoffen, wo dies geeignet ist, oder mit individuell
gemischten anwendungsbereiten AIO-Nährmischungen (Compounding, Herstellung in der Regel täglich oder
wöchentlich und Kühllagerung bei 2-8°C). Die physikochemische und mikrobiologische Stabilität von AIOMischung ist entscheidend für die Sicherheit und Wirksamkeit einer patientenspezifischen PE und erfordert auch
für die Qualitätssicherung pharmazeutisches Fachwissen. Die Stabilität muss für eine Applikationsdauer von 24
(-48) Stunden dokumentiert werden. Sinnvoll ist eine begrenzte Zahl an PE-Regimen im einzelnen
Krankenhaus. Um die Arzneimittel- und Medikationssicherheit zu gewährleisten ist die korrekte Beschriftung von
2
patientenspezifisch vorbereiteten PE Mischungen notwendig. Die Vorgaben zur Aufbewahrung müssen auch
während des Transportes kontinuierlich garantiert werden. Ein Monitoring ist notwendig. Mikronährstoffe sollen
grundsätzlich getrennt von AIO-Mischungen verabreicht werden. Spurenelemente und/oder
Kombinationspräparate wasserlöslicher bzw. wasserlöslicher/fettlöslicher Vitaminpräparate Mischungen dürfen
bei dokumentierter Kompatibilität und Stabilität zur PE auch zugespritzt werden unter Beachtung strenger
Asepsis. AIO-Mischungen sollten in der Regel nicht als Träger für Medikamente verwendet werden
(Inkompatibilitäten).
All-in-one (AIO) Admixtures
Definition and Significance of AIO Admixtures


Water, energy (carbohydrates and lipids), amino acids, vitamins and trace elements are infused together
with parenteral nutrition (PN) (B).
All-in-one admixtures (AIO-admixtures) provide safe, effective and low-risk PN for practically all
indications and applications (B).
Commentary
Infusion Systems
Infusion systems for the administration of PN comprise of:



Individual substrates (carbohydrates, lipids and amino acids) administered with separate bottles (multibottle system/modular system).
Combination solutions (carbohydrate/amino acid mixtures) with separate administration of lipids.
AIO admixtures where the substrates (carbohydrates, lipids, amino acids, electrolytes and micronutrients)
are admixed in a single container and simultaneously administered through one intravenous line ("all-inone"). Ideally, all substrates are administered together, taking compatibility and stability of the
components and the admixture into account and limiting particulate matter. This system results in
reduced manipulation and savings of material, time and personnel workload. AIO admixtures require only
one intravenous line, and the risk of infection is lowered by the closed system. The complete and
simultaneous administration of all substrates reduces the risk for metabolic complications. AIO
admixtures offer a convenient system for patients, clinicians and nursing staff.
AIO Admixtures
AIO admixtures may be obtained by two different ways:


Industrially-manufactured standard AIO provided as two- or three-chamber bags: In case of a twochamber bag, a lipid emulsion is admixed with a transfer set shortly before its administration to the
patient, thus creating an AIO admixture. Three-chamber bags contain all the macronutrients and
electrolytes in three separate compartments. The substrates are mixed together immediately prior to
intravenous application by breaking the separation seals between the bag chambers. Vitamins and trace
elements are injected into the bag prior to administration or infused by a separate intravenous line. When
not mixed together, these standard multi-chamber bags have usually a shelf life of more than 12 months.
Individually admixed AIO admixtures (compounding): These allow for the provision of patient-specific
ready-to-use admixtures, individually adapted according to energy, volume and substrate needs. These
are aseptically manufactured from various components, usually in hospital pharmacies, and are designed
for immediate intravenous administration, with no mixing or admixing required prior to administration.
These bags are usually manufactured on either a daily or weekly basis due to their limited stability. They
require storage at 2-8°C.
Both approaches require aseptic techniques of handling, because it is not possible to sterilise an AIO admixture
after ready-to-use completion [1].
Significance
AIO systems in PN provide microbiological and metabolic advantages as well as benefits in handling and
compatibility, as compared to the use of individual components or combination solutions [2-8].
The use of standardised parenteral admixtures simplifies prescription, compounding and reduces complications.
In addition, it improves patient safety and efficiency of treatment [6, 9].
A cost-benefit analysis by Durand-Zaleski et al. [3] compared the costs and financial benefits of multi-bottle
3
systems with an AIO system. The expenditure included the costs for compounding, substrates and equipment.
Financial benefits were estimated from reduction in costs due to prevented infections (especially catheter-related
infections) and reduction in risks due to the use of an AIO system. Frei et al. [5] took into consideration the costs
for material required (bottles, bags, substrates, etc.), tests (laboratory) and staffing. A two-chamber bag together
with a separate bottle for lipid emulsion represented the AIO system. Although the multi-bottle system was more
economical, the total daily cost was lower when the two-chamber bag system was used.
Quality assurance is an important aspect of PN therapy. Increased manipulations during PN raise the frequency
of nosocomial infections [10-12]. This risk is higher with multi-bottle systems due to an increased frequency of
manipulation and the necessary admixing into bottles. Durand-Zaleski et al. [3] showed a reduction in
nosocomial infections with using an AIO system, which resulted in overall savings due to elimination of
subsequent expenses.
An AIO admixture comprises 50 or more components in a ready-to-use bag, and represents an extremely
complex pharmaceutical formulation. Good Manufacturing Practice (GMP) is a quality standard (materials, room
conditions, equipment, employees (training), processes, documentation, distribution etc.) that must be followed
for manufacturing AIO admixtures [13]. PN preparations must be [14]:




therapeutically and pharmaceutically suitable for the patient
free of microbiological impurities and pyrogens
correctly dosed and admixed (proven compatibility)
correctly labelled, stored and administered
Total complete admixtures which are true ready-to-use PN are not yet commercially available due to physicochemical instabilities. Adaptation of AIO admixtures to meet individual requirements must be prepared in
accordance to specific pharmaceutical manufacturing regulations and strict aseptic conditions [15, 16] at every
step. The evaluation of microbiological (aseptic preparation) and physico-chemical stability (emulsion dispersion,
solubility, decomposition, sorption phenomena etc.) requires specialised pharmaceutical knowledge [16, 17].
These parameters influence the quality of PN [18].
Standardisation is a sensible option in PN, when balancing requirements and simplification of treatment, but
individual regimens are also needed to meet specific requirements, e.g. in infants and children, long-term
(home) PN, etc. [19]. Industrially-prepared multi-chamber bags, with established standard compositions, often
are an attractive method of providing PN. They are predominantly used in the short-term PN-treatment of
hospitalised adults. Individual compounding is, however, still required [20]. Industrial multi-chamber bags allow
the admixing of the stable components in a closed system (asepsis) directly before administration. Multi-layer
plastic containers enable long-term storage of the compartmented components (reduction of oxygen permeation
in oxidation-sensitive components [21]; cover wrapping with oxygen absorbers further increase this stability).
Glucose and amino acids are separated in two-chamber bags so that Maillard reactions (browning) are
prevented; the lipid component, which is normally critical for the overall stability (fat droplet distribution), is
admixed to the remaining AIO admixture. Addition of electrolytes, trace elements or vitamins into the AIO
admixture must follow GMP standards and the compatibility of the components (controlled conditions,
documentation) must be ensured [13, 14].
If further admixing is required (e.g. special amino acids such as glutamine; lipids such as LCT, LCT/MCT,
special fatty acid compositions, or electrolytes such as phosphate, magnesium or calcium), these should be
individually admixed. Cost-benefit analyses of multi-chamber bags as compared to individual compounding
should incorporate the effectiveness and rational for PN use. The presently available studies addressing this
topic are either very basic or are outdated [6, 18, 22]. Local specifications and requirements should decide
whether individual compounding or commercial multi-chamber bags are used for administration of PN.
Logistics, Stability
Role of the Pharmacist in the Nutrition Team in PN

Close collaboration between a pharmacist and the multidisciplinary nutrition support team is
recommended; the extent of such collaboration will depend on the pharmacist's specific skills, standard of
knowledge in clinical nutrition and experience in (clinical) pharmacy practice (C).
Commentary
Areas of pharmaceutical care within the nutrition support team are [23-25]:

Transfer of pharmaceutical knowledge on products and equipment used for PN.










4
Potential interactions or incompatibilities between components and other administered
admixtures/medicines, and their prevention.
Providing instructions regarding the stability of PN regimes and their correct handling (storage, light
protection, administration, etc.).
Checking the patient-specific prescriptions of admixtures, their preparation and concomitant drugs.
Advisory function regarding the selection, composition and administration of PN as well as further
additions in hospital patient and patients discharged on home PN.
Advising on drug-related problems or observations: admixing, stability, incompatibility, bioavailability,
documentation/clarification of adverse reactions to drugs.
Providing an insight into measures to increase drug safety (evidence-based medicine/pharmacy).
Support in integration and standardisation of treatment regimens, including suggestions for therapeutic
strategies.
Advisory role on allergies to drugs or nutrition components.
Support of education and training.
Co-operation in quality assurance and quality improvement by means of establishing medical and nursing
standards as well as monitoring.
Preparation and Manufacturing Regulations
Strict requirements and conditions for compounding the all-in-one admixtures are required because it is
impossible to sterilise the end product, and because of the large number of components with potential physicochemical incompatibilities and instabilities (o/w emulsion systems with potential admixture of drugs) [15, 26-28].
The compatibility of the individual components, and the pH and homogeneity of the emulsion need to be tested,
and a weight control inspection of mass (target/actual check) be carried out. The maximum amount of selected
components tested as being compatible (or which are known to be compatible according to literature research),
must be established. It is essential to work under strict aseptic conditions. This requires the necessary premises
(laminar airflow benches, clean rooms, defined air turnover, compounding machines), the validation of the
manufacturing process with suitable measures for quality control, and quality assurance according to GMP and
supplementary guidelines. The manufacture of AIO admixtures with a defined admixture sequence should be
carried out as close to the time of administration as possible because of stability problems. Defined in-process
and end-product tests should be carried out, and the maintenance of hygiene standards guaranteed. A
standardised and reproducible record of the complete manufacturing process must be documented to enable
precise traceability. The expiry dates are established through suitable, validated laboratory tests. Suitable
electronic support and use of compounding machines are useful if a large number of PN admixtures are being
prepared.
Physico-chemical Stability (assessment and documentation)



Physico-chemical stability of an AIO admixture is essential for the safety and effectiveness of patientspecific PN, and its assurance requires specialist pharmaceutical knowledge (A).
The stability should be documented for an application period of 24 (-48) hours (C).
It is suitable to select and restrict the number of different PN regimes offered in each hospital (C).
Commentary
The large amounts of dissolved (reactive) components, and the underlying disperse, meta-stable water-in-oil
emulsion system in an AIO PN admixture are reasons for a high potential of incompatibility and instability. The
physico-chemical instabilities include:




Lipid emulsion destabilisation (lipid droplet aggregation, lipid coalescence, creaming and breaking of the
emulsion) [29].
The formation and precipitation of insoluble salts (i.e. calcium monohydrogen phosphate) or complexation
and altered bioavailability of components (trace elements).
Chemical changes or decomposition of components (oxidation, reduction, hydrolysis) (vitamins, PUFA
(lipid peroxidation), amino acids), condensation (Maillard reactions with amino acids and glucose).
Adsorption, absorption and desorption processes with the container material (insulin, vitamin A, diluents).
These reactions are time-dependant, dependant on the concentration of reactants, pH-value, temperature, light
exposure, the presence of catalytically active components and the container material [15, 17, 21]. There are
differences in the composition and purity of the starting materials of various providers, which are relevant for the
stability and potentially toxicity (e.g. aluminium), thus making extrapolation of data extremely difficult [30].
Manufacturing processes have to be defined, qualified and validated in order to get the necessary final product
quality (GMP). A pharmaceutical assessment/documentation of the following factors is required for the ready-touse manufacture of a PN admixture:





5
Defined starting materials
Manufacturing procedures (admixture sequence)
Lot-specific documents (process controls, process conditions, involved staff)
Suitable final product analyses like pH, concentration testing of selected components etc.
Stability-documented storage and application guidelines (tests).
Problems can occur particularly in the stability (i.e. solubility of phosphate and calcium salts or electrolyte-related
destabilisation of lipid emulsion) of paediatric PN admixtures due to the relatively high contents of individual
components. Here it is helpful to use only binary, lipid-free PN admixtures and organic phosphates or calcium
compounds. Solubility curves [17] or specific data for emulsion destabilisation [30] are useful data for the
determination of compatible, and thus allowed electrolyte dosages.
Simple methods are required for the documentation of stability, considering time, expenses, equipment of a
hospital pharmacy, for example, using microscopic instead of other methods in the testing of a lipid emulsion
[29-31].
Defined amino acids (glutamine, cysteine etc.) and oxydisable vitamins and lipids (PUFA) are critical for
chemical stability. The presence of oxygen, catalysts (trace elements, light) and anti-oxidants have a significant
influence on oxidative decomposition. Toxic and reactive products, like free radicals, can be formed in the
process along with the inactivation of important nutrition components [21, 32-35].
Lipophilic compounds may result in interactions with the container and administration materials. Plastic
components can be extracted (e.g. phthalates from PVC), or PN components can be either absorbed or
adsorbed [16].
The need to document the stability of PN admixtures shows the necessity of selecting and restricting the number
of PN regimes and products available in a hospital. This will enhance safety and effectiveness in relation to
physico-chemical stability data over the period of storage and administration. These tasks require specific
pharmaceutical knowledge and need to be supported by (own) investigations.
Labelling

PN admixtures prepared for individual patients must be correctly labelled for reasons of drug safety (A).
Commentary
Complete labelling principally serves to prevent incorrect administration and to provide controls prior to
administration. It is part of the documentation process. Labelling, therefore, should contain both the patient
(name, date of birth, body weight) and the product data. This comprises the following points:
⇒ Date of manufacture
⇒ Expiry date (storage period, administration period)
⇒ Composition including indication of concentration and daily dosage (in SI units)
⇒ Energy and protein content
⇒ Storage instructions
⇒ Administration instructions
⇒ Lot number
⇒ Manufacturer
⇒ Patient name and date for use
Standardised, printed labels are a useful and practical solution.
Storage and Transport

Specifications for storage conditions must also be followed during transport, and monitoring is required
where applicable (A).
Commentary
Admixtures should be protected from light and stored in the fridge (2 - 8°C) for reasons of hygiene and stability.
If the admixture is lipid-free it can also be frozen. Cool boxes are suitable as a means of transport [13, 15, 17,
26].
6
Addition of Micronutrients (trace elements and vitamins)




Micronutrients can be administered separately to AIO admixtures since there is a lack of specific documentation
regarding compatibility and stability (B), even though micronutrients injected to the admixture in home PN prior
to administration are without identifiable adverse effects (C).
Trace elements and/or combination preparations including water-soluble or water-soluble/fat soluble vitamin
supplements can be added to PN admixtures for PN compatibility and stability has been documented (B).
Considering micronutrient stability it can be stated:
 Trace elements may be added to AIO admixtures in the event of documented compatibility
(B).
 Fat-soluble vitamins formulated as lipid emulsion are added to lipid-containing AIO
admixtures or lipid infusions prior to administration (B).
Micronutrients must be injected to admixtures under strict asepsis, optimally and according to GMP using a
laminar airflow. Admixing should be restricted on hospital wards for hygienic reasons (A). If this is not possible
due to, structural or organisational reasons, this may be carried out according to pharmaceutical guideline in
individual cases, immediately before administration, by specially trained medico-pharmaceutical staff. Medical
prescription, pharmaceutically documented stability and authorised ready-to-use preparations (authorised
product information) have to considered. The procedure to be followed should be documented in a written
Standard Operating Procedure (C).
Commentary
Simultaneous administration of trace elements and multivitamins in AIO admixtures is problematic due to
physico-chemical reasons; it shows increased degradation of oxidation-sensitive vitamins; (lipid) peroxidation is
increased. Trace elements and vitamins normally have a high reactivity in the solution: some individual trace
elements show catalyst functions for chemical decomposition reactions. Oxidation/reduction reactions can be
further intensified by light (especially UV radiation), see peroxide formation [32, 33, 35, 37]. Therefore, the coadministration of multi vitamins and trace elements is not generally recommended, even if administered
separately from AIO admixtures.
Micronutrients can inactivate each other (e.g. vitamin C and ionised iron), can be inactivated by light (e.g.
vitamin K, A, B2) or absorbed into plastic (e.g. vitamin A). Degradation products form insoluble salts (e.g. Ca and
oxalate as a degradation product of vitamin C) [38, 39].
Trace elements should only be added to AIO admixtures if stability has been documented. Trace element
solutions show a strong acidic pH and represent in part polyvalent cations, which can greatly reduce the
emulsion stability [16, 29, 37] depending on their concentration.
Suitable concentrations of antioxidative vitamin supplements (vitamin C and tocopherols) in an AIO admixture
help reduce lipid peroxidation [34, 40]. They have a synergistic effect as chemical stabilisers of unsaturated
lipids in vitro.
Fat soluble vitamins (vitamins A, D, E, K) can be injected into lipid-containing PN admixtures; lipid emulsion
provides light protection. Micellar-dissolved lipophile vitamins can, according to manufacturer's instructions, also
be administered in aqueous admixtures taking into consideration stability and compatibility. If the daily-applied
combination preparations of fat and water-soluble vitamins do not contain vitamin K the weekly or even monthly
administration of vitamin K added to the lipids in the AIO admixture is often still practice adequate in adults and
children [32]. To better control potential osteoporosis a daily administration is recommended.
An example of a hospital guideline for the administration of vitamins and trace element dosage in PN is cited
here (cf. chapter "Water, Electrolytes, Vitamins and Trace Elements").
If no specific deficiency is present: in case of PN providing >50 % of daily energy requirements:
- Vitamins:
- Cernevit® 1 vial (5 ml) per day as a piggy bag infusion over 15-30 minutes or a slow 5minute bolus at the end or at the beginning of the daily PN administration. Cernevitâ can
also be added to PN during manufacture, if compatible (light protection).
- Konakion MM® vial 10 mg (diluted to 10 ml): doses of 150 µg (150 µl of the dilution) added
daily to the AIO-PN
- Option:
- Vitalipid N Adult® (A, D, E, K!) 1 vial (10 ml) per day
- Soluvit N Adult® 1 vial (10 ml) per day
Trace elements:
Trace elements 1 vial (Spur-el KSA® 10 ml) per day
Effects of adding electrolytes on the osmolarity of the solution are shown in Table 1.
Table 1: Approximate increases of osmolarity with electrolyte additions. Adapted from Sobotka et al. [36]
Electrolyte Standard PN Salt form
(mmol/day)
Daily dosage
mosmol (theoretical)
Na+
80-100
NaCl
160-200
K+
60-150
KH2PO4
180-450
KCl
120-300
CaCl2
7.5-15
Ca++
2.5-5
7
Ca (organ.) 2.5-5
Mg++
8-12
MgSO4
16-24
Micronutrients are not included in commercially available multi-chamber bags because of their limited stability in
solution and their high risk of incompatibility. They must be prescribed seperately, [15] and in a suitable dosage
for a PN regime. This mutual incompatibility usually requires separate administration/admixture of trace
elements and (multi) vitamins, i.e. two separate intravenous applications, one for vitamins and one for trace
elements. The stability of vitamins is extremely limited in the presence of trace elements (vitamin C is
decomposed within hours in presence of catalytically active trace elements like iron or copper and oxygen). That
is why trace elements and vitamins are not suitable for combined administration in admixtures (accelerated
(catalysed) degradation of selected vitamins). Compatibility with the other components in the AIO admixture i.e.
physical lipid stability or chemical fatty acid stability (peroxidation) has to be documented with the parenteral
admixture even if selected vitamins are compatible with trace elements, especially fat-soluble and water-soluble
vitamins with sufficient degradation stability like pantothenic acid or nicotinamide. The increased concentration
of polyvalent cations (iron, zinc) is cited as an example for the stability of lipid emulsion or the influence of multi
vitamins on lipid peroxidation.
Light protection must be provided when micronutrients in aqueous solutions are applied as a (piggy bag)
infusion. Light protection with overwraps must have a documented and proven effectiveness [40-42]. Fat-soluble
vitamins, which are formulated as lipid emulsion, should be added to a lipid emulsion or an AIO admixture
containing lipids.
Drugs
AIO Admixtures as vehicles for drugs

AIO admixtures are usually not used as vehicles for drugs due to the possibility of complex interactions. If
additions of drugs to the AIO admixture are required as an exception, the stability and effectiveness must
be documented (B).
Commentary
Instabilities and physico-chemical incompatibilities often occur due to the many components of AIO admixtures
(lipid emulsion, amino acids, glucose, trace elements, vitamins) [43-45]. New formulations, created in emulsion
systems with lipophilic drugs, show clinically relevant differences in pharmacokinetics or changes in
bioavailability of the substrates as compared to the original product [46]. Incompatibilities due to pH changes,
redox reactions, complex formations, drug association and solvolysis can also contribute to inactivation. Even if
some incompatibilities are recognised by precipitation, colourings or gas formation, not all interactions can be
analysed in this macroscopic manner. Detailed investigation or analysis and documentation, therefore, are
essential before admixing.
References
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Nutrition and Metabolism, 1996
2. Didier ME, Fischer S, Maki DG. Total nutrient admixtures appear safer than lipid emulsion alone as regards
microbial contamination: growth properties of microbial pathogens at room temperature. JPEN J Parenter
Enteral Nutr 1998; 22: 291-296
3. Durand-Zaleski I, Delaunay L, Langeron O, Belda E, Astier A, Brun-Buisson C. Infection risk and costeffectiveness of commercial bags or glass bottles for total parenteral nutrition. Infect Control Hosp Epidemiol
8
1997; 18: 183-188
4. Flechsenhar K, Müller I, Zutt A. Handhabung eines parenteralen Ernährungsregimes. Schwester Pfl 1996; 6:
555-557
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Total Parenteral Nutrition. Geneva: XVIII ESPEN Congress on Clinical Nutrition and Metabolism, 1996
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infection of hyperalimentation catheters. J Infect Dis 1986; 154: 808-816
11. Sitges-Serra A, Linares J, Perez J. A randomised trial on the effect of tubing changes on hub contamination and
catheter sepsis during parenteral nutrition. JPEN J Parenter Enteral Nutr 1985; 9: 322-325
12. Snydman DR, Murray SA, Kornfeld SJ, Majka JA, Ellis CA. Total parenteral nutrition-related infections.
Prospective epidemiologic study using semiquantitative methods. Am J Med 1982; 73: 695-699
13. No authors listed. Vorschriften geltender Arzneibücher: Europäisches Arzneibuch (Ph. Eur.), Arzneibuch der
Vereinigten Staaten (USP), Britisches Arzneibuch (British Pharmacopeia). 2005
14. Delanghe M. Good manufacturing in All in One compounding. Nutrition 1989; 5: 352-354
15. ASPEN Board of Directors. Safety practices for parenteral nutrition. JPEN J Parenter Enteral Nutr 1998; 22: 4966
16. Driscoll DF. Compounding TPN admixtures: then and now. JPEN J Parenter Enteral Nutr 2003; 27: 433-438
17. Hardy G, Ball P, McElroy B. Basic principles for compounding all-in-one parenteral nutrition admixtures. Curr
Opin Clin Nutr Metab Care 1998; 1: 291-296
18. Hartmann B, Berchtold W, Aeberhard P, Mühlebach S. Umfang, Rationalität und Qualität der parenteralen
Ernährung. Akt Ern Med 1998; 23: 43-49
19. Mühlebach S. [Home Parenteral Nutrition (HPN): International Background and Long-Term Experience in
Switzerland]. Article in German. Akt Ern Med 2002; 27: 425-430
20. Pichard C, Mühlebach S, Maisonneuve N, Sierro C. Prospective survey of parenteral nutrition in Switzerland: a
three-year nation-wide survey. Clin Nutr 2001; 20: 345-350
21. Steger PJ, Mühlebach SF. In vitro oxidation of i.v. lipid emulsions in different all-in-one admixture bags assessed
by an iodometric assay and gas-liquid chromatography. Nutrition 1997; 13: 133-140
22. Dice JE, Burckart GJ, Woo JT, Helms RA. Standardized versus pharmacist-monitored individualized parenteral
nutrition in low-birth-weight infants. Am J Hosp Pharm 1981; 38: 1487-1489
23. Allwood MC, Hardy G, Sizer T. Roles and functions of the pharmacist in the nutrition support team. Nutrition
1996; 12: 63-64
24. ASPEN Board of Directors and The Clinical Guidelines Task Force. Standards for Nutrition Support
Pharmacists. Nutr Clin Pract 1993; 8: 124-127
25. Driscoll DF. Roles and functions of the hospital pharmacist on the nutrition support team. Nutrition 1996; 12:
138-139
26. ASHP Board of Directors. ASHP Guidelines on quality assurance for pharmacy-prepared sterile products. AJHP
2000; 57: 1150-1169
27. Driscoll DF, Bhargava HN, Li L, Zaim RH, Babayan VK, Bistrian BR. Physicochemical stability of total nutrient
admixtures. Am J Health Syst Pharm 1995; 52: 623-634
28. FDA Safety Alert. Hazards of precipitation associated with parenteral nutrition. Department of Health and Human
Services. FDA 1994
29. Washington C. The stability of intravenous fat emulsions in TPN mixtures. Int J Pharmaceutics. Int J
Pharmaceutics 1999; 66: 1-21
30. Schmutz C, Werner R, Keller U, Mühlebach S. Emulsion stability of all-in-one TPN admixtures assessed by
microscopy. Comparison of different lipid emulsions and amino acid solutions. Clin Nutr 1993; 12: 59-60
31. Driscoll DF, Bacon MN, Bistrian BR. Physicochemical stability of two types of intravenous lipid emulsion as total
nutrient admixtures. JPEN J Parenter Enteral Nutr 2000; 24: 15-22
32. Gräflein C. Parenterale Ernährung mit stabilitätsgeprüften, modularen Standardlösungen in der Neonatologie
(Dissertation). Philosophisch-Naturwissenschaftliche Fakultät der Universität Basel:
http://pages.unibas.ch/diss/2004/DissB_6720.pdf external link externer Link, 2004
33. Laborie S, Lavoie JC, Pineault M, Chessex P. Contribution of multivitamins, air, and light in the generation of
peroxides in adult and neonatal parenteral nutrition solutions. Ann Pharmacother 2000; 34: 440-445
34. Steger J, Mühlebach SF. Lipid peroxidation of iv lipid emulsions in TPN bags: the influence of tocopherols.
Nutrition 1998; 14: 179-185
35. Steger PJ, Mühlebach SF. Lipid peroxidation of intravenous lipid emulsions and all-in-one admixtures in total
parenteral nutrition bags: the influence of trace elements. JPEN J Parenter Enteral Nutr 2000; 24: 37-41
36. Sobotka L, Allison SP, Stanga Z. Water and electrolytes. In: Sobotka L, Allison SP, Fürst P et al. (Hrsg.). Basics
in clinical nutrition: Edited for ESPEN Courses. Prague, Czech Republic: Publishing House Galén, 2000:
37. Allwood MC, Kearney MC. Compatibility and stability of additives in parenteral nutrition admixtures. Nutrition
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1998; 14: 697-706
38. No authors listed. Basics in clinical nutrition: Edited for ESPEN Courses. Prague, Czech Republic: Publishing
House Galén, 2000
39. Dupertuis YM, Morch A, Fathi M et al. Physical characteristics of total parenteral nutrition bags significantly
affect the stability of vitamins C and B1: a controlled prospective study. JPEN J Parenter Enteral Nutr 2002; 26:
310-316
40. Silvers KM, Sluis KB, Darlow BA, McGill F, Stocker R, Winterbourn CC. Limiting light-induced lipid peroxidation
and vitamin loss in infant parenteral nutrition by adding multivitamin preparations to Intralipid. Acta Paediatr
2001; 90: 242-249
41. Martinelli E, Mühlebach S. [Plastic covers as light protective for infusions. Results of a close to practice study
using vitamin K 1 as test probe.] Article in German. Krankenhauspharmazie 1995; 16: 286-289
42. Silvers KM, Darlow BA, Winterbourn CC. Lipid peroxide and hydrogen peroxide formation in parenteral nutrition
solutions containing multivitamins. JPEN J Parenter Enteral Nutr 2001; 25: 14-17
43. Barnett MI, Cosslett AG, Duffield JR, Evans DA, Hall SB, Williams DR. Parenteral nutrition. Pharmaceutical
problems of compatibility and stability. Drug Saf 1990; 5 Suppl 1: 101-106
44. Gikic M, Di Paolo ER, Pannatier A, Cotting J. Evaluation of physicochemical incompatibilities during parenteral
drug administration in a paediatric intensive care unit. Pharm World Sci 2000; 22: 88-91
45. Trissel LA, Gilbert DL, Martinez JF, Baker MB, Walter WV, Mirtallo JM. Compatibility of medications with 3-in-1
parenteral nutrition admixtures. JPEN J Parenter Enteral Nutr 1999; 23: 67-74
46. Schmid U, Mühlebach S. Interactions of drugs and i.v. lipids: influence of cyclosporin on fat clearance in vitro.
Clin Nutr 2001; 20: 27
Mühlebach S1, Franken C2, Stanga Z3 *
1CSO
Vifor Pharma Ltd, Villars-sur-Glâne, and University of Basel Switzerland, 2Central Pharmacy, University of
Dusseldorf, 3Polyclinic for Endocrinology, Diabetology and Clinical Nutrition, Clinic for General Internal Medicine,
University of Berne, Switzerland for the working group for developing the guidelines for parenteral nutrition of
The German Association for Nutritional Medicine
Erstellungsdatum:
04/2014
10
AWMF online - Guidelines on Parenteral Nutrition: Complications and Monitoring
1
AWMF online
Wissenschaftlichen
Medizinischen
Fachgesellschaften
Nr. 073-018e_11
Entwicklungsstufe:
3
Zitierbare Quelle:
Chapter 11: Complications and Monitoring
Kapitel 11: Komplikationen und Monitoring
Key words: Refeeding syndrome, hyperglycaemia, hypertriglyceridemia, liver disease, catheter infection
Schlüsselwörter: Refeeding Syndrom, Hyperglykämie, Hypertriglyzeridämie, Hepatopathie, Katheterinfektion
Abstract
Compared to enteral or hypocaloric oral nutrition, the use of PN (parenteral nutrition) is not associated with increased mortality, overall frequency of
complications, or longer length of hospital stay (LOS). The risk of PN complications (e.g. refeeding-syndrome, hyperglycaemia, bone demineralisation,
catheter infections) can be minimised by carefully monitoring patients and the use of nutrition support teams particularly during long-term PN. Occuring
complications are e.g. the refeeding-syndrome in patients suffering from severe malnutrition with the initiation of refeeding or metabolic,
hypertriglyceridemia, hyperglycaemia, osteomalacia and osteoporosis, and hepatic complications including fatty liver, non-alcoholic fatty liver disease,
cholestasis, cholecystitis, and cholelithiasis. Efficient monitoring in all types of PN can result in reduced PN-associated complications and reduced costs.
Water and electrolyte balance, blood sugar, and cardiovascular function should regularly be monitored during PN. Regular checks of serum electrolytes
and triglycerides as well as additional monitoring measures are necessary in patients with altered renal function, electrolyte-free substrate intake, lipid
infusions, and in intensive care patients. The metabolic monitoring of patients under long-term PN should be carried out according to standardised
procedures. Monitoring metabolic determinants of bone metabolism is particularly important in patients receiving long-term PN. Markers of intermediary,
electrolyte and trace element metabolism require regular checks.
Zusammenfassung
Im Vergleich zu einer enteralen bzw. hypokalorisch oralen Ernährung ist die PE (parenterale Ernährung) nicht mit einer erhöhten Letalität,
Komplikationshäufigkeit insgesamt und Krankenhausverweildauer verbunden. Das Risiko durch PE verursachter Komplikationen (wie z.B. Refeeding
Syndrom, Hyperglykämie, Knochendemineralisierung, Katheterinfektionen) kann durch eine sorgfältige Überwachung des Patienten und durch den
Einsatz von Ernährungsteams, besonders während einer Langzeit-PE, minimiert werden. Auftretende Komplikationen sind z.B. das Refeeding Syndrom
bei Patienten mit ausgeprägter Mangelernährung, bei denen eine erneute Ernährung begonnen wird. Weitere schwere Nebenwirkungen können
metabolische und hepatische Komplikationen sein, wie eine Hypertriglyzeridämie, Hyperglykämie, Fettleber, Steatohepatitis, Cholestase, Cholezystitis,
Cholelithiasis sowie Osteomalazie und Osteoporose. Die Effizienzkontrolle bei jeder Art von PE kann zur Reduktion von PE-assoziierten Komplikationen
und zur Kostensenkung führen. Unter PE sollte Wasser,- Elektrolyt- und Zuckerhaushalt sowie die kardiozirkuläre Funktion engmaschig überwacht
werden. Regelmäßige Kontrollen der Serumelektrolyte und der Triglyzeride sind unter PE erforderlich sowie zusätzliche Überwachungsmaßnahmen bei
Patienten mit Nierenfunktionsstörungen, bei elektrolytfreier Substratzufuhr, Fettinfusion bzw. bei Intensivpatienten. Das metabolische Monitoring von
Patienten unter längerfristiger PE sollte nach standardisierten Schemata erfolgen. Unter Langzeit-PE sind zusätzlich die metabolischen Determinanten
des Knochenstoffwechsels überwachungspflichtig. Variablen des Intermediär-, Elektrolyt- und Spurenelementstoffwechsels bedürfen einer Kontrolle in
regelmäßigen Abständen.
Complications
Preliminary Remarks and General Information
Parenteral Nutrition (PN) is beneficial and life-saving in a variety of clinical conditions, but can also result in numerous, potentially serious, side-effects
[1,2]. The risk of such complications can be minimised by carefully monitoring patients and the use of nutrition support teams.
One of the most dramatic side effects of PN is the so-called refeeding syndrome, which can occur in severely malnourished patients who are receiving
aggressive PN. In addition, hyperglycaemia can occur due to parenteral carbohydrate intake in diabetic patients, in response to postaggression
metabolism or the systemic inflammatory response syndrome (SIRS), or due to systemic steroid therapy. In extreme cases PN can result in a
hyperosmolar, hyperglycaemic non-ketotic coma. When suddenly discontinuing parenteral intake, rebound hypoglycaemia, although rare, may occur.
Abnormalities in the acid-base-balance can occur due to PN and may result in significant electrolyte shifts. Hypertriglyceridemia with dyslipoproteinaemia
may occur. High carbohydrate intakes may result in excessive carbondioxide production. Hepatic complications of PN include steatosis (fatty liver) and
cholestasis. Special complications like metabolic bone disease wih bone demineralisation and osteoporosis may occur in patients receiving long-term
PN. In all forms of PN there is an imminent risk of infectious complications. Finally, intestinal side-effects (mucosal atrophy, increased translocation of
micro organisms and their toxins) may also occur.
Relevance of complications in short-term PN with respect to patient outcome

Compared to enteral or hypocaloric oral nutrition, total PN is not associated with increased mortality, overall frequency of complications, or longer
length of hospital stay (LOS) (I).
2
Commentary
Benefits and side effects of PN have been the subject of extensive literature analyses and intensive scientific discussions. The most extensive meta
analysis on this topic was presented by Koretz and co-workers in 2001 [3]. Eighty-two randomised controlled studies were evaluated in which
parenterally nourished patients received intravenous fluids with a mixture of amino acids and at least 10 kcal/kg body weight per day of non-protein
calories. Control patients were either not given intravenous nutrition at all (only spontaneous oral food intake) or received up to 5 % glucose solutions
intravenously as basal fluid intake. PN did not significantly change either mortality or morbidity (overall rate of complications) compared to the control
group. There was, however, a significant increase in infectious complications (+5%) with PN, which caused one additional infection per 20 PN treated
patients. A subgroup analysis revealed that this side-effect occurred mainly in tumour patients receiving oncologic therapy. In other subgroups, for
example perioperative patients, the infection frequency was not increased. The overall LOS with PN was not increased despite the increased incidence
of infection.
A further meta-analysis on the frequency of complications was published by Braunschweig and co-workers [4]. The inclusion criteria varied from those of
Koretz's analysis in that only those studies were considered where the calorie intake with PN either met or exceeded energy requirements. Some 27
studies, with a total of 1,829 patients, were identified comparing PN with appropriate enteral intake. This analysis showed that infectious complication
incidence increased significantly when patients received PN relative to patients in the control group who received either isocaloric enteral nutrition or oral
nutrition. Mortality was unaffected by PN. Malnourished patients receiving PN had a lower infection frequency and a significantly lower mortality than
those receiving only oral food intake. The increased infectious morbidity is likely due to the relatively high amounts of carbohydrates administered
parenterally in some of the older studies included in the analysis. The hyperglycaemic episodes that must be expected with high dosage of parenteral
supply are a well-known complication of PN. The incidence of hyperglycaemia is evidently higher even with normocaloric PN intake as compared to
enteral or oral food intake [4].
Persistent hyperglycaemia and associated immunosuppression are considered causal factors for a poor patient outcome [5], which would explain the
better results of the meta-analysis by Koretz and co-workers who included in their meta-analysis studies with a minimum daily energy intake of approx.
15 kcal/kg body weight. The frequency of infectious complications is probably reduced with a low substrate intake and hence a low incidence of
hyperglycaemia.
The known complications of PN caused a fierce controversy in 2003 on clinical benefits or damage [6]. A polemic point of view expressed ("Death by
parenteral nutrition", TPN = total poisonous nutrition) resulted in a numerous responses [7-9] criticising the extremely unbalanced evaluation and
presentation of the literature, particularly data from animal studies. The known links between intravenous energy supply, frequency of hyperglycaemia
and associated immune suppressive effects led experts to conclude that PN would likely be without adverse effects for patients if prescribed only when
clinically indicated, handled correctly and administered in appropriate dosages [10-12]. Clear clinical benefits to justify PN are given clinical indications,
particularly in malnourished patients with impaired gastrointestinal function.
Complication rates with short-term and long-term PN

Some complications (demineralisation of the bones, catheter infections) occur more frequently with long-term PN than with short-term PN because
of metabolic alterations and venous access problems associated with long-term PN (III).
Commentary
In a meta-analysis of 37 studies evaluating long-term PN, the most frequent complication was catheter sepsis with 0.34 episodes per catheter and year
[13]. The second most common complication was occlusion of the central venous catheter, with 0.071 episodes per catheter and year, and the third,
central venous thrombosis with 0.027 episodes per catheter and year. Pathological hepatic changes with increased liver enzymes were found at 0.025
episodes per treatment year.
Metabolic bone changes are of significant clinical relevance, as they may result in severe illness. Slight changes in the bone metabolism probably occur
frequently with PN. In some studies, bone pain and fractures occur in 29 % or more of long-term PN patients [1]. A multitude of risk factors are
associated with occurrence of these complications, such as long term systemic steroid therapy, short bowel syndrome, physical inactivity, menopause
and a genetic disposition for specific bone disorders.
Refeeding Syndrome

Initiation of refeeding in patients suffering from severe malnutrition may result in severe adverse effects, the so-called refeeding syndrome (III).
Commentary
Refeeding syndrome is especially prevalent in severely malnourished patients and usually occurs during the first few days after initiating refeeding [14].
The exact incidence is not known give a considerable heterogeneity of studies. Although some of the symptoms are typical of oral/enteral food intake
(diarrhoea, nausea, vomiting), most symptoms are observed both with enteral and parenteral refeeding. Among the several complications are:
 Vitamin B1 deficiency and acute beriberi,
 Volume overload with oedema, cardiac insufficiency and lung oedema,
 Electrolyte disorders including hypophosphataemia, hypokalemia and hypomagnesaemia,
 Arrhythmia (bradycardia, ventricular tachyarrhythmia)
 Glucose intolerance (hyperglycaemia, glucosuria, dehydration and hyperosmolar coma)
Intestinal Complications
Altered intestinal function with with total PN

In contrast to data from animal studies, clinically relevant changes in mucosal or intestinal function are usually not induced in patients by receiving
long-term PN who are not critically ill. The extent to which this also applies to critically ill patients is not known (II).
Commentary
An overview of studies examining the influence of total PN on mucosal morphology or proliferation in patients without severe malnutrition or critically
illness is shown in Table 1. All the studies available on this topic [15-20] used glutamine-free amino acid solutions. Despite this potential selective amino
acid deficit, total parenteral energy intake reduced the height of the villi only slightly or not at all, irrespective of the underlying illness. This was also the
case in patients with mild malnutrition. The enterocyte proliferation was not affected by prolonged PN. It is remarkable that glutamine-free total parenteral
nutrition over a 2-months period does not result in distinctive changes in mucosal morphology [17].
Parallel to these discrete histological or histochemical changes, protein homeostasis was unaltered in the small intestinal mucosa. Mucosal protein, DNA
and RNA contents remain unchanged with glutamine-free total PN for over 2 weeks [15], and the concentration of free intercellular amino acids also
remains unaltered [21]. However, selective functional changes are observed under glutamine-free PN despite complete maintenance of the mucosal
structure. Enzyme activities on the brush border of the micro villi are reduced [16]. Furthermore, intestinal permeability assessed by the
lactulose/mannitol ratio was increased after only 2 weeks of PN [15,19]. The clinical relevance of this increased permeability is not clear, and
translocation of (much larger) microorganisms from the intestinal lumen was not demonstrated under clinical conditions. Sedmann and co-workers [18]
found no effect of preoperative total PN on bacterial growth in intestinal lymph nodes or on the intestinal serosa. These studies were carried out on
surgical patients who had tissue samples surgically removed for microbiological examination after total PN. Preoperative total PN, over 12 days, resulted
3
in microbial growth in 3 out of 28 patients, whereas in enterally nourished patients, 14 out of 175 demonstrated the presence of microorganisms in the
lymph nodes of the serosa (not significant). It can be concluded that glutamine-free total PN does not result in a significant loss of structural integrity of
the intestinal mucosa in patients who are not severely malnourished, which differs from findings in rodents. A discrete loss of function with reduced
enzyme activity may be due to preferential utilisation of amino acids for the synthesis of structural protein, which might explain why the mucosal anatomy
is largely maintained.
There is lack of data for critically ill patients and severely malnourished patients. Glutamine-free PN induced more distinctive impairment in mucosal
function of intensive care patients. Duodenal protein content dropped significantly in critically ill patients receiving PN already within 4 days [22]. There is
also a limited nutrient absorption and increased intestinal permeability in intensive care patients [23]. The extent to which these processes are influenced
by PN, or only reflect an expression of an overall poor general condition, has not been clarified. Many findings in animal experiments so far have not
been validated in patients [12].
Table 1: Effects of total PN on mucosal function
Author
Patient Type (n)
PN Length Villus height Proliferation Reference
Guedon 1986
Crohn's/Colitis [7]
21 days
Sedmann 1995
Preoperative [28]
12 days
Buchmann 1995
Normal volunteers[8]
14 days
Van der Hulst 1993/97 Various conditions[10] 12 days
Pironi 1994
Crohn's [2]
60 days
+0
-
[16]
+0
-
[18]
- 20 %
+0
[15]
- 10 %
+0
[19, 20]
- 20 %
+0
[17]
Hepatic and metabolic complications

Metabolic and hepatic complications comprise hypertriglyceridemia, hyperglycaemia, fatty liver, non-alcoholic fatty liver disease, cholestasis,
cholecystitis, cholelithiasis, osteomalacia and osteoporosis (III).
Commentary
Hypertriglyceridemia, hyperglycaemia, fatty liver, non-alcoholic fatty liver disease, cholestasis, cholecystitis, cholelithiasis, osteomalacia and osteoporosis
occur after different durations of PN [2, 12, 24]. While hypertriglyceridemia and hyperglycaemia can also occur with short-term PN (intensive care),
hepatic complications as well as changes in the bones usually manifest themselves after longer term PN for weeks, months or even years.
Hypertriglyceridemia



Hypertriglyceridemia is found in approximately 25-50 % of PN patients. The extent of hypertriglyceridemia depends on the presence of
accompanying hyperglycemia, simultaneous renal insufficiency, steroid administration, extent of the illness and the amount of lipids infused (I).
Severe hypertriglyceridemia (>1000 mg/dL or 11.4 mmol/L and particularly >5000 mg/dL or 57.0 mmol/L) can induce acute pancreatitis, similar to
patients with severe hypertriglyceridemia without PN, and it can affect micro circulation (I). It is not known whether long-term hypertriglyceridemia
in PN patients is associated with increased cardiovascular risk.
One should aim for plasma triglyceride concentrations below 400 mg/dL (4.6 mmol/L) during PN infusion (C).
Commentary
A multicentre study demonstrated that not only the dosage of intravenous lipids, but also a variety of other factors (hyperglycaemia, renal insufficiency,
steroid administration, disease severity, simultaneous administration of heparin) influence the extent of hypertriglyceridemia [25]. Severe PN-associated
hypertriglyceridemia may present a similar risk of pancreatitis as severe hypertriglyceridemia of other origins. It is unclear whether PN-associated
hypertriglyceridemia, even when long standing, presents a risk for atherosclerosis as it is not asscoaited with an increase in lipoproteins containing
apolipoprotein B.
To manage hypertriglyceridemia the above-mentioned causative factors should be corrected. Hyperglycaemia plays an especially important role. Heparin
activates lipoprotein lipase and hence can lower blood triglyceride levels but it increases non-esterified fatty acid concentrations.
Hyperglycaemia



Hyperglycaemia is found in up to 50 % of PN patients. Important predictors are insulin resistance or diabetes mellitus, severity of the underlying
illness, concomitant steroid therapy, and the amount of glucose provided (III).
Hyperglycaemia adversely affects morbidity and mortality in surgical and medical intensive care patients (I).
Normoglycaemia (approximately 80-145 mg/dL) should be aimed for in critically ill patients to improve outcome (A).
Commentary
Numerous clinical studies have associated hyperglycaemia with increased morbidity and mortality in surgical patients with sepsis, patients after bypass
surgery, and patients with myocardial infarction or stroke [26-34]. Experimental data demonstrate a causal link between hyperglycaemia and
complications.
It appears important to tightly control control blood sugar in intensive care patients irrespective of simultaneous PN administration. Hyperglycaemia is
detected in up to 50% of intensive care patients who are not receiving PN, and the rate increases with added PN [35]. A study in surgical intensive care
patients showed benefits of tight blood glucose control (glucose 80-110 mg/dL) with regards to mortality and morbidity when compared to conventional
blood sugar control (glucose 80-200 mg/dL) [32]. A more recent study indicated a possible maximum threshold of 145 mg/dL beyond which there are no
additional benefits [26]. Although a strict blood glucose control is linked to a more frequent rate of moderate hypoglycaemia, this does not seem to pose a
significant clinical problem or have any influence on patient outcome [26, 32] as long as strict blood glucose monitoring is followed.
Acceptable blood glucose values for non-acutely ill patients receiving PN can not be determined based on controlled studies. Possible complications are
similar to those seen in patients with diabetes mellitus. The risk of infectious complications is increased due of venous access for PN. The likelihood of
hyperglycaemia induced complications may depend on concomitant diseases, duration of PN, and life expectancy. However, even in case of limited life
expectancy, lasting blood glucose values over 200 mg/dL appear unacceptable because they interfere with quality of life by inducing e.g. dehydration
and polyuria.
Hepatic Complications

Hepatic complications of long-term PN are fatty liver, non-alcoholic fatty liver disease and intrahepatic cholestasis as well as cholecystitis and
cholelithiasis. Hepatic complications may occur in 15-40% of patients (III).



4
Ursodeoxycholic acid may be tried in cholestatic liver disease (B). Phenobarbital or antibiotics have no demonstrated effect on hepatic
complications (II).
Biliary complications occur frequently - after 6 weeks of therapy, up to 100% of patients have sludge in the gallbladder (III).
Establishing at least a minimal enteral food intake is recommended to lower the risks of biliary complications (C).
Commentary
Fatty liver, non-alcoholic fatty liver disease, intrahepatic cholestasis, cholecystitis and cholelithiasis may occur with PN [36,37]. Fatty liver is the most
common complication, whereas intrahepatic cholestasis or hepatitis are less frequent. Hepatic complications are particularly frequent in paediatric
patients (cf. chapter "Neonatology/Paediatrics"). The etiology of the hepatic complications is unclear. Various factors such as unbalanced nutritional
supply (excess or deficiency of specific amino acids), hormonal factors, excess calories, lipids and bacterial overgrowth of the small intestine are
discussed [36-40]. Immaturity of the biliary secretory system and early infections seem to play an important role in paediatric patients. Potentially
hepatotoxic substances (drugs) should be avoided whenever possible.
Most studies on the hepatic complications of PN either refer to paediatric patients or were carried out at a time when a much larger amount of energy
was administered.
Ursodeoxycholic acid, phenobarbital and gentamycine have been evaluated for treatment therapy of PN induced cholestasis in clinical studies.
Improvement of cholestasis was reported with ursodeoxycholic acid but not with phenobarbital or gentamycin [41-43].
Biliary complications are enhanced by a lack of enteral food intake, while a minimal enteral nutrient intake may largely prevent the occurrence of sludge
[44]. Cholecystokinin and the rapid infusion of amino acid solution have been tested experimentally [36, 45-47] but not as part of clinical routine where
they seem impractical to apply.
Metabolic Bone Diseases


An adequate intake of calcium, phosphate and vitamin D intake should be approached with PN to help prevent and treat osteoporosis and
osteomalacia (C).
Bisphosphonates may be used for treating low bone density associated with PN (C).
Commentary
The prevalence and pathogenesis of osteomalacia and osteoporosis associated with PN is unclear, with the reported prevalence ranging from rare cases
to up to 40% of patients with long-term PN. Bone changes are probably linked to supoptimal calcium, phosphate and vitamin D intakes, lack of physical
activity, lack of light exposure with poor vitamin D status, and side-effects of other therapies (e.g. heparin, steroids) [48]. Therapeutic measures involve
approaching adequate substrate intakes as well as preventing other risks. A small study show improved bone density in PN patients receiving
pamidronate [49].
Monitoring
Monitoring of Clinical Efficiency

Regular monitoring is necessary in all types of PN. Efficient monitoring can result in reduced PN-associated complications and reduced costs (A).
Commentary
PN is associated with significant costs and sometimes serious complications. Regular clinical monitoring and diligent care of the patient are necessary to
support a good outcome. Nutritional monitoring of patients receiving PN is needed to determine efficiency, to discover and prevent complications, and to
document changes in the clinical course. Monitoring should preferably be carried out by a nutrition support team, which monitors efficiency and
sufficiency of PN with regards to specific endpoints. The definition of these endpoints should depend on the underlying illness of the patient, his/her
clinical state, the facilities available in the institution caring for the patient, and the requests of the individual patient [5, 14, 50, 51].
The aims of PN should be established according to specific markers and targets when the decision for PN is made. These goals can include the
maintenance or regeneration of protein inventory in cells, a drop in morbidity and mortality, an improvement in quality of life or an improvement in clinical
variables, e.g. a drop in LOS or treatment costs.
Most studies carried out on patients receiving artificial nutrition use surrogate variables of nutritional state as targets for outcome (Table 2). These
markers include energy balance, measures of body composition and body weight, determination of specific serum proteins, nitrogen balance, and
functional outcomes [20]. Many of these parameters are influenced by the course of disease or injury and thus, do not only reflect nutritional supply.
Nutritional state is an intermediate marker; while the aim of PN should ultimately be improvement in the clinical course and outcome. The monitoring of
such clinical variables like quality of life, morbidity and mortality, as well as LOS and costs is clearly more relevant.
Numerous clinical studies monitored PN patients, according to defined protocols, to evaluate the efficiency of a nutritional regime with certain markers.
Such studies have been carried out in intensive care patients with polytrauma, and in perioperative patients. Most frequently nitrogen balance,
concentrations of specific serum proteins and energy expenditure were used for the evaluation of the efficiency of a certain nutrition regime [52].
The extent to which such monitoring improves the patient's clinical outcomes such as morbidity, mortality, and quality of life is unknown, but it is
concluded that such monitoring is associated with an improved cost-benefit ratio. Three randomised prospective studies analysed the efficiency of
nutritional monitoring on prognosis and costs [20,25,53]. The main outcome was a significant drop in complications and costs compared to studies in
which such monitoring was not applied.
It is also important to perform target-oriented, consecutive re-evaluations of nutritional state. The parenteral substrate supply should be compared to the
predicted energy and protein requirements. Changes in the clinical state and level of activity may require a periodic recalculation of energy requirements.
Indirect calorimetry can be used, if the course appears to be unsatisfactory, to determine changes in the energy requirements and expenditure [54]. The
requirement for total PN therapy should be regularly reevaluated, particularly to explore whether it might be complemented or replaced by enteral or oral
feeding.
Table 2: Some approaches to monitoring PN effects
a) Clinical methods
Body Mass Index
Anthropometry (skinfold thickness and muscle circumference on the upper arm)
Creatinine -height index
Subjective Global Assessment
b) Laboratory methods
Plasma protein concentration (albumin, pre-albumin, retinol-binding protein)
Combined variables (Buzby Index, Prognostic Nutritional Index)
5
c) Physical methods
Bio-impedance analysis
Isotopic dilution (H2 18O)
Dynamometry (hand muscle power)
X-ray absorptiometry
Neutron activation
Metabolic Complications
Measures to prevent the refeeding syndrome

Water and electrolyte balance, blood sugar, and cardiovascular function should be regularly monitored in patients receiving PN in order to detect a
refeeding syndrome (C).
Commentary
Severely malnourished patients, in whom PN is provided after a long period of fasting, need to be strictly monitored. Water balance, cardiovascular
function and serum electrolytes should be carefully monitored at the start and during PN. Serum electrolyte shifts, particularly hypokalemia and
hypophosphataemia, should be corrected before starting PN. Sufficient thiamine intake should be established prior to PN. During the first week of PN,
fluid intake should be limited to approximately 800 ml/day plus compensation for insensible losses thereby avoiding both fluid overload and dehydration.
Daily monitoring of body weight can aid in determining the necessary fluid volume. A weight gain of >0.25 kg/day or 1.5 kg/week likely is typically
indicative of fluid accumulation and not of an improved nutritional state. The amount of carbohydrates administered daily should not exceed 2-3 g/kg
body weight/day and blood glucose concentration should be strictly monitored because of the high risk of hyperglycaemia. Patients with normal renal
function should be generously substituted with phosphate, potassium and magnesium with appropriate laboratory checks. It is necessary to check also
the fluid balance (fluid intake, urine production) on a daily basis [14].
Blood Glucose Monitoring

Depending on the patient's individual risk, blood glucose should be closely checked during PN in view of an inverse correlation between the extent
or duration of hyperglycaemia and patient outcome (A).
Commentary
Hypo- and hyperglycaemia are the most severe metabolic complications occuring in patients receiving PN. Some 7% of patients on PN who receive a
maximum of 5 mg/kg/min. glucose, develop hyperglycaemia (blood glucose >200 mg/dL). If patients receive more than 5 mg/kg/min glucose, the
hyperglycaemia rate rises to almost 50% [51]. Patients with diabetes mellitus, systemic steroid therapy or organ failure were excluded in the latter study.
In extreme cases, such hyperglycaemia can result in hyperosmolar hyperglycaemic coma, and mortality can increase up to 14% in patients over 50 years
of age [50]. In addition to increased blood glucose concentrations, neurological symptoms like dementia, slowdown or lethargy often occur, preceding the
actual coma. Thus, careful and regular examination of clinical-neurological symptoms is necessary for monitoring and diagnosis of hyperglycaemiaassociated side effects. It is recommended that the maximum glucose intake should not exceed 3-4 mg/kg/min. Hyperglycaemic complications are
intensified by underlying disease such as diabetes mellitus or surgical trauma. Strict control and monitoring of blood glucose concentration (diurnal blood
glucose profile with 3-4 values daily) is recommended particularly in these patients, because hyperglycaemia is associated with impaired immune
function and increased rates of infection.
The frequency of severe hypoglycaemia whilst receiving insulin therapy (as an adjunct to PN) has greatly increased because of the wide use of
intravenous insulin for lowering of blood glucose concentration below 150 mg/dL. The incidence ranges between 4 and 5% [5] and is accompanied by
severe neurological function deficits. Therefore, it is of utmost importance to strictly control the blood glucose concentration especially with intravenous
insulin therapy. Checks may be carried out every 2-3 hours in unstable patients and those with short-term insulin dosage changes [20].
Special attention is necessary if there is a sudden withdrawal of carbohydrate and insulin intake under insulin therapy. Severe hypoglycaemia can occur
due to the longer biological effect of insulin (15-30 min). It may be necessary to prophylactically continue the carbohydrate supply beyond the end of
insulin supply in case of low blood glucose levels to prevent rebound hypoglycaemia with unmeasurably low blood glucose concentrations.
Further monitoring measures



Regular checks of serum electrolytes and triglycerides are necessary with PN (A).
Enhanced monitoring is necessary in patients with altered renal function, electrolyte-free substrate intake, lipid infusions, and in intensive care
patients (C).
The metabolic monitoring of patients under long-term PN should be carried out according to standardised procedures (C).
Commentary
Marked increases in plasma triglyceride concentrations may occur in patients receiving intravenous lipids. The frequency of such hypertriglyceridemia
during a 7-day PN is up to 26% in unselected patients [25]. If left unnoticed and untreated, severe hypertriglyceridemia might induce pancreatitis and
changes in lung function. Therefore, regular monitoring of plasma triglyceride concentrations whilst providing parenteral lipid intake is recommended.
Pathological alterations of the acid-base status are often observed in PN patients. On average, pathological partial pressures of CO2 are present in 13%
of cases, and abnormal values for serum chloride concentrations are found in 1-7% of cases [52]. These changes occur as a result of PN induced
increases in glucose oxidation or associated CO2 production. It may be difficult to correct specific imbalances that develop with severe ileus or renal
failure when using fixed, predetermined electrolyte concentrations in the PN solutions. As acid-base balance and electrolyte balance are closely linked,
serum electrolytes as well as the acid-base status should be regularly monitored, particularly in intensive care patients and patients with altered renal
function. The necessary targets for the monitoring of complications are shown in Table 3 and Table 4.
Table 3: Measures for the Monitoring Patients on PN (according to [53]).
1. Clinical monitoring
a.
b.
c.
d.
Neurological status
Check for oedema in dependent body parts
Clinically manifest signs of malnutrition
Extent of physical activity
2. Vital Functions
6
a. Respiratory rate, type of breathing
Gas exchange with O2 partial pressure, CO2 partial pressure, oxygen saturation
b. Haemodynamics (heart rate, systolic and diastolic blood pressures)
c. Water and electrolyte status, acid base status /pH
d. Haematocrit, osmolality, sodium, potassium, glucose, lactate, triglyceride levels
e. Parameters reflecting in the renal function:
Urine volume per time, plasma concentrations of urea and creatinine
Table 4: Laboratory Monitoring Programme for Patients with long-term PN (Mayo diagram [55])
Parameters
Sample
Material
Default
Week 1 Week 2 Week 3 Week 4 Week 6 Week 8 Month: Month Month Month Quarterly Annually
Value
before
start
of
Nutrition
Sodium
P.S.
+
+
+
+
+
+
+
+
+
+
+
+
+
Potassium
P.S.
+
+
+
+
+
+
+
+
+
+
+
+
+
Chloride
P.S.
+
+
+
+
+
+
+
+
+
+
+
+
+
Bicarbonate
P
+
+
+
+
+
+
+
+
+
+
+
+
+
Creatinine
P.S.
+
+
+
+
+
+
+
+
+
+
+
+
+
Urea
S
+
+
+
+
+
+
+
+
+
+
+
+
+
Calcium
S
+
+
+
+
+
+
+
+
+
Phosphate
S
+
+
+
+
+
+
+
+
+
Glucose
P.S.WB
+
+
+
+
+
+
+
+
+
Alkaline
Phosphatase
S
+
+
+
+
+
+
+
Bilirubin
(tot. a. dir)
S
+
+
+
+
+
+
+
+
+
Total protein
S
+
+
+
+
+
+
+
+
+
Albumin
S
+
+
+
+
+
+
+
+
+
AST
S
+
+
+
+
+
+
+
+
+
Uric acid
S
+
+
+
+
+
+
Copper
S
+
Zink
S
+
Magnesium
S
+
Selenium
S
+
Manganese
S.WB
+
Ferritin
S
+
S
+
Time
P
+
+
Folic acid
S
+
+
Vitamin B12
S
+
+
Vitamin A,E
S
+
+
Vitamin C
P
25 OH Vit.D
S
Parathormone
S
Haemogram
WB
Urinary Creatinine
24-h
urine
+
Urinary Calcium
24-h
urine
+
Urinary Magnesium
24-h
urine
+
Urinary Sodium
24-h
urine
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Alkaline
Phosphatase
Isoenzymes
+
Prothrombin-
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
P = Plasma, S = Serum, WB = Whole Blood
7
Special monitoring measures in long-term PN patients

The metabolic determinants of bone metabolism should be monitored in patients receiving long-term PN. Markers of intermediary, electrolyte and
trace element metabolism require regular checks (C).
Commentary
Maintenance of physiological bone metabolism requires adequate serum concentrations of vitamin D, calcium, magnesium and phosphate. In long-term
PN patients, severe disorders resulting in osteoporosis and fractures may occur. The parenterally administered substrates or cyclic infusion favour renal
calcium excretion. This hypercalciuria is closely associated with the PN associated metabolic bone disease (PN-MBD) [54].
Monitoring of bone density by dual energy X-ray absorptiometry (DEXA) or peripheral quantitative computer tomography (pqCT) is recommended.
Recommendations are available for diagnosing or monitoring at-risk patients or patients with bone-related complaints (Table 5) [54].
Table 5: Monitoring and Clarification of Patients with Metabolic Bone Diseases receiving PN (according to [54]).
Parameter
Commentary
Serum
Calcium, ionised calcium, magnesium, phosphate before beginning the therapy and
then 1 x weekly for at least 3 months.
iPTH
Suspicion of malabsorption or
hyperparathyroidism
25-hydroxvitamin D
Suspicion of malabsorption
TSH
Suspicion of hyperparathyroidism
N-telopeptide collagen
Proof of a metabolic bone disease
Urine
24-hour excretion of calcium and magnesium
regular monitoring every 6-12 months
X-ray examinations,
before the beginning of therapy and then
DEXA
depending on clinical complaints
iPTH = intact Parathormone; TSH = Thyroid stimulating hormone, DEXA = Dual energy X-ray absorptiometry
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16. Guedon C, Schmitz J, Lerebours E et al. Decreased brush border hydrolase activities without gross morphologic changes in human intestinal mucosa
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17. Pironi L, Paganelli GM, Miglioli M et al. Morphologic and cytoproliferative patterns of duodenal mucosa in two patients after long-term total parenteral
nutrition: changes with oral refeeding and relation to intestinal resection. JPEN J Parenter Enteral Nutr 1994; 18: 351-354
18. Sedman PC, MacFie J, Palmer MD, Mitchell CJ, Sagar PM. Preoperative total parenteral nutrition is not associated with mucosal atrophy or bacterial
translocation in humans. Br J Surg 1995; 82: 1663-1667
19. van der Hulst RR, van Kreel BK, von Meyenfeldt MF et al. Glutamine and the preservation of gut integrity. Lancet 1993; 341: 1363-1365
20. van der Hulst RR, von Meyenfeldt MF, Tiebosch A, Buurman WA, Soeters PB. Glutamine and intestinal immune cells in humans. JPEN J Parenter
Enteral Nutr 1997; 21: 310-315
21. van der Hulst RR, von Meyenfeldt MF, Deutz NE, Stockbrugger RW, Soeters PB. The effect of glutamine administration on intestinal glutamine content. J
Surg Res 1996; 61: 30-34
22. Ahlman B, Ljungqvist O, Persson B, Bindslev L, Wernerman J. Intestinal amino acid content in critically ill patients. JPEN J Parenter Enteral Nutr 1995;
19: 272-278
23. Hadfield RJ, Sinclair DG, Houldsworth PE, Evans TW. Effects of enteral and parenteral nutrition on gut mucosal permeability in the critically ill. Am J
Respir Crit Care Med 1995; 152: 1545-1548
24. No authors listed. Safe Practices for Parenteral Nutrition Formulations. National Advisory Group on Standards and Practice Guidelines for Parenteral
Nutrition. JPEN J Parenter Enteral Nutr 1998; 22: 49-66
25. Llop J, Sabin P, Garau M et al. The importance of clinical factors in parenteral nutrition-associated hypertriglyceridemia. Clin Nutr 2003; 22: 577-583
26. Finney SJ, Zekveld C, Elia A, Evans TW. Glucose control and mortality in critically ill patients. JAMA 2003; 290: 2041-2047
27. Malmberg K. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes
mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. BMJ 1997; 314: 1512-1515
28. Meier JJ, Deifuß S, Gallwitz B, Klamann A, Schmiegel W, Nauck MA. [Influence of impaired glucose tolerance on long-term survival after acute
myocardial infarction]. Article in German. Dtsch Med Wochenschr 2002; 127: 1123-1129
29. Norhammar AM, Ryden L, Malmberg K. Admission plasma glucose. Independent risk factor for long-term prognosis after myocardial infarction even in
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nondiabetic patients. Diabetes Care 1999; 22: 1827-1831
30. Parsons MW, Barber PA, Desmond PM et al. Acute hyperglycemia adversely affects stroke outcome: a magnetic resonance imaging and spectroscopy
study. Ann Neurol 2002; 52: 20-28
31. Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE. Hyperglycemia: an independent marker of in-hospital mortality in patients with
undiagnosed diabetes. J Clin Endocrinol Metab 2002; 87: 978-982
32. van den Berghe G, Wouters P, Weekers F et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001; 345: 1359-1367
33. Weir CJ, Murray GD, Dyker AG, Lees KR. Is hyperglycaemia an independent predictor of poor outcome after acute stroke? Results of a long-term follow
up study. BMJ 1997; 314: 1303-1306
34. Zindrou D, Taylor KM, Bagger JP. Admission plasma glucose: an independent risk factor in nondiabetic women after coronary artery bypass grafting.
Diabetes Care 2001; 24: 1634-1639
35. Kim H, Son E, Kim J et al. Association of hyperglycemia and markers of hepatic dysfunction with dextrose infusion rates in Korean patients receiving total
parenteral nutrition. Am J Health Syst Pharm 2003; 60: 1760-1766
36. Angelico M, Della GP. Review article: hepatobiliary complications associated with total parenteral nutrition. Aliment Pharmacol Ther 2000; 14 Suppl 2:
54-57
37. Chung C, Buchman AL. Postoperative jaundice and total parenteral nutrition-associated hepatic dysfunction. Clin Liver Dis 2002; 6: 1067-1084
38. Adamkin DH. Total parenteral nutrition-associated cholestasis: prematurity or amino acids? J Perinatol 2003; 23: 437-438
39. Forchielli ML, Walker WA. Nutritional factors contributing to the development of cholestasis during total parenteral nutrition. Adv Pediatr 2003; 50: 245267
40. Sandhu IS, Jarvis C, Everson GT. Total parenteral nutrition and cholestasis. Clin Liver Dis 1999; 3: 489-508, viii
41. Gleghorn EE, Merritt RJ, Subramanian N, Ramos A. Phenobarbital does not prevent total parenteral nutrition-associated cholestasis in noninfected
neonates. JPEN J Parenter Enteral Nutr 1986; 10: 282-283
42. Spagnuolo MI, Iorio R, Vegnente A, Guarino A. Ursodeoxycholic acid for treatment of cholestasis in children on long-term total parenteral nutrition: a pilot
study. Gastroenterology 1996; 111: 716-719
43. Spurr SG, Grylack LJ, Mehta NR. Hyperalimentation-associated neonatal cholestasis: effect of oral gentamicin. JPEN J Parenter Enteral Nutr 1989; 13:
633-636
44. Buchman AL. Complications of long-term home total parenteral nutrition: their identification, prevention and treatment. Dig Dis Sci 2001; 46: 1-18
45. Doty JE, Pitt HA, Porter-Fink V, Denbesten L. Cholecystokinin prophylaxis of parenteral nutrition-induced gallbladder disease. Ann Surg 1985; 201: 7680
46. Kalfarentzos F, Vagenas C, Michail A et al. Gallbladder contraction after administration of intravenous amino acids and long-chain triacylglycerols in
humans. Nutrition 1991; 7: 347-349
47. Sitzmann JV, Pitt HA, Steinborn PA, Pasha ZR, Sanders RC. Cholecystokinin prevents parenteral nutrition induced biliary sludge in humans. Surg
Gynecol Obstet 1990; 170: 25-31
48. Cohen-Solal M, Baudoin C, Joly F et al. Osteoporosis in patients on long-term home parenteral nutrition: a longitudinal study. J Bone Miner Res 2003;
18: 1989-1994
49. Nishikawa RA. Intravenous pamidronate improves bone mineral density in home parenteral nutrition patients. Clin Nutr 2003; 22: 88-88
50. Kaminski MV, Jr. A review of hypersomolar hyperglycemic nonketotic dehydration (HHND): etiology, pathophysiology and prevention during intravenous
hyperalimentation. JPEN J Parenter Enteral Nutr 1978; 2: 690-698
51. Rosmarin DK, Wardlaw GM, Mirtallo J. Hyperglycemia associated with high, continuous infusion rates of total parenteral nutrition dextrose. Nutr Clin
Pract 1996; 11: 151-156
52. Owens JP, Geibig CB, Mirtallo JM. Concurrent quality assurance for a nutrition-support service. Am J Hosp Pharm 1989; 46: 2469-2476
53. Grünert A. [Monitoring patients on nutritional therapy--biophysical and biochemical measurement values]. Article in German. Klin Anasthesiol Intensivther
1990; 40: 193-195
54. Seidner DL. Parenteral nutrition-associated metabolic bone disease. JPEN J Parenter Enteral Nutr 2002; 26: S37-S42
55. Kelly DG. Guidelines and available products for parenteral vitamins and trace elements. JPEN J Parenter Enteral Nutr 2002; 26: S34-S36
see Parenteral Nutrition Overview 073-018.htm and Chapter 1: Introduction and Methodology 073-018e_01.htm
Hartl WH1, Jauch KW1, Parhofer K2, Rittler P1*
1Dept
Surgery Grosshadern, University Hospital, Munich; 2Dept. Medicine II, University of Munich for the working group for developing the guidelines for
parenteral nutrition of The German Association for Nutritional Medicine
* English version edited by Sabine Verwied-Jorky, Rashmi Mittal and Berthold Koletzko, Univ. of Munich Medical Centre, Munich, Germany
Erstellungsdatum:
04/2014
9
AWMF online - Guidelines on Parenteral Nutrition: Ethical and Legal Points of View in Parenteral Nutrition
1
AWMF online
Wissenschaftlichen
Medizinischen
Fachgesellschaften
Nr. 073-018e_12
Entwicklungsstufe:
3
Zitierbare Quelle:
Chapter 12: Ethical and Legal Points of View in
Kapitel 12: Ethische und rechtliche Aspekte der parenteralen Ernährung
Abstract
Adequate nutrition is a part of medical treatment and is influenced by ethical and legal considerations. Patients,
who cannot be sufficiently fed via the gastrointestinal tract, have the fundamental right to receive PN (parenteral
nutrition) even so patients who are unable to give their consent. General objectives in nutrition support are to
supply adequate nutrition with regards to the prevention of malnutrition and its consequences (increased
morbidity and mortality), and thereby promoting improved outcome and/or quality of life for the patient
considering always the patient's needs and wishes. The requests of the patient to renounce PN should be
respected where a signed living will is helpful. During the course of a terminal illness the nutrition has to be
adapted individually according to the needs and wishes of a patient in the corresponding phase. Capability of
consent should be checked in each individual case and for each measure on an individual basis. Consent
should only be accepted if the patient is capable of recognizing the nature, meaning and importance of the
intervention as well as the consequences of relinquishment of such an intervention, and is capable to make a
self-determined decision. If the patient is not capable of consenting, the patient's living will is the most important
document when determining their assumed will and legally binding. Otherwise a guardian appointed by the
patient, or the representative appointed by the court (if the patient has made no provisions) can make the
decision.
Zusammenfassung
Eine angemessene Ernährung ist Teil des medizinischen Behandlungsauftrags und wird in hohem Maße durch
ethische und rechtliche Überlegungen beeinflusst. Patienten, die über den Gastrointestinaltrakt nicht
ausreichend ernährt werden können, haben grundsätzlich Anspruch auf PE (parenterale Ernährung).
Allgemeine Ziele der Ernährungstherapie sind die Gewährleistung einer im Hinblick auf Grundkrankheit und
Ernährungszustand adäquaten Ernährung, das Vorbeugen einer Mangelernährung und deren Folgen - erhöhte
Morbidität und Mortalität - und somit letztlich die Verbesserung der Prognose oder der subjektiven
Lebensqualität des Patienten unter Berücksichtigung der Bedürfnisse und Wünsche des Patienten. Der Wille
des Patienten zum Verzicht auf PE ist zu respektieren, wobei eine vorhandene unterschriebene
Patientenverfügung hilfreich ist. Im Verlauf einer unheilbaren Erkrankung muss die Ernährung an die jeweilige
Phase individuell unter Berücksichtigung der Bedürfnisse und Wünsche des Patienten angepasst werden. Die
Einwilligungsfähigkeit ist in jedem Einzelfall und für jede Maßnahme erneut zu überprüfen und dann
anzunehmen, wenn der Patient in der Lage ist, Wesen, Bedeutung und Trageweite des Eingriffs sowie des
2
Verzichts auf einen solchen zu erkennen und eine selbst bestimmte Entscheidung zu treffen. Wenn der Patient
nicht einwilligungsfähig ist, ist vor allem die Patientenverfügung das wichtigste Indiz bei der Ermittlung des
mutmaßlichen Willens des Patienten und rechtlich verbindlich. Liegt diese nicht vor, entscheidet der von ihm
benannte Vorsorgebevollmächtigte oder, falls der Patient insoweit keine Vorsorge getroffen hat, der vom Gericht
bestellte Betreuer.
Preamble
Adequate nutrition is a part of medical treatment. Nutrition has a particular effect on the communicative and
social needs of a person, and this is why questions regarding the commencement and cessation of PN are, to a
great extent, influenced by ethical and legal considerations. In this section, criteria for decision making, legal
requirements and potential procedural steps are presented to enable competent decision-making.
Fundamentals
Patients, who cannot be sufficiently fed via the gastrointestinal tract, have the fundamental right to receive PN.
This also applies to the growing group of patients who are unable to give their consent. General objectives in
nutrition support are to supply adequate nutrition with regards to the prevention of malnutrition and its
consequences (increased morbidity and mortality), and thereby promoting improved outcome and/or quality of
life for the patient. In the individual patient, the specific objectives of nutritional support are determined
considering the patient's needs. Nutrition support should prevent weight loss, aims at improving the nutritional
state and at providing a benefit on the overall clinical situation. In contrast, the aim of palliative nutrition carried
out in patients with terminal diseases is support quality of life.
The decisions to start and to end PN should be made by the physician-in-charge, in consideration of the
patient's wishes. Other caregivers involved in the treatment and relatives should also be involved in the
decision-making process whenever possible and appropriate. In case of diverging views, an ethical consultation
is strongly recommended.
The requests of the patient to renounce PN should be respected. In the case of non-existing informed consent
and the necessity to determine the presumable wishes of a patient, it is helpful if the patient has previously
recorded such wishes and mentioned the situations in which it should be followed, e.g. in a living will. The
patient's medical consultation should include possible indications for enteral or parenteral nutrition as well as the
consequences of relinquishing nutrition and fluid intake in the various phases of an illness, when drawing up a
living will
Indications for PN
The medical indication for artificial nutrition is classically present when the patient is not "allowed to or cannot"
eat or be enterally fed. PN is indicated if the gastrointestinal tract is partially functioning or not functioning at all.
Severe malnutrition may also be an indication for (at least partial) PN despite the possibility to provide enteral
nutrition.
Medical, legal and ethical issues, as described below, are to be considered when deciding on the indication for
artificial nutritional support. In the evaluation of medical criteria, it should be noted that a good nutritional state
has a positive influence not only on outcome but also on subjective quality of life. Imminent malnutrition must be
treated as an adverse risk factor for outcome.
In defining an indication for PN, there should be clarity as to the purpose and objective of PN, and the attitude of
the patient towards it. The will of the patient, the prognosis and the subjective quality of life often changes
repeatedly with treatment and duringthe course of a disease. Therefore, the indication of PN should be reviewed
on a regular basis.
Contraindications
In addition to absolute medical contraindications, PN is also contraindicated when the patient can be sufficiently
fed either orally or enterally via a nasogastric tube or PEG/PEJ, respectively. For legal and ethical reasons PN
has to be omitted if the patient refuses to consent to PN or if the refusal is apparent from the presumed will,
given the patient has known the ledge of possible consequences.
Medical Responsibility in Terminal Care
3
The course of a terminal illness can be divided into the rehabilitation phase, preterminal phase and terminal
phase [1]. The treatment objective during the rehabilitation phase, which can sometimes last for years, is to
return or maintain the patient's independence and level of performance. Therapeutic objectives and the main
focus of care need to be re-established in the preterminal phase, which can last weeks and months, and in the
terminal phase during which the death of the patient is imminent [1-4]. The main objectives in these last phases
are to alleviate symptoms and suffering, maintaining quality of life, enabling self-determination and supporting a
"good death" [1, 3-9]. Classical objectives of nutrition, such as maintaining nutritional status, retaining functions,
and a positive influence on the course of illness or life span, are of little relevance in terminal care.
The task of suppressing uncomfortable feelings of hunger and thirst are of prime importance. The needs and
wishes of the patient may change during the last phase of life, where individual person differ in the behaviour
and needs until their death. Artificial nutrition is only indicated after carefully considering the potential risks and
benefits based on the new objectives [1-3, 8, 9]. According to studies, patients often have a dry mouth,
premature feeling of satiation, sickness and dysgeusia, but rarely feel hungry and thirsty. Hunger and thirst can,
however, often be addressed with only small amounts of oral fluid and food intake. Indiscriminate and high fluid
intake can be problematic if it results in oedema (particularly pulmonary oedema), shortness of breath, nausea,
vomiting, and increased urine production. A detailed observation of the patients is necessary, as symptoms of
xerostomia and thirst do not correlate with the body's hydration state. Parenteral fluid intake does not always
result in improvements of thirst symptoms. The feelings of xerostomia and thirst are also caused by medications,
oxygen therapy, breathing through the mouth as well as fear and depression. Measures such as lip care
(cleaning and retaining moisture in lips) and mouth care with mouth washes, frequent offers of fluids, and the
application of ice chips or ice cubes should be the main interventions at the outset of treating xerostomia and
thirst [1, 2, 7, 9-11]. Hydration may be necessary if a patient still complains of thirst despite good care. Further
reasons may be sudden, unexplained confusion, unexplained agitation as well as the increased toxic actions of
drugs. Low amounts of fluid, i.e. 1000 ml/24 h, should be administered via peripheral access in order to prevent
dehydration [3, 7-9].
Legal Aspects
Patients capable of giving consent
The insertion of a central venous catheter and administration of PN are legally assessed as physical bodily
harm, which are, therefore, only permissible with the patient's consent [12-16]. As long as the patient is capable
of consenting, she/he will be the sole receiver of a comprehensive document of clarification, which must contain
potential complications and risks as well as the consequences of not having treatment. Consent and clarification
of the patient must be documented.
Capability of consent does not mean legal capability in terms of civil law. Children and teenagers over the age of
14 are usually capable of giving consent. Patients, for whom a legal guardian has been appointed due to health
matters also remain potentially capable of consent in all areas. Capability of consent should be checked in each
individual case and for each measure on an individual basis. Consent should only be accepted if the patient is
capable of recognizing the nature, meaning and importance of the intervention as well as the consequences of
relinquishment of such an intervention, and is capable to make a self-determined decision. If the capability of
consent has been established by the physician, the opinion of the guardian, relatives or persons responsible for
the care and custody of the patient is legally irrelevant [5, 12].
Capability of consent can be lifted for complex questions, but may remain for simple questions. It, therefore,
should be checked whether the decision for or against nutrition can be fully understood, intellectually and
emotionally, by the patient [5, 12].
Patients who are not capable of consenting
If the patient is not capable of consenting, a guardian appointed by the patient, or the representative appointed
by the court (if the patient has made no provisions) can make the decision. The commencement of legal
proceedings to appoint a guardian is only legally waived in urgent cases. The local court is responsible.
The patient's living will is the most important document when determining their assumed will. If the patient has
made statements in a living will regarding PN and situations in which it is to be rejected, then this living will is
legally binding for the doctors, guardians and representatives according to current jurisdiction [13, 14] and the
guidelines of the Federal Chamber of Physicians [6,17]. A legal investigation of nutrition withdrawal is only
necessary (according to the current jurisdiction of the Federal Court of Justice [13,14]) when there is an
indication for nutrition from a medical point of view, but the guardian chooses to go against medical advice and
refuse nutrition, and the issue cannot be resolved.
4
Although the decision to introduce PN can necessitate the commencement of guardianship proceedings, it does
not require judicial authorisation. An analogous use of § 1904 of the German Civil Code does not come into
consideration despite the existing risks of inserting a central venous catheter, because although the risk of death
cannot be completely excluded due to the risk of infection, the insertion of a central venous catheter is not
evaluated as "typically life threatening" in terms of § 1904 of the German Civil Code.
Individual Questions on Liability and Organisation
Prescription and administration of PN is the task of the doctor. The doctor remains responsible even if individual
steps are delegated to nursing staff. The personal responsibility of the pharmacist for the preparation and mixing
of the composition remains unaffected. The compositions used and the quantity prescribed, as well as the serial
number of the bag, should be documented.
References
1. Richter G. Ernährungs- und Flüssigkeitstherapie in der Terminalphase des Lebens: Ethische und medizinische
Grundlagen. In: Schauder P, Ollenschläger G (Hrsg.). Ernährungsmedizin - Prävention und Therapie. München:
Urban & Fischer, 2003: 933-953
2. ASPEN Board of Directors and the Clinical Guidelines Task Force. Guidelines for the use of parenteral and
enteral nutrition in adult and pediatric patients. JPEN J Parenter Enteral Nutr 2002; 26: 1SA-138SA
3. Bruera E, MacDonald N. To hydrate or not to hydrate: how should it be? J Clin Oncol 2003; 21: 84-86
4. Fainsinger RL, Bruera E. When to treat dehydration in a terminally ill patient? Support Care Cancer 1997; 5:
205-211
5. Körner U, Biermann E, Bühler E et al. DGEM Leitlinie Enterale Ernährung: Ethische und rechtliche
Gesichtspunkte. Akt Ernähr Med 2003; 28: 36-41
6. Bundesärztekammer. Grundsätze der Bundesärztekammer zur ärztlichen Sterbebegleitung. Deutsches
Ärzteblatt 2004; 101(19): A1298-A1299
7. Bruera E, Belzile M, Watanabe S, Fainsinger RL. Volume of hydration in terminal cancer patients. Support Care
Cancer 1996; 4: 147-150
8. Ludwig C. Bedarf die terminale Dehydration der Korrektur? In: Arends J, Aulbert E (Hrsg.). Beiträge zur
Palliativmedizin. Band 4 Ernährung und Flüssigkeitssubstitution in der Palliativmedizin. Stuttgart: Schattauer,
2001: 56-58
9. Binsack T. Ernährungs- und Flüssigkeitszufuhr bei Todkranken. Münch Med Wochenschr 1994; 136: 550-551
10. Kolb C. Nahrungsverweigerung bei Demenzkranken. PEG-Sonde - ja oder nein? Frankfurt am Main: MabuseVerlag GmbH, 2003
11. Mayer J, Nagel E. Künstliche Ernährung aus ethischer Sicht. In: Hartig W, Biesalski HK, Druml W, Fürst P,
Weimann A (Hrsg.). Ernährungs- und Infusionstherapie. Stuttgart: Thieme, 2003: 745-754
12. Rothärmel S. Einleitung und Abbruch der künstlichen Ernährung. Wer entscheidet bei einem nicht
einwilligungsfähigen Patienten? Der Internist 2004; 45: 485-491
13. BGH. "Lübecker Beschluss" vom 17. März 2003 - XII ZB 2/03 (Schleswig). Neue Juristische Wochenschrift
2003; 1588ff14. OLG Karlsruhe. Genehmigung des Vormundschaftsgerichts zum Abbruch lebensverlängernder Maßnahmen
(Beschluss vom 26.03.2004 - 11 Wx 13/04). Neue Juristische Wochenschrift 2004; 1882-1883
15. Hufen F. Verfassungsrechtliche Grenzen des Richterrechts. Zeitschrift für Rechtspolitik 2003; 248-252
16. BGH. "Kemptener Urteil" vom 13.9.1994 (1 StR 357/94). BGHSt 1994; 40: 257ff17. Bundesärztekammer. Handreichungen für Ärzte zum Umgang mit Patientenverfügungen. Deutsches Ärzteblatt
1999; 96(43): A2720-A2721
Rothaermel S1, Bischoff SC2, Bockenheimer-Lucius G3, Frewer A4, Wehkamp KH5, Zuercher G6 *
1Institute
for Biological, Health and Medical Law, University of Augsburg, 2Dept. Nutritional Medicine and
Prevention, University Stuttgart-Hohenheim, 3Senckenberg Institute for the History and Ethics of Medicine,
University of Frankfurt, 4Dept. of History, Ethics and Philosophy of Medicine, Medical University Hannover,
5University for Applied Science, Hamburg, 6Dept. of Internal Medicine I, University of Freiburg for the working
5
group for developing the guidelines for parenteral nutrition of The German Association for Nutritional Medicine
Erstellungsdatum:
04/2014
AWMF online - Guidelines on Parenteral Nutrition: Neonatology/Paediatrics
1
AWMF online
Wissenschaftlichen
Medizinischen
Fachgesellschaften
Nr. 073-018e_13
Entwicklungsstufe:
3
Zitierbare Quelle:
Chapter 13: Neonatology/Paediatrics
Kapitel 13: Neonatologie/Pädiatrie
Key words: Premature infant, low birth weight infant, newborn infant, monitoring, childhood
Schlüsselwörter: Frühgeborenes, Low birth weight infant, Neugeborenes, Monitoring, Kindheit
Abstract
There are special challenges in implementing parenteral nutrition (PN) in paediatric patients, which arises from
the wide range of patients, ranging from extremely premature infants up to teenagers weighing up to and over
100 kg, and their varying substrate requirements. Age and maturity-related changes of the metabolism and fluid
and nutrient requirements must be taken into consideration along with the clinical situation during which PN is
applied. The indication, the procedure as well as the intake of fluid and substrates are very different to that
known in PN-practice in adult patients, e.g. the fluid, nutrient and energy needs of premature infants and
newborns per kg body weight are markedly higher than of older paediatric and adult patients. Premature infants
<35 weeks of pregnancy and most sick term infants usually require full or partial PN. In neonates the actual
amount of PN administered must be calculated (not estimated). Enteral nutrition should be gradually introduced
and should replace PN as quickly as possible in order to minimise any side-effects from exposure to PN.
Inadequate substrate intake in early infancy can cause long-term detrimental effects in terms of metabolic
programming of the risk of illness in later life. If energy and nutrient demands in children and adolescents cannot
be met through enteral nutrition, partial or total PN should be considered within 7 days or less depending on the
nutritional state and clinical conditions.
Zusammenfassung
Eine besondere Herausforderung bei der Durchführung parenteraler Ernährung (PE) bei pädiatrischen Patienten
ergibt sich aus der großen Spannbreite zwischen den Patienten, die von extrem unreifen Frühgeborenen bis hin
zu Jugendlichen mit einem Körpergewicht von mehr als 100 kg reicht, und ihrem unterschiedlichen
Substratbedarf. Dabei sind alters- und reifeabhängige Veränderungen des Stoffwechsels sowie des
Flüssigkeits- und Nährstoffbedarfs zu berücksichtigen sowie auch die klinische Situation, in der eine PE
eingesetzt wird. Das Vorgehen unterscheidet sich deshalb ganz erheblich von der PE-Praxis bei erwachsenen
Patienten, z.B. ist der Flüssigkeits-, Nährstoff- und Energiebedarf von Früh- und Neugeborenen pro kg
Körpergewicht höher als bei älteren pädiatrischen und bei erwachsenen Patienten. In der Regel benötigen alle
Frühgeborenen <35. SSW und alle kranken Reifgeborenen während der Phase des allmählichen Aufbaus der
enteralen Nahrungszufuhr eine vollständige oder partielle PE. Die Zufuhrmengen der PE bei Neonaten müssen
berechnet (nicht geschätzt) werden. Der Anteil der PE sollte zur Minimierung von Nebenwirkungen sobald wie
möglich durch Einführung einer enteralen Ernährung vermindert (teilparenterale Ernährung) und schließlich
2
komplett durch enterale Ernährung abgelöst werden. Eine unangemessene Substratzufuhr im frühen
Säuglingsalter kann langfristig nachteilige Auswirkungen im Sinne einer metabolischen Programmierung des
Krankheitsrisikos im späteren Lebensalter haben. Wenn bei älteren Kindern und Jugendlichen dagegen der
Energie- und Nährstoffbedarf eines Patienten im Vorschul- oder Schulalter durch eine enterale Nährstoffzufuhr
nicht gedeckt werden kann, ist abhängig von Ernährungszustand und klinischen Umständen spätestens
innerhalb von 7 Tagen eine partielle oder totale PE zu erwägen.
Preliminary Remarks
The majority of recommendations on substrate intake (with the exception of the chapters on "Amino Acid
Requirements" and "Information on the Selection and Production of Amino Acid Solutions" in the attachment,
which have been specially drawn up for this set of guidelines) have been drawn up according to the "Guidelines
on Paediatric Parenteral Nutrition", a combined study group from the European Society of Paediatric
Gastroenterology, Hepatology and Nutrition (ESPGHAN, www.espghan.org external link) and the European
Society for Clinical Nutrition and Metabolism (ESPEN, www.espen.org external link) [1]. Systematic literature
research has already been carried out for the development of the European guidelines, therefore further
research for the current guidelines was unnecessary.
Introduction
Systematic review in a number of fields produced a series of published studies from which evidence-based
recommendations can be drawn up for the neonatal period (1-28 days) and period of infancy (1-12 months). The
situation in children and teenagers is, however, different with extremely limited data available from randomised
controlled clinical studies on children after the neonatal period.
There is a special challenge in implementing parenteral nutrition (PN) in paediatric patients, which arises from
the wide range of patients, ranging from extremely premature infants up to teenagers weighing up to and over
100 kg, and their varying substrate requirements. Age and maturity-related changes of the metabolism and fluid
and nutrient requirements must be taken into consideration along with the clinical situation during which PN is
applied. The indication, the procedure as well as the intake of fluid and substrates are very different to that
known in PN-practice in adult patients Therefore, it makes sense to briefly present some of physiological
features of paediatric patients that are significant for PN in order to understand the nutritional strategies used for
children and teenagers.
 The fluid, nutrient and energy intake of premature infants and newborns is higher per kg body weight than
that of older paediatric and adult patients (II).
 The substrate requirements of paediatric patients cannot be proportionally derived from adult
requirements on the basis of body weight, but are determined according to age-specific, physiological
conditions (II).
 The fluid, nutrient and energy intake during the post-partal adaptation and stabilisation phase is subject to
specific conditions, which necessitates a specific approach. (II).
 In comparison to older paediatric patients or adults, newborns and infants have an extremely low body
store of nutrients and in many respects immature regulatory mechanisms, thus requiring an carefully
adapted intake to suit their specific requirements in order to prevent imbalances (II).
 Inadequate substrate intake in early infancy can cause long-term detrimental effects in terms of metabolic
programming of the risk of illness in later life (II).
Physiological Principles
The body water content is age-related and diminishes from approx. 90% in a premature infant born after 24
weeks gestation to below 70% in a 12 month old infant [2, 3].
The fluid volume per kg body weight is higher in newborns than in older patients [4]. Contributing factors for this
are renal immaturity (diminished ability to concentrate urine resulting in increased urine volume) [5], higher
energy expenditure, greater body surface area compared to body volume and epidermis immaturity resulting in
high insensible perspiration [6]. The regulatory mechanisms in the water and electrolyte balance are reduced in
comparison to adults due to renal immaturity. Alongside the diminished ability of the kidneys to concentrate urine
[7], the renal glomerular filtration rate, renal tubular reabsorption and elimination of H+-ons are also lower when
compared to those of older children [8, 9]. Based on body weight, the energy and nutrient requirements of
newborns are higher than in older patients. This results from the increased (metabolic) activity and growth [10]
resulting in increased nutrient substrate requirements [11-14].
Apart from the known nutritional effects of nutrition, there is also increasing evidence of long-term changes in the
metabolism triggered by nutrition in early childhood (early metabolic programming of early nutrition on health in
later life) [15, 16].
Accordingly, newborns, infants and toddlers require an intake of nutrients that has been carefully adapted to suit
their metabolic requirements to a far greater degree than older paediatric patients or adults. It is never
appropriate to convert intake recommendations from other patient groups like adults on the basis of body weight
3
and to apply them to infants or toddlers without taking into consideration the different physiological conditions.
Apart from age-related changes in nutritional requirements, adaptation processes after birth (to a greater extent
in premature infants) pose a special challenge with regard to the individual requirements for fluid and other
nutrient substrates. There is a day-to-day increase in fluid and energy requirements due to the adaptation of
metabolism and kidney functions as well as initial high perspiration. Daily adjustments to parenteral nutrition are,
therefore, required over the first few days of a child's life [17]. This adaptation and stabilisation phase (5-7 days
after the birth) is followed by the phase of stable growth. After the neonatal period, the hydration percentage in
the fat-free body mass changes only slightly and the percentage of body water content is mainly determined by
the percentage of fat in the body mass.
Indications for Parenteral Nutrition:
Neonatal patients


All premature infants <35 weeks of pregnancy and most ill term infants require full or partial PN whilst
enteral nutrition is gradually introduced (IV).
The percentage of PN should be reduced as quickly as possible by the introduction of enteral nutrition
(partial PN) and finally be replaced completely by enteral nutrition in order to minimise any side-effects
from exposure to PN (II).
Commentary
There are a variety of reasons why premature infants (<35 weeks gestation) and seriously ill full-term infants
may be unable to receive adequate enteral nutrition after birth, such as gastrointestinal tract immaturity with
threat of developing necrotising enterocolitis, muscular and neurological immaturity, illnesses etc., and, hence,
will require immediate PN in most cases.
The choice of nutrition administered (oral, enteral, partial PN or total PN) should be made on an individual basis
according to medical indication and based on the principle of such nutrition being "as non-invasive as possible".
This process promotes low complication rates [18-21] and is the reason why the highest possible percentage of
nutrition should be administered orally, or enterally wherever possible. If this is not possible, (partial) parenteral
nutrition should be used to supplement the enteral intake to provide adequate nutrition [22].
Premature infants are born with low food reserves (low subcutaneous fatty tissue, low glycogen reserves in the
liver) in comparison to full-term newborns. There is specific risk of hypoglycaemia in connection with their high
nutrient requirements. Premature infants <35 full weeks of pregnancy should therefore be prophylactically (re)
introduced to solid food whilst administering (partial) PN. The "optimum supply" with various different nutritional
components in premature and ill newborns is still being discussed. Principally it makes sense to differentiate
between the recommendations for the adaptation and stabilisation phase and the recommendations for the
phase of stable growth, due to differing nutritional requirements.
Published recommendations (e.g. [11, 15, 23-26]) do not always take into consideration the specific conditions
of the adaptation and stabilisation phase after birth (5-7 days after birth), which precede the phase of stable
growth.
This means that the stunted growth occurring during that phase (compared to intrauterine percentiles) is often
not regained by the pregnancy due date [27]. There are discussions about this target stating that the majority of
eutrophic premature infants should have once again attained their birth percentile by the pregnancy due date.
This target seems necessary, because growth retardation could be a risk factor for long-term neurological
development [27-29]. The potential long-term risks of growth retardation and the side-effects of increased
substrate intake in the newborn period have to be weighed up as there is no evidence-based data on long-term
development when considering the different growth rates of premature infants. The ideal target for premature
infants is usually seen as growth corresponding with intrauterine growth percentiles. It is, therefore, necessary to
adapt the nutrient supply to the respective needs of the individual premature infant. This is also the case in the
phase of continual growth (see below), where the target is not only to attain a positive nitrogen balance, as in the
adaptation and stabilisation phase, but also to promote catch-up growth wherever possible right up to the birth
percentile.
Older children and teenagers

If the energy and nutrient demands of a patient cannot be met through enteral nutrition during pre-school or
school age, then partial or total PN is to be considered within 7 days at the latest in dependance on the
nutritional state and clinical conditions (C).
Commentary
The beginning of (partial) parenteral nutrition in patients above the period of infancy should be specific to the
4
individual circumstances, age and illness of the child or teenager. In contrast to infants, a period of inadequate
nutrition and depletion of the body's store can be tolerated in pre-school and school children with positive
nutritional status for up to seven days subject to their clinical conditions.
Energy and Nutrient Requirements
Energy requirements
Energy requirements are age-related (see table 1) and influenced by illness and therapy. Tables can provide
sufficient help in typical clinical situations providing a rough approach to calculating the estimated requirements
of individual patients, with the appropriate additions and deductions (e.g. in cases of pyrexia/respiratory
therapy). The estimate should account for the fact that all details are based on data taken from healthy patients.
Individual circumstances (e.g. reduced physical activity in case of bed rest, infections, inflammatory processes,
energy losses from the stomata etc.) result in differences between the actual energy requirements and the
calculated (estimated) energy requirements.
The actual requirements of the treated patient can be narrowed down further (e.g. weight chart) by means of
monitoring measures (cf. chapter "Complications and Monitoring").
If the desired therapy effect (e.g. percentile parallel growth) is not attained with the estimated energy
requirements and monitoring offers no solid references regarding an adequate energy intake, then various
formulas can be helpful when calculating the evaluation. The equations (WHO 1985, Schofield 1985, and HarrisBenedict 1919 [30-32]) have, however, also been established for healthy children and have to be corrected for
individual patients as specified in the figures published in tables. Measuring the energy expenditure is rarely
carried out routinely during daily clinical routines and is indicated, if, despite estimation aids and monitoring,
there are still doubts regarding an adequate energy intake.
We refer to the "Guidelines on Paediatric Parenteral Nutrition" of ESPGHAN and ESPEN for a more detailed
overview of aspects regarding the energy requirements of children of various age groups and in case of varying
clinical pictures [1].
Table 1: Benchmark for overall parenteral energy intake (incl. amino acids) in stable patients [1]
age (years)
kcal/kg body weight/day
premature infants
0-<1
1-<7
7 - < 12
12 - 18
110-120
90-100
75-90
60-75
30-60
Carbohydrate requirements





The endogenous glucose production varies from approx. 2 mg/kg/min (3 g/kg/day) in adults to approx. 8
mg/kg/min (11.5 g/kg/day) glucose in premature infants (II).
The maximum glucose oxidation is approx. 7 mg/kg/min (10 g/kg/day) in premature infants, and approx.
12 mg/kg/min (18 g/kg/day) in full-term infants and infants (II-III).
In full-term infants and children up to two, the glucose intake should usually not exceed approx. 12 mg/kg
and min (18 g/kg and day) (C).
The glucose intake should also be adapted to the age and/or clinical situation (e.g. malnutrition, acute
illness, drug administration) (C).
An excessively high carbohydrate intake can result in net lipogenesis with hepatic fat deposition and
steatosis of the liver (II-III).
Commentary
Glucose is the sugar used for PN and usually contributes substantially to osmolarity in the PN solution. The
osmolarity of a glucose solution rises significantly with increasing concentration from 255 mosm/l in a 5%
glucose solution to 1020 mosm/l in a 20% glucose solution. Based on experience, glucose concentrations of up
to 12.5% are well tolerated through a peripheral vein cannula as long as no other osmolarity-increasing agents
are added.
Glucose can be directly metabolised by the central nervous system. The endogenous glucose production varies
from approx. 2 mg/kg/min (3 g/kg/day) in adults to approx. 8 mg/kg/min (11.5 g/kg/day) glucose in premature
5
infants [33-36]. The maximum glucose intake should not exceed the glucose oxidation rate in PN. Maximum
glucose oxidation is approx. 7 mg/kg/min (10 g/kg/day) [37, 38] in premature infants and approx. 12 mg/kg/min
(18 g/kg/day) in full-term newborns and infants under long-term PN [39-41]. In critically ill children with burns,
maximum glucose oxidation of 5 mg/kg/min has been described [41]. Excessive glucose intake results in net
lipogenesis and subsequent fat deposition [42, 43]. Excessive intake can lead to hepatic steatosis with an
impairment of the liver function [44, 45].
Special characteristics in neonatal patients (hyper/hypoglycaemia)


Higher incidence of hyperglycaemia with increasing immaturity (lower gestational age) (II).
An early start of parenteral glucose together with amino acids (2-3 g/kg and day) from the very first day
onwards contributes to preventing hyperglycaemia in premature infants. An early insulin therapy is also
promising but associated with risks. Further controlled studies should be awaited prior to a general
recommendation (B).
Commentary
There are often fluctuations in blood sugar levels in premature infants during the adaptation and stabilisation
phase which can be influenced by low substrate reserves (hypoglycaemia) or insulin resistance
(hyperglycaemia) [46-48]. Common definitions of hypo- or hyperglycaemia, respectively, are a blood glucose
level of 50 mg/dl (2.75 mmol/l) or 150 mg/dl (8.3 mmol/l), respectively, although these levels are not based on
short and long term outcome studies. The incidence of hyperglycaemia increases with diminishing gestational
age [49, 50]. An early supply of intravenous insulin in hyperglycaemia has been proposed in order to more
rapidly attain the targeted energy intake and a positive nitrogen balance [51], but this advantage should be
weighed against potential complications. There are no controlled studies regarding the advantages and
disadvantages of an early insulin therapy in premature infants. It has also been suggested that an added amino
acid supply of 2-3 g/kg body weight and day should be started from the very first day to reduce hyperglycaemia
during the adaptation and stabilisation phase, since it may stimulate endogenous insulin secretion and hence
reduce the frequency and extent of neonatal hyperglycaemia [52]. This approach should be evaluated further in
controlled studies.
Amino acid requirements

The requirements for essential amino acids are higher per kg body weight in infants, and particularly in
premature infants, than in older children or adults (II).
Commentary
Crystalline amino acid solutions in concentrations of 3.5-15% (osmolarity 450-1450 mosmol/l) are used in PN.
Some specifics are to be taken into consideration when using amino acid solutions in children compared to
adults due to the special amino acid metabolism and growth-specific requirements.
The composition of amino acid solutions which are suitable for infants and toddlers, have to be adapted to the
demands of metabolic immaturity and requirements of physical growth. Apart from the eight classic essential
amino acids (Phe, Thr, Val, Leu, Ile, Tyr, Ser, Met), cysteine, tyrosine, histidine, taurine, glutamine and arginine
are regarded as essential or conditionally essential especially in premature infants: (see "Information on Amino
Acid Intake" in the attachment).
Amino acid requirements for newborns



Some amino acids regarded as non-essential in older children and adults are regarded as conditionally
essential amino acids in newborns(II).
Amino acid imbalances can result in toxic organ damage and may be involved in the development of PNassociated cholestasis (II).
Ursodesoxycholic acid and the reduction of protein intake have a positive effect on the development of
PN induced cholestasis in newborns (II).
Commentary
The need for essential amino acids is higher in premature infants than in older children or adults [11].
Various metabolic pathways for metabolising amino acids are immature in newborns (phenylalanine
hydroxylase, tyrosine-aminotransferase, cystathionase [53, 54]). As a consequence amino acids regarded as
non essential in adults i.e. cysteine, tyrosine, histidine, taurine, glutamine and arginine, become "conditionally"
essential amino acids in newborns [55, 56]. Other amino acids like methionine quickly reach high levels because
6
key enzymes are immature. Amino acid imbalances develop quicker in newborns than in adults or older children
due to the immaturity of the neonatal metabolism. Such imbalances could have potential negative effects on
organ development [57].
The plasma amino acid levels in infants receiving parenteral nutrition differ to those in breast-fed infants despite
extensive endeavours to create optimised amino acid solutions for infants [58-60]. This is partly due to the poor
solubility or stability of various amino acids (e.g. glutamine, tyrosine, cysteine) such that not all admixtures can
be used. The nitrogen balance is not significantly influenced by the diverse composition of amino acid solutions
[61, 62].
The maximum intake is basically influenced by two given facts:
1. Physiological rate of protein synthesis subject to age:
According to data by Pohlandt et al. [63] and Micheli [64] premature infants, who are physiologically in
approx. week 30 of pregnancy, have a maximum rate of protein synthesis with protein requirements of
approx. 2.7 g/kg body weight/day, which returns to >2.0 g/kg body weight/day until week 40 of pregnancy.
A positive nitrogen balance can usually be attained in premature infants with an amino acid intake of 2.5
g/kg body weight/day and 60-90 kcal/kg body weight/day [65]. In individual cases an amino acid intake of
up to 3.5-4 g/kg body weight/day may be necessary in order to achieve protein synthesis according to the
intrauterine ratio [64].
2. Urea and ammoniac concentrations in plasma:
The urea production rate is a sensitive measurement for amino acid utilisation. Monitoring plasma
concentrations of functional proteins like, for example, prealbumin, fibrinogen or retinol binding protein
can provide information about the sufficient amino acid supply of the liver. It should be considered that
strong insulin secretion due to high glucose intake guides the n-flow to the muscles.
Nitrogen balance studies in premature infants receiving parenteral nutrition show that approx. 380 mg (70%) are
retained from an intake of 530 mg nitrogen, similar to the ratios found in enteral nutrition [66, 67]. Amino acid
imbalances in PN are also discussed as a factor for developing cholestasis in young infants (a frequent sideeffect of long-term PN; up to 50% of long-term ELBW-premature infants receiving parenteral nutrition develop
cholestasis [68]) [18, 69, 70].
Amino acid requirements in older children and teenagers
References are made to the recommendations for enteral intake of amino acids due to insufficient data
regarding the parenteral intake of amino acids in older children [71] (see Table 2).
Table 2: Reference values for enteral protein intake according to new reference values for nutrient intake in
Germany, Austria and Switzerland (DACH reference values) [71]
Age
g/kg body weight/day
g/day
m
m
f
f
0 - <1 month
2.7
12
1 - <2 months
2.0
10
2 - <4 months
1.5
10
4 - <6 months
1.3
10
6 - <12 months 1.1
10
1 - <4 years
1.0
14
13
4 - <7 years
0.9
18
17
7 - <10 years
0.9
24
24
10 - <13 years 0.9
34
35
13 - <15 years 0.9
46
45
60
46
15 - <19 years 0.9
0.8
7
Lipid emulsions








Lipid emulsions are an integral component of longer-term PN in children (C).
Lipid emulsion should usually amount to approx. 25-40% of the non-protein energy in patients receiving
total parenteral nutrition (C).
A glucose intake over 18 g/kg body weight and day induces net lipogenesis in infants and should
generally be avoided (B).
To prevent a deficiency of essential fatty acids, a minimum intake of 0.25 g/kg body weight and day of
linoleic acid is recommended in premature infants and a minimum intake of 0.1 g/kg body weight and day
linoleic acid is recommended in full-term newborns and children (C).
In infants the parenteral lipid intake should usually not exceed 3-4 g/kg body weight and day (0.13 - 0.17
g/kg body weight and h) (B) generally and in older children it should not exceed 2-3 g/kg body weight and
day (0.08 - 0.13 g/kg body weight and h) (C).
Premature infants, full-term newborns and infants should usually receive lipid emulsions over 24 h (B) or
in case of cyclic infusion after the first few months of life along with the residual PN (C).
Triglyceride concentrations in serum or plasma should be specified in patients receiving lipid emulsions
especially if there is increased risk of hyperlipidaemia (e.g. high lipid intake, catabolism, sepsis, ELBW)
(C).
A reduction in lipid intake should be considered if triglyceride concentrations in serum or plasma in
continuous infusions exceed 250 mg/dl (2.8 mmol/l) in infants or 400 mg/dl (4.5 mmol/l) in older children
(C).
Commentary
Lipid emulsions are used in PN in paediatric patients as they provide an energy source with low osmolarity and
high energy content per volume unit. In addition, they also safeguard the essential fatty acid supply. The CO2
production is lowered compared to PN with a high proportion of carbohydrates [72-74]. The nitrogen metabolism
can be improved by adding lipid emulsions to PN [75-77].
Lipid oxidation depends on the overall energy intake and consumption, intake of carbohydrates and triglycerides
and the carbohydrate/lipid ratio [72, 73]. Lipid oxidation decreases as the carbohydrate intake increases and is
replaced by lipid storage. Lipogenesis takes place in infants with a carbohydrate intake of 18 g/kg/day and
above [39, 72]. In older children the level of carbohydrate intake, above which net lipid deposition takes place, is
lower. Lipid oxidation reaches its maximum at a parenteral lipid intake of 40% of non-protein energy intake in
neonates [74] or 50% in infants [72]. Generally a lipid intake of 25-40 % of non-protein calories is recommended.
A deficiency of essential fatty acids can be biochemically shown in parenterally fed premature infants only after a
few days with continuous glucose but not lipid infusion [78-80]. At least 0.25 g/kg body weight/day of linoleic acid
should be administered to premature infants in order to prevent a deficiency of essential fatty acids [80, 81]. An
intake of 0.1g/kg body weight/day is probably sufficient in full-term infants and older children. The different
linoleic acid content in varying lipid emulsions has to be taken into consideration in the calculation for lipid
intake. It is difficult to define the minimum requirements of alpha linolenic acid. The majority of data on this
subject has been gained from animal experiments [82]. In children there is only one case study on alpha
linolenic acid deficiency [83]. All lipid emulsions used in Germany contain alpha linolenic acid.
It is also difficult to define the upper limit for lipid intake. In premature infants an intake of 3 g/kg body weight/day
is well tolerated as a continuous infusion according to the concentration of plasma triglycerides and cholesterol
and also the ratio of non-esterified fatty acids/albumin [84-86]. In premature infants it may be desirable to
achieve a lipid intake surpassing the oxidation capacity in order to attain weight gain and lipid deposition.
Caution is, however, recommended in premature infants weighing less than 1000 g as tolerance to intravenous
lipid emulsions may be more limited [87].
Maximum lipid oxidation of 4 g/kg body weight/day is attained in full-term infants with a glucose intake below 18
g/kg per day [73, 75].
It is important to monitor plasma triglycerides because lipid utilisation varies depending on age, the severity of
the illness and various other factors.
An increase in the concentration of plasma triglycerides is to be expected if the infusion speed of the lipid
emulsions exceeds the speed of hydrolosis of the triglycerides.
In premature infants the gradual increase in lipid intake compared to immediate administration of the target
amount did not result in raised lipid tolerance [88]. If a gradual increase of 0.5 to 1 g/kg per day is carried out,
this can serve the purpose of monitoring with measurements of plasma triglycerides concentrations.
In premature infants tolerance of a lipid infusion is raised by continuous versus intermittent administration [84,
86, 88]. In stable patients intermittent administration can also be carried out within the framework of cyclic home
PN.
The speed of triglyceride hydrolysis depends on lipoprotein lipase activity. The activity of the post heparin
lipoprotein lipase can be raised by administering heparin but this does not increase lipid utilisation [89, 90].
8
Raised lipoprotein lipase activity results in increased non-esterified fatty acids, which are not necessarily
metabolised at the same speed [90, 91].
Lipid supply may result in enhanced lipid peroxidation and the formation of free radicals [92-94]. An increased
lipid utilisation by reducing the carbohydrate/lipid ratio, at a constant lipid intake and therefore reduced energy
intake, results in a reduction of lipid peroxidation and free radical formation [92]. PN should be supplemented
with multi-vitamin preparations including both vitamin C and vitamin E (alpha-tocopherol) which have antioxidative effects [95-97].
PN with 20% lipid emulsions results in more physiological phospholipid and cholesterol levels, due to its low
phospholipid content compared with PN containing classic 10% lipid emulsions [98]. At the same time there is,
however, a lower proportion of long-chain polyunsaturated fatty acids (LC-PUFA) contributed by the
phospholipid emulsifier. LC-PUFAs are "conditionally" essential for premature infants. Deficiency could result in
malformations of the retina and central nervous system [99, 100].
Vitamin requirements
No age differentiation is indicated in literature due to the limited data situation.
Neonatal patients, older children and teenagers






Vitamin supplementation should be given during parenteral nutrition (C).
The vitamin requirements of premature infants and newborns (excluding Vitamin D and K) as well as in
infants and children have not been extensively examined (IV).
No parenteral vitamin supplement available on the German market meets the current recommendations
for premature infants (IV).
Vitamin preparations should, if possible, be administered together with the lipid emulsion (C).
Premature and ill full-term infants should be given their first two doses of Vitamin K
subcutaneously/intramuscularly or intravenously (II).
An oral intake of 1000 IU Vitamin D/day is adequate in extremely premature infants (II).
Commentary
The optimum time to begin vitamin supplementation in newborns and premature infants is not clear. It should be
taken into consideration, that water soluble vitamins, with the exception of Vitamin B12, are inadequately stored.
Insufficient thiamine intake can result in severe lactic acidosis within only a few days in children on PN [101]. It
is, therefore, recommended that vitamin substitution is started early with PN.
Vitamin intake should be administered daily. All clinical studies have been carried out with commercially
available vitamin preparations, therefore existing intake recommendations [11, 23, 102] are based on the
composition of available preparations. At this time there is no commercially produced vitamin supplement
available on the market, which completely meets the current intake recommendations for premature infants as a
supplement for long-term PN. In the practical administration of PN it should be considered that vitamins can be
degraded by oxygen, light and heat. Degradation reactions can be accelerated by catalytically active trace
elements like copper and iron. Fat-soluble vitamins can be adsorbed on specific synthetic materials (infusion
needles) in rare cases. Thus, the administered dose is uncontrolled and significantly reduced [103]. In Europe,
combined preparations are available which, by dissolving the vitamins in a lipid emulsion, reduce absorption on
plastic. Furthermore, the formation of peroxides in lipid emulsions can be reduced by adding multi-vitamin
preparations [104]. Vitamin preparations should, if possible, be administered together with the lipid emulsion.
The clinical impact of free radicals, which can develop in intravenous multi-vitamin emulsions when exposed to
light, is being currently discussed. They can result in an increase in peroxide excretion in urine of newborns
[105]. Feed lines with light protection should be used when administering parenteral solutions with vitamins until
the clinical significance of these results has been determined [106].
Vitamin D rickets prophylaxis: Oral vitamin D prophylaxis with 1000 IU Vitamin D/day per os from day seven of
life is sufficient as a prophylaxis in extremely premature infants [107].
Vitamin K prophylaxis: Premature infants (<week 35 of pregnancy) and ill full-term infants should receive their
first two doses of Vitamin K prophylaxis intramuscularly, subcutaneously or intravenously due to the unclear
resorption from the gastrointestinal tract [108, 109]. The dose of intravenous Vitamin K prophylaxis is still being
discussed at present. Vitamin K levels after one administration of 1 mg Vit K intramuscularly on the first day of
life were higher in premature infants than in full-term infants [110].
Detailed specifications can be found in the "Guidelines on Paediatric Parenteral Nutrition" from ESPGHAN and
ESPEN [1].
Trace element requirements
No age differentiation is indicated in literature on account of the limited data situation.
9
Neonatal patients, older children and teenagers





The optimum time to begin with trace element supplementation in premature infants < 1500 g birth weight
is not clear. We recommend beginning supplementation to coincide with an increase in body weight (5th
day of life) (C).
The trace element requirements of premature infants and newborns as well as children have not
undergone extensive testing (IV).
A parenteral trace element supplement, which meets the current intake recommendations, is not available
on the German market (II).
Trace elements should be supplemented in long-term PN (C).
Zinc deficiency has to be excluded in infants and children with unclear, poor development (especially
linear growth) and/or skin efflorescences (typically on acra, mechanically burdened parts of the body or in
the nappy region) or diarrhoea (II).
Commentary
Trace element requirements and optimum time to begin supplementation in premature and full-term infants, as
well as infants and children, are not completely clear. The enteral absorption of trace elements in partialparenteral nutrition mainly depends on the existing compound and the composition of the nutrition [111] such
that it is extremely difficult to evaluate the remaining parenteral needs. Requirements for some trace elements
have at least been narrowed down by controlled studies [102, 111-114]. There is no trace element supplement
for long-term PN which meets the current recommendations [102]. In long-term PN (>7 days), where enteral
nutrition provides less than 50% of the energy intake, we recommend administering trace element supplements
according to manufacturer instructions.
Premature and ill full-term infants have an increased risk of developing a trace element deficiency. Premature
infants are born with lower trace element stores as the laying down of these stores occurs during the last
trimester of the pregnancy. Rapid growth at unidentified requirement levels and variable resorption are further
risk factors contributing to the development of a trace element deficiency in premature infants [115]. In ill fullterm infants the requirements and intake vary according to the basic illness. The optimum time to begin
supplementation is disputed.
Zinc: Zinc deficiency should be considered in newborns where the reason for unclear, poor development
(especially linear growth) and/or skin efflorescences (acra, mechanically burdened parts of the body) are not
clear [116, 117]. A multitude of case studies have been published on zinc deficiency in neonates [116]. Rare
genetically-related trace element metabolic disorders are also to be considered in the case of unclear clinical
symptoms [117].
Other supplements


There is no documentation indicating a benefit from parenteral supplementation of glutamine or arginine
in children (C).
Carnitine supplementation should be considered in individual cases in premature and newborn infants on
PE (B).
Commentary
Tests on arginine supplementation [118] in adult intensive care patients as well as some studies on enteral or
parenteral glutamine administration in newborns show potential positive effects [119, 120] (II), although these
are controversially discussed. There is no evidence from meta analyses to document the benefit of the
parenteral supplementation of glutamine or arginine in premature and newborn infants [121].
Vitamin A is necessary for physiological lung growth (lung epithelial cells). A meta-analysis, which is based on
seven randomised, controlled studies, documents the effectiveness of a supranutritive Vitamin A
supplementation on reducing oxygen requirements and improving survival at one month of age in premature
infants with a birth weight <1000 g. There is a tendency towards lower values regarding the incidence of
retinopathy in premature infants [122, 123] (I). The authors of the systematic analysis of the Cochrane database
feel there is a need to carry out further studies on the effects of intravenous Vitamin A supplementation.
Carnitine is necessary for the transportation of long-chain fatty acids via the mitochondrial membrane and its
oxidative metabolism. Carnitine is found in breast milk and baby foods, but is not usually added to conventional
PN. Low carnitine levels have been measured in body tissues in premature infants on PN [124]. The clinical
significance of this has not been determined. An impairment in fatty acid oxidation is only to be anticipated
where a massive drop in serum carnitine concentrations occurs. For the metabolic availability of carnitine its free
nonesterified percentage, is essential. The availability of free carnitine is reflected in the concentration and the
acyl-carnitine/free carnitine (AC/FC) ratio. This ratio is in dynamic equilibrium with the intramitochondrial acylCoA/free CoA ratio. Lower intramitochondrial CoA-availability is assumed with an AC/FC ratio >0.4 (>0.7 when
fasting) Carnitine supplementation results in a release of intramitochondrial CoA and should be considered in
case of an explicit AC/FC ratio. A meta analysis (based on 14 randomised, controlled studies) showed there to
10
be no effect of carnitine supplementation on the metabolism of lipids, lipogenesis or weight gain [125].
Practical Procedure
Short, medium and long-term (partial) parenteral nutrition



The utilisation of an adapted glucose/electrolyte solution (usually 10% glucose) with potassium and
sodium supplementation in short-term (<48 h) intravenous intake is recommended in well-nourished
toddlers and school children without specific metabolic or nutritional risks (IV).
An adapted glucose/electrolyte solution (usually 10% glucose) with the required supplementation of
sodium, potassium, amino acids, lipids and vitamins should be administered in medium-term PN (>2-7
days) (IV).
An additionnal supplementation of magnesium, phosphate, and trace elements (where enteral nutritional
provides 50% of the energy intake or less) should be administered in long-term PN (>7 days) (IV).
Commentary
If intravenous intake is required in well-nourished toddlers and school children without specific metabolic or
nutritional risks, the following situations should be considered when anticipating duration:
I.
II.
III.
IV.
short-term parenteral intake for less than 48 h.
medium-term parenteral nutrition for 2 to 7 days.
long-term PN for >7 days.
It makes sense to differentiate between short, medium and long-term parenteral intake, because the
procedure varies according to the duration of PN
V. The utilisation of an adapted glucose/electrolyte solution (usually 10% glucose) with potassium and
sodium supplementation in short-term (<48 h) intravenous intake is recommended in well-nourished
toddlers and school children without specific metabolic or nutritional risks (IV).
VI. An adapted glucose/electrolyte solution (usually 10% glucose) with the required supplementation of
sodium, potassium, amino acids, lipids and vitamins should be administered in medium-term PN (>2-7
days) (IV).
VII. An additional supplementation of magnesium, phosphate, and trace elements (where enteral nutritional
provides 50% of the energy intake or less) should be administered in long-term PN (>7 days).
Newborns and infants




There should be a written concept on the provision of PN in order to minimise errors (C).
Newborns can be divided up into the following groups with regard to their nutrient requirements and PNsupport in order to minimise errors:
 premature infants <1500 g,
 premature infants >1500 g,
 ill full-term infants (C).
The actual amount of PN administered must be calculated (not estimated) in neonates (avoid rounding
error) (C).
The use of PN standard solutions can reduce the the risk of errors.
Commentary
Due to the heterogeneity in pathophysiology and the differing maturity of patients it may be necessary to vary
procedures during the neonatal period (e.g. fluid volumes, electrolyte substitution etc.). Classification according
to, for example, birth weight is recommended for the calculation of PN in neonates:



premature infants <1500 g,
premature infants >1500 g, and
ill full-term infants.
This differentiation makes sense with regards to variations in the administration of different nutrients. The
described protocol can result in the procedures in (partial) parenteral nutrition being structured during the daily
clinical routine and errors minimised.
A standardised questionnaire or electronic programme, which takes into account partial parenteral nutrition and
enteral nutrition (see attachment for an example of a procedure questionnaire), should be used for prescribing
PN to neonates.
The prescription of nutrition for neonates must be calculated and not estimated in order to ensure the nutrient
11
intake in neonates and infants is adapted to their specific needs.
PN in premature infants and newborns
PN in the adaptation and stabilisation phase after birth








There is no evidence-based data on the scale of postpartal weight loss required during the adaptation
and stabilisation phase for long-term development (IV).
Amino acid and lipid supply should begin on the first day of life (B).
The fluid intake in premature infants <1500 g should only replace the estimated losses in the first days of
life (mainly perspiratio insensibilis). Electrolyte supplementation is often not necessary (B).
The incidence of hyperkaliaemia can be lowered by supplementing PN with 1 g amino acids from the first
day of life in premature infants <1500 g (II).
The maximum parenteral intake of amino acids should be between 2 and max. 4 g/kg body weight per
day in premature infants and newborns (B).
Max. lipid intake should not exceed 3-4 g/kg body weight per day in premature infants and newborns (B).
Restricted fluid management with limited supply of sodium chloride results in a reduction in the amount of
days with respiratory aids or respiratory therapy (II).
The early enteral (re)establishing of solid foods (within <4 days after the birth) in premature infants lowers
the incidence nosocomial infections, the duration of PN and the frequency in the utilisation of central
venous catheters (I).
Commentary
In premature infants and full-term newborns there is a period of adaptation and maturation which occurs in the
first seven days after birth (see "Physiological Principles" above) which requires daily adjustments in the nutrient
intake of ill full-term and premature infants. There is surprisingly little evidence-based data on physiology and
nutrient requirements for this stage of life (optimum weight loss, optimum time to begin amino acid and lipid
supply). Lipid (0.5-1 g/kg body weight/day) and amino acid intake (0.5-1 g/kg body weight/day) should begin on
the first day of life [126], and a stepwise increase in amino acid intake to max. 2-3(-4) g/kg body weight/day and
lipid intake to 3-4 g/kg body weight/day is widely practised and results in more rapid achievement of a positive
nitrogen balance [52, 127]. Questions remain with regard to extremely small premature infants with a birth
wieght <800 g with regard to potential adverse effects of early intravenous lipid intake on the first day of life
[128]. A restricted fluid volume improves the outcome of neonates considerably by lowering the "perspiratio
insensibilis" [129]. In premature infants a restrictive "dry" fluid management with sodium chloride restriction
seems to have a favourable effect on the duration of respiratory aids / respiratory therapy [130-132]. Only the
losses should be replaced in the first days of life in premature infants under 1500 g birth weight [17]. The
incidence of hyperkaliaemia can be lowered by supplementing 1 g amino acids from the first day of life in this
patient group. The early (re)establishing of enteral nutrition(<4 days after birth) lowers the incidence of
nosocomial infections, the duration of (partial) parenteral nutrition and the utilisation of central venous catheters
compared to later (re)establishing [133, 134].
PN in premature infants and newborns in the phase of continual growth



Parenteral nutrition should be the exception in neonatal patients during the phase of continuous growth. If
necessary, treatable reasons for delayed enteral (re)establishing of nutrition should be ascertained (C).
The energy requirement shows great intraindividual and interintervidual variability (II).
The energy intake can be adapted to the weight gain, whereby weight development should aim to be
close to the intrauterine growth curve (C).
Commentary
The enteral (re)establishing of nutrition is usually completed in the first week of the continual growth phase
(about the 2nd week of life) in premature infants and sick full-term infants. If PN is also required during this
phase, treatable reasons for delayed enteral (re)establishing of nutrition should be ascertained. The energy
requirements show great variability in this stage of life. They can be estimated according to weight development
compared to intrauterine growth curves (if other reasons for growth not following percentiles have been
excluded, it should be assumed that a too low energy intake will result in a decline and a too high energy intake
will result in gains compared to intrauterine percentiles). The necessary energy to build up 1 g body tissue varies
with the lipid content of the newly formed tissue (20-40 %) but averages at approx. 5 kcal/g. The proportion of
the newly formed fatty tissue is influenced by the nutritional regime. It should be considered with lesser fatty
tissue built up, the energy required for growth is lower [135].
12
Methods of Access


Peripheral vein cannulae have a lower complication rate compared to central access points and should
be used in infants whenever possible (II).
A routine heparin supply to prevent thrombosis or to proling central venous catheter survival time has no
proven benefit in infants and is not recommended (Ib).
Commentary
Peripheral commercial vein cannulae (PCVC) have a lower complication rate in infants (infection, thrombosis)
than central venous catheters (CVC) [20]. Peripheral commercial vein cannulae (PCVC) can be used in partial or
total parenteral nutrition if the osmolarity and state of the veins allow for this (risk of paravasatation/skin
necrosis!).
Long-term total parenteral nutrition often cannot be applied safely in older children or teenagers without central
venous catheters (CVC) due to the osmolarity. An individual decision is required on the choice of access while
taking into consideration the underlying illness, therapy, osmolarity of the nutritional solution used or drugs and
the expected duration. Two meta-analyses showed no positive effect of heparin supply on central venous
catheter lifetime or the formation of thromboses in neonates with percutanous central venous catheters [136,
137].
Use of standardised or individually tailored PN solutions

After requirements have been calculated, standard solutions (e.g. produced by the hospital pharmacy),
which are adapted to suit the specific nutrient needs of the respective age group, can be administered in
short-term PN (B).
Commentary
Using ready-made standard solutions requires fewer personnel and allows for less risk regarding dosage errors
or microbial contamination. Individually mixed infusions can be adapted to individual characteristics. Standard
solutions are suitable for short-term total and partial PN [138].
PN provision
A standardised procedure should be followed and the individual steps systematically documented in order to
minimise errors. Computer programmes, which enable the fast and exact calculation of enteral and parenteral
intake, are recommended (and in part commercially available). The fluid, glucose and electrolyte intakes and
additional intakes with drugs can be calculated.
The following aspects should be considered: Estimation of the required duration of PN, enteral nutrition, fluid
intake, protein and lipid intake, parenteral vs enteral/oral intakes , electrolyte/vitamin and trace element supply,
concentration of the glucose solution, infusion speed, monitoring, and validation (see Fig. 1 "Example of a
procedure questionnaire" in the attachment).
Fig. 1: Example of a procedure questionnaire in premature and ill full-term infants
Volume: lipid emulsion 20 % [ml]
Residual volume [ml/d]
Calories/kg body weight/day [kcal/kg body weight/day]
Name: ________________ First Name:____________Birth Weight:____________
Sheet No.:_____
Date
Day of life [n]
Corr. age [week of pregnancy]
Act. weight [g] difference to previous day [± g]
Expulsion in [ml/day]
Urine
Expulsion in [ml/body weight/day]
13
Fluid requirements [ml/day]
Fluid Req.
Deductions/Additions [± %]
Daily fluid requirements [ml/day]
Nutrition type [BM/PIM/Formula]
No. meals/ml/Meals
Daily volume [ml/day]
Enteral
Protein content/day [g]
Lipid content/day [g]
Enteral supplements [ml]
Enteral supplement [ml]
Protein requirements/d [g/kg body weight/day]
Overall volume/d (requirements x weight)
Proteins
IV prot. percentage (overall enteral requirements for protein)
Volume: AA solution 10 % [ml]
Lipid requirements/d [g/kg body weight/day]
Overall volume/d (requirements x weight)
Lipids
IV lipid proportion (overall lipids - enteral)
NaCl 5.85 %
KCl 7.45 %
Electrolytes
[ml] 1ml ≈ 1mmol
[ml] 1ml ≈ 1mmol
Ca-Gluconate 10 % [ml] 1ml ≈ 0.22mmol
Mg-Verla 10%
[ml] 1ml ≈ 0.32mmol
Na-Glycero-phosphate [ml] 1ml ≈ 1mmol P+2mmol Na
Water soluble vit. [ml]
Supplements
Fat soluble vit.
[ml]
Trace elements….[ml]
Drug volume [ml]
Vol.
Glucose 5 % [ml]
Glucose
Glucose 10 % [ml]
Glucose % [ml]
14
Glucose intake/day [g/day]
Glucose intake in [mg/kg body weight/min]
Calories/d [kcal/day]
Kcal.
Speed of mixed infusion [mL/h]
FLow
rate
Speed of lipid emulsion [mL/h]
Doctor's initials
Breast milk (BM)*;
Formula;
+ Fortifier
Lipid content
[g/100 ml]:
4.0
Energy content
[kcal/100 ml]: 71.0
Carbohydrate content [g/100 ml]:
7.1
Protein content
[g/100 ml]:
1.1
Lipid content
[g/100 ml]:
4.0
*BM data after: Zuppinger K.: Berner Datenbuch der
Pädiatrie, G. Fischer Verlag, Stuttgart, 4. Aufl. 1992, S. 161
Procedure questionnaire from: Jochum F. Infusionstherapie
und Diätetik in der Pädiatrie. Springer Verlag 2005, 516-517
Neonatal patients
A practical example is shown in table 3 in the attachment, which illustrates the (re)establishing of enteral food in
newborns during the adaptation and stabilisation phase.
Table 3: Example of the (re)establishing of nutrition in premature and ill full-term infants1
Birth
Weight
Day 1:
Day 2:
Requirement
with total PN1
Infusion
Requirement
Requirement
Fluid
Energy
Glu AA
[ml/kg body
weight/day]
[kcal/kg body
weight/day]
[g/kg body
weight/day]
Lipids NaCl
KCl
Enteral
Nutrition
[mmol/kg body
weight/day]
[ml/d]
PI <1000 g 90
4-8
1,0 (3.0)
1.0
0
0
0
PI 1-1.5 kg 80
4-8
1.0 (3.0)
1.0
0
0
0
NB ≥1.5
kg
60
410
1.0 (3.0)
1.0
2-5
1-3°
8/6x5-10
BM/SN
PI<1000g
110
4-8
1.0 (3.0)
1.0
0
0
6x0.5 BM/PIF
PI 1-1.5 kg 100
4-8
1.0 (3.0)
1.0
0
0
12x0.5
BM/PIF
NB ≥1.5
kg
80
410
1.0 (3.0)
1.0
2-5
1-3
8/6x1020BM/SN
PI < 1000
g
130
5-9
1.0 (3.0)
1.0
0
0
12x0.5
BM/PIF
PI 1-1.5 kg 120
5-9
1.0 (3.0)
1.0
{2-5}
{1-3}
12x1.0
BM/PIF
Day 3:
Day 4:
Day 5:
15
NB ≥1.5
kg
100
510
1.0 (3.0)
1.0
2-5
1-3
8/6x15-30
BM/SN
PI <1000
150
510
2.0 (3.0)
1.0
{2-5}
{1-3}
Increase by
10-15
PI 1-1.5 kg 140
510
2.0 (3.0)
1.0
2-5
1-3
15-20
NB ≥1.5
kg
120
612
2.0 (3.0)
1.0
2-5
1-3
15-25 ml/kg
body
weight/day
PI <1000 g 160
612
2.5 (3.0)
2.0
2-5
1-3
Increase by
10-15
PI 1-1.5 kg 160
612
2.5 (3.0)
2.0
2-5
1-3
15-20
NB ≥1.5
kg
715
2.5 (3.0)
2.0
2-5
1-3
15-25 ml/kg
body
weight/day
140
PI <1000 g 160
80-160
714
2.5 (3.0)
3.0
2-5
1-3
Increase by
10-15
PI 1-1.5 kg 160
70-140
714
2.5 (3.0)
3.0
2-5
1-3
15-20
NB ≥1.5
kg
160
60-120
716
2.5 (3.0)
3.0
2-5
1-3
15-25 ml/kg
body
weight/day
PI ≥1.5 kg
160
80-160
716
2.5 (3.0)
3.5
2-5
1-3
Increase by
10-15
PI 1-1.5 kg 160
70-140
716
2.5 (3.0)
3.5
2-5
1-3
15-20
NB ≥1.5kg 160
60-120
716
2.5 (3.0)
3.5
2-5
1-3
15-25 ml/kg
body
weight/day
PI <1000 g 160
80-160
716
2.5 (4.0)
3.5
2-5
1-3
Target: 160
ml/kg body
weight/day
PI 1-1.5 kg 160
70-140
716
2.5 (4.0)
3.5
2-5
1-3
Divided up
into
NB ≥1.5kg 160
60-120
716
2.5 (4.0)
3.5
2-5
1-3
N meals:
PI <1000 g 160
80-160
716
2.5 (4.0)
3.5
2-5
1-3
<1500 g 12
meals
Day 28: PI 1-1.5 kg 160
70-140
716
2.5 (4.0)
3.5
2-5
1-3
≥1500 g 8
meals
60-120
716
2.5 (4.0)
3.5
2-5
1-3
≥2000 g 6
meals
Day 6:
Day 7:
Day 14:
NB ≥1.5
kg




160
1Cave:
The demand for nutritional substrates varies greatly and has to be adapted to suit each individual
patient. Specifications apply to eutrophic newborns. The proportion of enteral nutrition (cave: intestinal
resorption rate!) is to be deducted from the nutrient requirements. The result provides the parenteral
proportion.
{} start Na/K supplement depending on plasma levels.
[F]= human milk fortifier. Supplement only if proportion of enteral nutrition is at least 75% and age > 7th
day of life, PIF="Premature infants formula"; SN="Starter nutrition".
°only add after first miction.
16
Measures to Reduce Side-Effects of PN






Procedures should be standardised wherever possible in order to minimise errors in the provision or
preparation of partial (PPN) or total PN (TPN).
Minimum enteral nutrition minimises the time until (re)establishing of total enteral nutrition and LOS
(Length of Hospital Stay) (I).
Non-nutritive sucking during PN reduces LOS (I).
There is a specific risk of developing osteopenia due to the rapid bone growth in premature and full-term
infants (III). Osteopenia prophylaxis should be started enterally once the (re)establishing of enteral
nutrition has been completed without complications (C).
In order to determine appropriate Ca and P intakes, the Ca and P excretion can be assesed in spot urine
samples (B).
The optimum duration of Ca and P supply is unclear (IV), but it appears reasonable to provide a Ca and P
supply up to the corrected third month of life in premature infants with a birth weight <1500 g (C).
Commentary
Minimum enteral nutrition. Total PN reduces the functional and structural integrity of the gastrointestinal mucosa,
the secretion of gastrointestinal hormones and the activity of mucosal enzymes like lactase [139], resulting in an
intolerance to enteral nutrition and an extension of LOS (Length of Hospital Stay). A meta-analysis of eight
randomised studies [134] investigated the effect of minimum enteral nutrition (<25 kcal/kg body weight/day for
>5 days) on the development of food intolerance in at-risk premature infants (<1500 g birth weight, <week 33 of
gestation) in comparison to total PN. The duration of (re)establishing of nutrition and LOS was significantly
reduced. There was no effect on the incidence of necrotising enterocolitis. Side-effects of minimal enteral
nutrition cannot be definitely excluded due to the inhomogeneity of the patients included and their low number
[134].
Non-nutritive sucking.
A meta-analysis (based on 14 randomised, controlled studies) documented a significant reduction in LOS
through non-nutritive sucking in premature infants. No effects have been found on weight gain, energy intake,
oxygen saturation, total intestinal transit or heart rate [140].
Osteopenia prophylaxis in premature infants <1500 g.
Due to their high growth rate, premature infants have high calcium and phosphate requirements which cannot be
met through breast milk or infant formula. Therefore, premature infants with a very low birth weight (<1500 g) are
particularly at risk of developing osteopenia. Osteopenia in premature infants is linked to an increased incidence
of fractures, prolonged respiratory therapy or requirement for respiratory aids and the development of a
dolichocephalus [141, 142]. Premature infants under 1500 g birth weight should receive Ca/P supplementation
depending on their individual requirements. The optimum duration of supplementation is unclear. We
recommend supplementation in premature infants with a birth weight <1500 g up to corrected third month of life.
The Ca and P excretion from spot urine specimens may be used to adapt the Ca and P supply to requirements,
which vary according to growth [143, 144].
Monitoring






Due to the low blood volume in infants, staff at facilities in which infants receive medium and long-term
parenteral nutrition must have access to a special laboratory with micromethods (IV).
Careful monitoring of the fluid volume must be carried out in premature infants due to their high fluid
volume, high body water content in comparison to older patients and immature regulatory mechanisms
(IV).
Dehydration in premature infants, with immature kidneys, leads to hyperchloraemia prior to the
development of acidosis as one of the first lab signs.
The measurement of the specific weight or osmolarity of urine can only be drawn upon in premature
infants and newborns in the first weeks of life when high values are measured. Low (normal) values can
be due to low renal concentrating ability in premature infants and newborns as a result of immature
kidneys (II).
Daily clinical tests, fluid balances, acid-base status, electrolytes and blood sugar are required during the
initial phase of PN, depending on the maturity and illness of neonates, (C).
In medium and long-term PN, routine clinical tests should also be accompanied by the following:
documentation of weight, length and head circumference development (in percentile questionnaires),
weekly evaluation of acid base status, blood sugar, electrolytes, haematocrit, urea, creatinine, at least
one transaminase, Y-GT, urine osmolarity or specific weight (alkaline phosphatase every two weeks) (C).
Commentary
17
Daily clinical tests, to include the monitoring of the fluid balance, checks of the acid base status, electrolytes and
blood sugar, are usually required in the initial phase of PN depending on the age and maturity of the children
and their underlying illness. In medium and long-term PN, routine clinical tests should also be accompanied by
the following: documentation of weight, length and head circumference development (in percentile
questionnaires), weekly evaluation of acid base status, blood sugar, electrolytes, haematocrit, urea, creatinine,
at least one transaminase, Y-GT, urine osmolarity or specific weight (alkaline phosphatase every two weeks).
Lipids
The concentration of plasma triglycerides at which undesirable effects occur is not known [145]. Average
triglyceride concentrations of 150 to 200 mg/dl and above are often specified in infants fed with breast milk or
infant formula [86, 146]. Values of 250 mg/dl in healthy infants are not unusual. In older children higher
concentrations of up to 300 and 400 mg/dl can also be acceptable as the lipoprotein lipase doesn't become
saturated until approx. 400 mg/dl [147]. When gradually introduced, plasma triglycerides should be initially
checked on a weekly basis for every 1 g/kg lipid intake increase and after reaching maximum intake levels.
Newborns
Monitoring the fluid balance in premature infants and sick newborns is extremely important due to their high fluid
volume, high body water content in comparison to older patients and immature regulatory mechanisms (see
above). Monitoring must take the special physiological features of neonates into consideration to be efficient:
 The measurement of the specific weight or osmolarity of urine are only indicative in premature infants and
newborns in the first weeks of life when high values are measured. Low (normal) values can be due to
low renal concentrating ability in premature infants and newborns because of immature kidneys.
 The immaturity of the kidney in premature infants in case of dehydration leads to hyperchloraemia prior to
the development of acidosis as one of the first lab-chemical signs.
 Due to the low blood volume in neonates, staff at facilities in which neonates can receive medium and
long-term parenteral nutrition must have access to a special laboratory with micro methods.
Attachment
Information on the selection and production of amino acid solutions

Several metabolic pathways involved in the synthesis of amino acids are still immature in newborn and
premature infants. As a result, some amino acids, which are regarded as non-essential for adults, may
become conditionally essential (e.g. cysteine, tyrosine, histidine, taurine, and glutamine). In addition,
individual plasma amino acids reach clearly increased levels because significant degradation enzymes
are still immature. Amino acid imbalances occur more rapidly in comparison to adults (I).
Commentary
Increased phenylalanine concentrations are toxic for the central nervous system and can result in serious
developmental disorders. Both hepatic phenylalanine hydroxylase activity and the enzymatic system of the
metabolism of tyrosine are still immature in premature infants. Premature infants (<week 30 of pregnancy) with
high amino acid intakes therefore have a tendency to develop hyperphenylalaninaemia and hypertyrosinaemia.
The enzyme activities in full-term infants result, however, in a rapid amino acid metabolism, causing low
phenylalanine and tyrosine concentrations. Attempts are made to increase the low plasma tyrosine
concentrations in infants receiving parenteral nutrition by supplementing with N-acetyl tyrosine, which is more
soluble. Newborns and premature infants do still, however, have a reduced deacetylation capacity such that
tyrosine may not be sufficiently utilised in this more soluble form [148-151].
There is an interaction between the branched-chain and aromatic amino acids: Leucine supports the
phenylalanine and tyrosine metabolism [152].
Methionine is a sulphurous, essential amino acid and is regarded as the precursor to cysteine and taurine.
Methionine is the major methyl group donator in the hepatic intermediary metabolism. It is converted to
homocysteine through demethylation, which remethylates to methionine when tetrahydrofolic acid is introduced
or which is finally converted to cysteine via a transsulfuration pathway forming cystathionine.
Cysteine is a largely essential amino acid in both premature infants and full-term newborns due to its immature
cystathionase activity. Plasma cysteine concentration is already a function of methionine intake in premature
infants. It is often observed that normal plasma cysteine concentrations only occur if plasma methionine
concentrations are raised. As a result cysteine supplementation of amino acid solutions is recommended in
young infants [153, 154].
Supplementation with cysteine-HCl is not usually applied because of its low solubility and risk of acidosis. The
available N-acetyl cysteine may not be effectively metabolised due to limited deacetylation and immature
metabolic rates in premature infants. Procysteine, a preliminary stage of glutathione, has also been tested [155].
18
Taurine is formed through decarboxylation of cysteine sulfinic acid, an enzyme stage that is still immature in
premature infants. The foetus accumulates approx. 50-60 µmol taurine/day during the last trimester of
pregnancy [156].
Taurine has many functions, not all of which are completely understood, although it is of importance to the
central nervous system, retina and gastrointestinal tract. The proven relevance of the maturing of acoustically
evoked potentials points to the clinical significance of taurine [157, 158]. Young infants on PN are, therefore,
dependent on exogenous taurine intake in order to maintain plasma concentrations [157, 159].
Threonine: The plasma threonine concentration is directly proportional to the intake as well as inversely
proportional to the gestational age in PN for premature infants [160]. A toxicity of raised plasma threonine
concentrations has not yet been proven, although it is kown that concentration levels in the brain increase
proportionally to plasma concentrations.
Lysine: Of all amino acids the materno-foetal gradient is most prominent in lysine. Plasma lysine concentrations
in the foetus are approx. four times higher than those of the mother. Both lysine deficiency and surplus have
negative effects on growth, brain DNA concentration and the dynamics of urea synthesis [161].
Leucine influences the speed of protein synthesis in the muscles. The demand for branched-chain amino acids
is greater in premature infants than in full-term infants, and thus they easily tolerate amino acid solutions with a
higher concentration of branched-chain amino acids. Histidine: Of all essential amino acids, the plasma
concentration of histidine is least influenced by the intake. Histidine is therefore regarded as a conditionally
essential amino acid in young infants.
Arginine: The arginine concentration in an amino acid solution contributes to preventing hyperammonaemia.
Premature infants with asymptomatic hyperammonaemia show lower plasma concentrations of urea cycle
intermediates, which can be normalised by raising the arginine intake. Part of the arginine requirement can also
be met by ornithine, which is taken into consideration in some amino acid solutions [162].
N-acetyl amino acids

Based on recent data, it is assumed that N-acetyl amino acids are only metabolised to a limited extent in
humans and therefore are only of limited significance as alternative amino acid sources in clinical nutrition
(IV).
Commentary
There are no documented benefits of additionally administering N-acetyl cysteine due to limited deacetylation
and immature metabolic rates in premature infants.
Notes on differences between lipid emulsions



PE with a low phospholipid triglyceride ratio (e.g. in 20% lipid emulsions) results in less elevated
phospholipid and cholesterol levels (II).
The use of lipid emulsions on the basis of soy bean oil, an olive oil-soy bean oil mixture as well as a
coconut oil (MCT)-soy bean oil mixture have been tested in paediatric patients and their use is well
established (I).
None of these lipid emulsions have a documented benefit regarding the attained clinical end points (C).
Commentary
Apart from the long established use of lipid emulsions based on soy bean oil, a new emulsion based on an olive
oil and soy bean oil mixture has been available for some time and studies with this new mixture have already
shown promising results in children, infants and premature infants [163, 164]. Postulated benefits of the olive oilbased lipid emulsions are reduced lipid peroxidation, lower PUFA intake and higher intake of antioxidative
substances. Currently data are insufficient to propose a recommendation for olive oil-based emulsions [165].
Soy bean and olive oil-based lipid emulsions contain long chain triglycerides. There are also lipid emulsions with
the equal proportions of LCT and MCT from coconut oil. They contain less PUFA, and the MCT proportion is
oxidised more rapidly [166]. A further potential benefit is that oxidation of MCT is less dependent on carnitine
that of LCT. The energy content of MCT per g fat is, however, approx. 16% lower than that of LCT. Studies in
adults and children show a higher lipid oxidation, less influence on the parameters of the liver function, improved
leukocyte function and less influence on pulmonary haemodynamics and the gas exchange than with LCT
emulsions [167-171]. There were no significant differences in regard to the plasma lipids and fatty acids [167,
172-174]. There is differing data concerning a nitrogen-saving effect when administering a MCT/LCT mixture.
One study describes increased nitrogen retention [175, 176], while another study describes a more unfavourable
leucine metabolism than when on LCT intake [177]. The current studies in children and newborns [125, 167,
173, 178, 179] do not justify any generally favoured utilisation of MCT/LCT emulsions compared to pure LCT
emulsions at present [165, 174].
The ratio between phospholipids (PL) and triglycerides (TG) is lower in 20% lipid emulsions than in standard
19
10% lipid emulsions [180]. Lipid emulsions with a low PL/TG ratio as in the standard 20% emulsions, should be
favoured in PN [98, 125, 181, 182]. Higher amounts of phospholipids impair the clearance of triglycerides from
the plasma, resulting in an increase in the plasma triglyceride concentration and of cholesterol and
phospholipids in Low-Density-Lipoproteins [98]. The emulsion characteristics (dispersity, stability) and various
incompatibilities are of great significance in the parenteral intake of lipids.
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Fusch C1, Bauer K2, Böhles HJ2, Jochum F3, Koletzko B4, Krawinkel M5, Krohn K4, Mühlebach S6 *
1Dept.
of Pediatrics, McMaster University, Hamilton, Canada, 2Dept. of Paediatrics, Johann-Wolfgang-Goethe
University of Frankfurt, 3Dept. of Paediatrics, Spandau Hospital, Berlin, 4Dept. Metabolic Diseases & Nutritional
Medicine, Dr. von Hauner Children's Hospital, University of Munich, 5Institute for Nutritional Science and Centre
for Paediatrics, University of Giessen, 6CSO Vifor Pharma Ltd, Villars-sur-Glâne, and University of Basel
Switzerland for the working group for developing the guidelines for parenteral nutrition of The German Society
for Nutritional Medicine.
23
Erstellungsdatum:
04/2014
AWMF online - Guidelines on Parenteral Nutrition: Intensive medicine
1
AWMF online
Wissenschaftlichen
Medizinischen
Fachgesellschaften
Nr. 073-018e_14
Entwicklungsstufe:
3
Zitierbare Quelle:
Chapter 14: Intensive medicine
Kapitel 14: Intensivmedizin
Key words: Substrate supply, critically ill, sepsis, intensive care
Schlüsselwörter: Substratzufuhr, kritisch krank, Sepsis, Intensivtherapie
Abstract
In intensive care patients parenteral nutrition (PN) should not be carried out when adequate oral or enteral
nutrition is possible. Critically ill patients without symptoms of malnutrition, who probably cannot be adequately
nourished enterally for a period of <5 days, do not require full PN but should be given at least a basal supply of
glucose. Critically ill patients should be nourished parenterally from the beginning of intensive care if they are
unlikely to be adequately nourished orally or enterally even after 5-7 days. Critically ill and malnourished patients
should, in addition to a possible partial enteral nutrition, be nourished parenterally. Energy supply should not be
constant, but should be adapted to the stage, the disease has reached. Hyperalimentation should be avoided at
an acute stage of disease in any case. Critically ill patients should be given, as PN, a mixture consisting of
amino acids (between 0.8 and 1.5 g/kg/day), carbohydrates (around 60% of the non-protein energy) and fat
(around 40% of the non-protein energy) as well as electrolytes and micronutrients.
Zusammensetzung
Eine parenterale Ernährung (PE) sollte nicht durchgeführt werden, wenn eine ausreichende orale oder enterale
Ernährung möglich ist. Kritisch Kranke ohne Zeichen der Mangelernährung, die voraussichtlich <5 Tage nicht
ausreichend enteral ernährt werden können, bedürfen keiner vollen PE, sollten aber zumindest eine basale
Glukosezufuhr erhalten. Kritisch Kranke sollten von Anbeginn der Intensivtherapie parenteral ernährt werden,
wenn sie voraussichtlich auch nach einem Zeitraum von 5-7 Tagen nicht ausreichend oral oder enteral ernährt
werden können. Kritisch Kranke mit einer Mangelernährung sollten - auch neben einer möglichen partiellen
enteralen Ernährung - parenteral ernährt werden. Die Energiezufuhr sollte nicht konstant sein, sondern muss an
den Verlauf der Erkrankung angepasst werden. Eine Hyperalimentation sollte im akuten Stadium der
Erkrankung auf jeden Fall vermieden werden. Kritisch Kranke sollten zur PE eine Mischung aus Aminosäuren
(0,8 und 1,5 g/kg/Tag), Kohlenhydraten (ca. 60% der Nicht-Protein Energie) und Fett (ca. 40% der Nicht-Protein
Energie) sowie Elektrolyten und Mikronährstoffen erhalten.
Indications for PN in critically ill patients

Parenteral nutrition (PN) should not be instituted when adequate oral or enteral nutrition is possible (C).

2
Critically ill patients without symptoms of malnutrition, who probably cannot be adequately nourished enterally
for a period of <5 days, do not require full PN but should be given at least a basal supply of glucose (B).
Commentary
Patients who can be nourished orally or enterally should certainly be nourished this way.
The negative consequences of PN observed in earlier studies [1] probably occurred as a result of unphysiologic
composition and infrequent monitoring of PN (too high energy used, badly monitored BS (blood sugar) levels)
rather than because of the parenteral substrate administration. Recent studies [2, 3] have shown that, compared
with enteral nutrition, there is not necessarily a connection between PN and a higher rate of complications or a
worse prognosis.
Nevertheless, it is concluded by the expert group that enteral application should be preferred, if possible, as it is
more physiological, and generally incurring lower costs. Furthermore, with the exception of one study, PN did
not have specific advantages over enteral nutrition.
There are still not enough randomised controlled studies to answer the question whether patients should be fed
parenterally when they cannot be adequately enterally nourished.
Experiences over the last years have shown that if enteral nutrition is started early, a higher proportion of
patients, requiring intensive care, can be adequately nourished enterally after a few days. In one such study [4],
it was observed that a reduced nutrition supply over a few days had no negative consequences, as long as the
patients showed no symptoms of malnutrition,. Adequately nourished patients who can be completely nourished
orally or enterally again within 5-7 days do not require PN. For such patients, one should provide at least a basal
glucose supply (2-3 g/kg kg/day). However, for malnourished patients one should start early with PN.
Indication for PN

Critically ill patients should be nourished parenterally from the beginning of intensive care if they are
unlikely to be adequately nourished orally or enterally even after 5-7 days (A).
Commentary
In the above-mentioned study [4], the electively operated patients, who were given infusions of only 250-300 g
glucose/day and were unable to take adequate nourishment orally after 14 days, showed a 10 times higher
mortality than patients who were nourished completely parenterally from the beginning of intensive care.
Therefore, post-operative patients who might develop a state of malnutrition, after a period of 8-12 days on only
glucose infusions, may be predisposed to a higher rate of mortality. Since it should not be the aim of nutrition
therapy to allow the patients to get into a state of malnutrition and then be treated for it, such patients should be
nourished parenterally from the beginning of intensive care.
Accordingly, the indication for PN should be made prospectively in critically ill parents. The number of days
required to re-establish adequate enteral or oral nutrition should be considered at the beginning of the therapy.
There are, at present, no established criteria, which could help in determining, with absolute certainty, which
patients are to be nourished parenterally. Therefore, it cannot be avoided that occasionally there are patients on
PN who are adequately nourished enterally sooner than expected, and some patients who unexpectedly
deteriorate and an indication for PN is established too late.
Combined nutrition therapy (enteral and parenteral nutrition)

Critically ill and malnourished patients should, in addition to a possible partial enteral nutrition, be
nourished parenterally (A).
Commentary
Several studies dealing with patients suffering from severe malnutrition, which have been summarized in one
meta-analysis [1], have reported a positive effect of PN with a reduction in complications and mortality.
Energy intake

The amount of energy supplied should follow the principles stated in the chapter on "Energy metabolism and
Energy intake".
This means that the energy supply should not be constant, but should be adapted to the stage, the disease has
reached. Hyper-alimentation should be avoided at an acute stage of disease in any case.
3
Substrate intake

Critically ill patients should be given, as PN, a mixture consisting of amino acids, carbohydrates, (around 60% of
the non-protein energy) and fat (around 40% of the non-protein energy) as well as electrolytes and
micronutrients (C).
Commentary
Typical metabolic changes in patients with systemic inflammatory reactions are a reduced oxidation of
carbohydrates and an increased oxidation of fat. The disproportion between endogenous glucose production
and peripheral glucose oxidation leads to hyperglycaemia in most patients. Accordingly, a lipid supply of 30-50
% of energy intake corresponds to the existing pattern of utilization. An increased glucose intake, in such
circumstance, does not reduce the endogenous glucose production [5], and leads to a further increase in the
already existing hyperglycaemia.
However, it has not been substantiated by studies whether in critically ill patients PN with lipids, and with which
kind of lipids, would be more effective than a carbohydrate intake without lipids with respect to outcome
parameters. Therefore, the recommendation of the group to give PN containing fat to critically ill patients is only
an expert opinion (C).
The comparative study of Batistella [6], which showed obvious disadvantages when lipids were administered to
trauma patients has the following shortcomings: a) not isocaloric in both arms of the study (the energy contents
in patients without lipids was about 25 % lower) and b) soya bean oil/lipid emulsion was used in the study, the
use of which is nowadays controversial for patients in a critical state (see below). Similarly, the higher rate of
complications that has been found in the meta-analysis of Heyland et al. [7] for patients given lipid infusions is
more a result of the special fat emulsion used than the fat administration in general.
Carbohydrates (cf. "Carbohydrates")

Critically ill patients should predominantly be given glucose as carbohydrate. There is no certain
indication for other carbohydrates in critically ill patients (C).
Commentary
Fructose and sorbitol are no longer used because of the grave side effects when there is an inborn
incompatibility.
With Xylit, a reduction of hyperglycaemia as well as a decrease in hepatic gluconeogenesis was shown in two
clinical studies on a small number of patients, when glucose intake was simultaneously decreased. These
results have not been confirmed in any further major study. This group does not recommend the use of Xylit,
particularly in consideration of observed complications (oxalose).
Hyperglycaemia arising from PN (cf. "Carbohydrates" and "Complications and Monitoring")
 At all times, a hyperglycaemia caused by PN should be avoided (A).
 If hyperglycaemia occurs, in spite of an adequate insulin supply, the carbohydrate supply should be
reduced (C).
Commentary
The study of van den Berghe et al. [8] showed that, for patients requiring intensive care, blood sugar levels of
over 110 mg/dl are linked to a significant increase in mortality and morbidity. Insulin can reduce blood glucose
level through an increase in cellular glucose uptake and partly through increased glucose utilization as well. The
insulin effect can, however, be reduced in particular illnesses such as diabetes mellitus, post-operative insulin
resistance, or sepsis.
There were indications in a more recent uncontrolled observational study, that a significantly higher mortality
was observed only at blood sugar concentration of >145 mg/dl [9]. In the controlled study from van den Berghe,
however, in the group of patients with blood sugar levels between 110-150 mg/dl there was already a
significantly higher mortality than in the group of patients in which blood sugar was strictly controlled at values
below 110 mg/dl [10]. Therefore, the objective should be to aim for a normoglycaemia with PN, ideally a level
between 80 and 110 mg/dl.
Basically two situations can occur:
a. Patients who are euglycaemic before the start of a PN: If there is a significant increase in the blood sugar
level to a value considerably > 110 mg/dl, while an adequate substrate supply is being administered
during the PN, then this should be lowered with a continuous intravenous insulin administration, by
means of an infusion pump. It is recommended to have a standardised protocol according to which the
4
insulin dose can be regulated in accordance with the measured blood glucose levels. If normoglycaemia
(<145 mg/dl, ideally <110 mg/dl) is not achieved, even with a maximum insulin dose of approximately 20
IU insulin/h, then the carbohydrate supply should be reduced until the target BS level is attained using
this insulin dose. The maximum level of approximately 20 IU insulin/h is not substantiated by any study
but is an expert opinion.
If the BS falls to a level <80 mg/dl with this therapy, then the carbohydrate intake should be increased
again until the target carbohydrate intake for euglycaemic conditions is achieved.
If the BS level falls at the maximum (= target) value of carbohydrate intake, the insulin dose should be
lowered.
b. Patients with a BS level >110 mg/dl before commencing PN:
For these patients, hyperglycaemia is a result of a disproportional rate of endogenous gluconeogenesis
and glucose oxidation. It is not recommended, under these conditions, to infuse even more glucose as
this would only augment the hyperglycaemia.
For this reason, one should start with a continuous insulin infusion. Only when the target BS level can be
reached and maintained with a dose of ≤ 4 IU insulin/h, one should start with an additional glucose
supply.
Fats


No choice of specific fat emulsion is recommended for critically ill patients, because there are no
conclusive clinical studies on varying endpoint effects of different lipid emulsions.
A preferential use of lipid emulsions with a lower content of polyunsaturated fatty acids, relative to pure
soybean oil emulsions, appears justifiable in critically ill patients (C).
Commentary
A large number of clinical, ex-vivo and animal studies have shown that the quality of the infused fatty acids has a
clinically relevant effects on the immune system. It was observed that classic soybean oil emulsions suppressed
the cellular immune response and stimulated the release of interleukins with a pro-inflammatory pattern. One
clinical study [6] has also demonstrated that soybean oil emulsions not affect killer cell activity but also induce a
higher rate of infection and longer duration of mechanical ventilation and treatment. However, in this study the
control group did not receive isocaloric nutrition.
The existing experimental data as well as this clinical study appear to justify the recommendation not to consider
pure soybean oil emulsions as the lipid emulsion of choice for critically ill patients.
Alternatives are mixtures consisting of soybean oil and MCT, a mixture consisting of soybean oil or soybean
oil /MCT and fish oil, a mixture consisting of 20% soybean oil and 80% olive oil, or a mixture consisting of
soybean oil, MCT, olive oil and fish oil, or a mixture consisting of soybean oil, MCT and fish oil. In addition, an
emulsion is available with re-esterified medium- and long-chain fatty acids.
No clinical studies have been published to demonstrate an obvious advantage of one of these emulsions over
others with respect to relevant clinical outcome parameters in critically ill patients.
Amino acids

The amino acid intake with PN for critically ill patients should usually be between 0.8 and 1.5 g/kg/day
(A).
Commentary
In several clinical studies it was observed that an amino acid infusion of more than 1.5 g/kg/day does not lead to
a better nitrogen balance, but instead to an augmented urea production [11-16]. Although this level has been
questioned recently by several authors [17, 18], on the basis of the existing data it is recommended to supply
parenteral amino acids between 0.8 and 1.5 g/kg body weight daily. Certain groups of patients (e.g. patients with
burns, patients with renal failure) need a higher infusion of amino acids.
Glutamine

Critically ill patients who are nourished parenterally for longer than 5 days, without receiving any
significant nutrition enterally, should be given, in addition to the parenteral infusion of amino acids,
glutamine dipeptide in a dose of 0.3-0.4 g/kg body weight/day (equivalent to 0.2-0.26 g glutamine/kg body
weight/day) (A).
Commentary
5
A meta-analysis [19] published in 2002 found that a glutamine supplementation leads to a lower rate of
complications and a decrease in mortality rate in critically ill patients. However, the validity of this meta-analysis
is limited because it was an evaluation of studies in which both parenteral and enteral glutamine
supplementation studies were evaluated together. Furthermore, there was one study dealing only with burn
patients [20].
After the publication of the above meta-analysis, two more studies were published, in which critically ill patients
were administered additional glutamine parenterally [21, 22]. The investigation by Goeters et al. [22] showed
that for patients who were treated with 0.2 g glutamine/kg body weight/day for a period of ≥9 days, the mortality
over a period of 6 months could be reduced significantly from 66.7 % to 40 %. These results confirm the results
of Griffiths et al. [23], where significant improvement in survival at 6 months was observed mainly in those
patients who were treated with glutamine for more than 5 days.
Another study, however, published in 2004 showed in patients with secondary peritonitis [21] only a tendency to
a decreased mortality with parental supplementation of glutamine. This was also observed by the study of
Powell-Tuck et al. [24] with patients clinically accepted for PN. On the basis of the results of these four studies, it
is concluded that a solution of amino acids enriched with glutamine dipeptides should be used at least in
patients who need PN for more than 5 days,
Branched-chain amino acids

In critically ill patients, there is no firm indication for the use of amino acids solutions with a higher
proportion of branched-chain amino acids, except for patients with severe hepatic encephalopathy (C).
Commentary
The published small studies [25-27] using amino acid solutions with an increased proportion of branched-chain
amino acids in critically ill patients did not show any advantages in outcome parameters till to date. The expert
group does not see a concrete indication for the use of such a solution at present, since a major study on this is
not yet published.
References
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Bertolini G, Iapichino G, Radrizzani D et al. Early enteral immunonutrition in patients with severe sepsis: results of an interim analysis of a
randomized multicentre clinical trial. Intensive Care Med 2003; 29: 834-840
Woodcock NP, Zeigler D, Palmer MD, Buckley P, Mitchell CJ, MacFie J. Enteral versus parenteral nutrition: a pragmatic study. Nutrition 2001; 17: 112
Sandstrom R, Drott C, Hyltander A et al. The effect of postoperative intravenous feeding (TPN) on outcome following major surgery evaluated in a
randomized study. Ann Surg 1993; 217: 185-195
Tappy L, Schwarz JM, Schneiter P et al. Effects of isoenergetic glucose-based or lipid-based parenteral nutrition on glucose metabolism, de novo
lipogenesis, and respiratory gas exchanges in critically ill patients. Crit Care Med 1998; 26: 860-867
Battistella FD, Widergren JT, Anderson JT, Siepler JK, Weber JC, MacColl K. A prospective, randomized trial of intravenous fat emulsion
administration in trauma victims requiring total parenteral nutrition. J Trauma 1997; 43: 52-58
Heyland DK, MacDonald S, Keefe L, Drover JW. Total parenteral nutrition in the critically ill patient: a meta-analysis. JAMA 1998; 280: 2013-2019
Van den Berghe G, Wouters P, Weekers F et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001; 345: 1359-1367
Finney SJ, Zekveld C, Elia A, Evans TW. Glucose control and mortality in critically ill patients. JAMA 2003; 290: 2041-2047
Van den Berghe G, Wouters PJ, Bouillon R et al. Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control.
Crit Care Med 2003; 31: 359-366
Seron AC, Avellanas CM, Homs GC, Larraz VA, Laplaza MJ, Puzo FJ. Evaluation of a high protein diet in critical care patients. Nutr Hosp 1999; 14:
203-209
Ishibashi N, Plank LD, Sando K, Hill GL. Optimal protein requirements during the first 2 weeks after the onset of critical illness. Crit Care Med 1998;
26: 1529-1535
van der Heijden A, Verbeek MJ, Schreurs VV, Akkermans LM, Vos A. Effect of increasing protein ingestion on the nitrogen balance of mechanically
ventilated critically ill patients receiving total parenteral nutrition. Nutr Hosp 1993; 8: 279-287
Larsson J, Lennmarken C, Martensson J, Sandstedt S, Vinnars E. Nitrogen requirements in severely injured patients. Br J Surg 1990; 77: 413-416
Wolfe RR, Goodenough RD, Burke JF, Wolfe MH. Response of protein and urea kinetics in burn patients to different levels of protein intake. Ann
Surg 1983; 197: 163-171
Schmitz JE, Lotz P, Ahnefeld FW, Grunert A. Protein and energy metabolism in intensive care patients. Infusionsther Klin Ernähr 1981; 8: 158-162
Scheinkestel CD, Kar L, Marshall K et al. Prospective randomized trial to assess caloric and protein needs of critically ill, anuric, ventilated patients
requiring continuous renal replacement therapy. Nutrition 2003; 19: 909-916
Hoffer LJ. Protein and energy provision in critical illness. Am J Clin Nutr 2003; 78: 906-911
Novak F, Heyland DK, Avenell A, Drover JW, Su X. Glutamine supplementation in serious illness: a systematic review of the evidence. Crit Care Med
2002; 30: 2022-2029
Wischmeyer PE, Lynch J, Liedel J et al. Glutamine administration reduces Gram-negative bacteremia in severely burned patients: a prospective,
randomized, double-blind trial versus isonitrogenous control. Crit Care Med 2001; 29: 2075-2080
Fuentes-Orozco C, Anaya-Prado R, Gonzalez-Ojeda A et al. L-alanyl-L-glutamine-supplemented parenteral nutrition improves infectious morbidity in
secondary peritonitis. Clin Nutr 2004; 23: 13-21
Goeters C, Wenn A, Mertes N et al. Parenteral L-alanyl-L-glutamine improves 6-month outcome in critically ill patients. Crit Care Med 2002; 30:
2032-2037
Griffiths RD, Jones C, Palmer TE. Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutrition 1997; 13:
295-302
Powell-Tuck J, Jamieson CP, Bettany GE et al. A double blind, randomised, controlled trial of glutamine supplementation in parenteral nutrition. Gut
1999; 45: 82-88
Freund HR, Hanani M. The metabolic role of branched-chain amino acids. Nutrition 2002; 18: 287-288
26.
27.
6
Garcia-de-Lorenzo A, Ortiz-Leyba C, Planas M et al. Parenteral administration of different amounts of branch-chain amino acids in septic patients:
clinical and metabolic aspects. Crit Care Med 1997; 25: 418-424
Wang XY, Li N, Gu J, Li WQ, Li JS. The effects of the formula of amino acids enriched BCAA on nutritional support in traumatic patients. World J
Gastroenterol 2003; 9: 599-602
Kreymann G1 Adolph M2, Druml W3, Jauch KW4 *
1Dept.
of Medicine, Univ. of Hamburg; currently Baxter S.A., Schaffhausenerstr., Zurich, Switzerland, 2Dept. of
Anaesthesiology and Intensive Medicine, Eberhard-Karl University, Tuebingen, 3Clinical Dept. of Nephrology
and Dialysis, University of Vienna, Austria, 4Dept. Surgery Grosshadern, University Hospital, Munich for the
working group for developing the guidelines for parenteral nutrition of The German Association for Nutritional
Medicine
Erstellungsdatum:
04/2014
AWMF online - Guidelines on Parenteral Nutrition: Gastroenterology
1
AWMF online
Wissenschaftlichen
Medizinischen
Fachgesellschaften
Nr. 073-018e_15
Entwicklungsstufe:
3
Zitierbare Quelle:
Chapter 15: Gastroenterology
Kapitel 15: Gastroenterologie
Key words: Inflammatory bowel disease, Crohn's disease, ulcerative colitis, pancreatitis
Schlüsselwörter: Chronisch entzündliche Darmerkrankungen, Morbus Chrohn, Colitis ulcerosa, Pankreatitis
Abstract
In patients with Crohn`s disease and ulcerative colitis PN is indicated when enteral nutrition is not possible or
should be avoided for medical reasons. In Crohn`s patients PN is indicated when there are signs/symptoms of
ileus or subileus in the small intestine, scars or intestinal fistulae. PN requires no specific compounding for
chronic inflammatory bowel diseases. In both diseases it should be composed of 55-60 % carbohydrates, 25-30
% lipids and 10-15 % amino acids. PN helps in the correction of malnutrition, particularly the intake of energy,
minerals, trace elements, deficiency of calcium, vitamin D, folic acid, vitamin B12, and zinc. Enteral nutrition is
clearly superior to PN in severe, acute pancreatitis. An intolerance to enteral nutrition results in an indication for
total PN in complications such as pseudocysts, intestinal and pancreatic fistulae, and pancreatic abscesses or
pancreatic ascites. If enteral nutrition is not possible, PN is recommended, at the earliest, 5 days after admission
to the hospital. TPN should not be routinely administered in mild acute pancreatitis or nil by moth status <7 days,
due to high costs and an increased risk of infection. The energy requirements are between 25 and 35 kcal/kg
body weight/day. A standard solution including lipids (monitoring triglyceride levels!) can be administered in
acute pancreatitis. Glucose (max. 4-5 g/kg body weight/day) and amino acids (about 1.2-1.5 g/kg body
weight/day) should be administered and the additional enrichment of TPN with glutamine should be considered
in severe, progressive forms of pancreatitis.
Zusammensetzung
Eine PE ist indiziert bei Patienten mit Morbus Crohn oder Colitis ulcerosa, wenn eine enterale Ernährung nicht
möglich ist bzw. aus medizinischen Gründen vermieden werden sollte. Bei Morbus Crohn Patienten kann eine
PE bei Manifestation im oberen Dünndarm und Ileus- und Subileussymptomatik, Narben oder Darmfisteln
indiziert sein. Die PE bedarf keiner speziellen Zusammensetzung für chronisch entzündliche
Darmerkrankungen. In beiden Erkrankungen sollte sich die PE aus 55-60 % Kohlenhydraten, 25-30 % Fett und
10-15 % Aminosäuren zusammensetzen. Die PE unterstützt die Korrektur der Mangelernährung, vor allem die
Aufnahme von Energie, Mineralstoffen, Spurenelementen, Mangel an Kalzium, Vitamin D, Folsäure, Vitamin B
12, Zink. Im Falle einer notwendigen künstlichen Ernährung bei einer schweren akuten Pankreatitis ist eine
enterale Ernährung einer parenteralen Ernährungsform eindeutig überlegen. Eine Unverträglichkeit der
enteralen Ernährung führt bei Komplikationen, wie Pseudozysten, intestinale und pankreatische Fisteln,
pankreatische Abszesse oder pankreatischem Aszites zum Einsatz der TPE. Sollte eine enterale Ernährung
2
nicht möglich sein, ist eine PE erst nach frühestens 5 Tagen nach Klinikeintreffen zu empfehlen. Die TPE sollte
bei milder akuter Pankreatitis, Nahrungskarenz < 7 Tage, nicht routinemäßig verabreicht werden, aufgrund
steigender Kosten und erhöhtem Infektionsrisiko. Der Energiebedarf liegt zwischen 25 und 35 kcal/kg KG/Tag.
Bei akuter Pankreatitis kann eine Standardlösung inklusive Fett verabreicht werden (Monitoring der
Triglyzeridspiegel!). Glukose von max. 3-6 g/kg KG/Tag und Aminosäuren von 1,2-1,5 g/kg KG/Tag sollten
zugeführt werden sowie eine zusätzliche Anreicherung durch Glutamin von TPE sollte bei schweren
Verlaufsformen einer Pankreatitis erwogen werden.
Crohn's Disease
Indication and Time of Parenteral Nutrition (PN)


PN is indicated when enteral nutrition is not possible or should be avoided for medical reasons (A).
PN is indicated when there are signs/symptoms of ileus or subileus in the small intestine, scars or
intestinal fistulae (C).
Substrate Intake



PN requires no specific compounding for chronic inflammatory bowel diseases.
It should be composed of 55-60% carbohydrates, 25-30% lipids and 10-15% amino acids (A). No
conclusive data is available on the use of admixtures in the form of polyunsaturated fatty acids (C).
PN helps in the correction of malnutrition, particularly the intake of energy, minerals, trace elements,
deficiency of calcium, vitamin D, folic acid, vitamin B12, and zinc (A).
Commentary
Once the use of PN has been decided upon, a PN solution should be used due to the high incidence of
malnutrition in chronic inflammatory bowel disease. PN should be administered via central venous access for
osmolarity over 800 mosmol/l and continuously over 24 hours.
The daily parenteral energy intake in well-nourished adult patients should amount to 25-30 kcal/kg body weight.
During the first 24-48 hours, the PN administration should be slowly started with a phase of an "up-titration",
starting with about 50% of the energy amount. The volume should be adjusted to 30-40 ml/kg body weight,
depending on the loss of fluid. Concentrations of 4-6 g glucose/kg body weight, 1.5-2 g lipids per kg body weight
and 1.5-2 g amino acids per kg body weight are recommended [1].
PN is indicated in cases of toxic megacolon, malabsorption syndrome, particularly short bowel syndrome,
insufficient growth and disturbance of growth in children as well as when enteral nutrition is not tolerated [2-10].
PN presents no advantage if the disease is chronically active (A). An increased rate of remission is not achieved
with PN, according to the official recommendations of the American Gastroenterological Association (AGA). PN
has no influence on the surgical intervention rate. According to these recommendations, it is not necessary to
bypass the intestinal passage to attain clinical remission.
An optimal supply of nutrients improves bowel motility, intestinal permeability and nutritional status, and lowers
inflammatory reactions [8, 11]. Malnutrition often occurs in patients with inflammatory bowel diseases. There are
extensive differences in the parameters for malnutrition between Crohn's disease and ulcerative colitis.
Malnutrition is diagnosed in 80% of Crohn's disease patients [5, 9, 10, 11]. The severity of malnutrition depends
on the duration of the illness, activity of the inflammation, the function of the small intestine and extent of the
diseased sections in the small intestine, and results in a higher incidence of protein energy malnutrition as well
as specific substrate deficiency.
Clinical symptoms, inflammatory and nutritional parameters in Crohn's disease can improve under enteral/oral
nutrition [2, 6, 10, 13, 14, 16]. There is no standardised data available regarding the remission rate with PN. It
was found that in complicated cases, remission could be more easily attained through PN than with enteral
nutrition [17].
Total PN is an important therapy in children and teenagers [5].
In terms of wound healing and reconstitution of the small intestine, PN shows no advantages as compared to
enteral nutrition. It is assumed that oral/enteral nutrition provides faster stability in organ function of the small
intestine.
Complications like venous thromboses, occlusion of the central venous vessels, sepsis,
cholestasis/cholangitis/cholecystitis, cholestatic liver dysfunction are associated with TPN [18-29]. Acute
elevation in transaminases, overall bilirubin and albumin are characteristics of PN metabolic complications [1824, 26, 27]. Numerous studies show that catheter-related sepsis occur on an average once or twice every two
years in patients on long-term PN who are suffering from a functional short bowel syndrome, as a result of
3
chronic inflammatory bowel diseases. Recurring catheter infections with septic components occur during
hospital stays in dependence of central access catheter models and in dependence of training and care
standards in the hospital in patients who are not receiving long-term PN [30]. There are no advantages of PN
therapy over enteral nutrition therapy regarding fistula healing. No differences can be seen in the rate of survival.
Ulcerative Colitis
Indication and Time of PN

PN is indicated when enteral nutrition is not possible or should be avoided for medical reasons (A).
Substrate Intake



PN requires no specific compounding for chronic inflammatory bowel diseases (A).
It should be composed of 55-60% carbohydrates, 25-30% lipids and 10-15% amino acids (A). No
conclusive data is available on the use of admixtures in the form of polyunsaturated fatty acids (C).
PN helps in the correction of malnutrition, particularly the intake of energy, minerals, trace elements,
deficiency of calcium, vitamin D, folic acid, vitamin B12, and zinc (A). In addition, the intake of vitamins,
trace elements and minerals can be orally or intravenously substituted irrespective of PN.
Commentary
No significant improvement in clinical parameters was observed in patients with ulcerative colitis with the use of
PN [2, 12]. There is no standardised data available regarding the remission rate with PN. It was also observed
that, in complicated cases, remission could be more easily attained with PN than with enteral nutrition [17].
Total PN is an important therapy in children and teenagers [5].
In terms of wound healing and the reconstitution of the small intestine, PN shows no advantages compared to
enteral nutrition. It is assumed that oral/enteral nutrition provides faster stability in organ function of the small
intestine.
Complications like venous thrombosis, occlusion of the central venous vessels, sepsis,
cholestasis/cholangitis/cholecystitis, cholestatic liver dysfunction are associated with TPN [18, 19, 21-24, 26, 27,
32].
Acute increase in transaminases, overall bilirubin and albumin are characteristics of metabolic complications of
PN [18, 19, 21-24, 26, 27, 32].
There are no advantages of PN therapy over enteral nutrition therapy regarding fistula healing. No differences
can be seen in the rate of survival.
Acute Pancreatitis




Enteral nutrition is clearly superior to PN in severe, acute pancreatitis (A).
An intolerance to enteral nutrition results in an indication for total PN in complications such as
pseudocysts, intestinal and pancreatic fistulae, and pancreatic abscesses or pancreatic ascites (B).
If enteral nutrition is not possible, PN is recommended, at the earliest, 5 days after admission to the
hospital (C).
TPN should be not be routinely administered in mild acute pancreatitis or nil by moth status <7 days,
due to high costs and an increased risk of infection (C).
Commentary
The nutritional therapy of acute pancreatitis depends on the severity of the disease, presence of any
complications and nutritional state of the patient. Enteral transduodenal feeding should be started once acute
pancreatitis is suspected. There is a clear benefit with enteral nutrition in numerous studies [33-43] regarding
LOS, infection-related morbidity and possible organ failures. Total PN should be started only when there are
4
contraindications to enteral nutrition or no possible access.
The time to start should be after the resolution of the acute phase in acute, complicated forms of pancreatitis
[15, 44]. A prospective, controlled and randomised study on acute pancreatitis [45] shows that exclusive TPN
results in a longer LOS and increase in costs with no improvement regarding the course of disease.
Recent studies have shown that enteral nutrition through a jejunal tube can be of an advantage in specific
patient groups [31, 46-48]. A similarly positive effect is also achieved by using nasogastric tubes, but in a smaller
study [49]. Jejunal feeding is assessed to be safe and effective in the postoperative stage in severe forms of
pancreatitis, according to the study by Pupelis [31]. TPN is presumed to prevent stimulation of the exocrine
pancreas as well as help in the maintenance of metabolic homeostasis in severe forms of pancreatitis [19, 32].
In severe cases (presence of ileus), the task of TPN is to compensate for the increased protein expenditure, as
well as to maintain the nutrition state of the patient. PN reduces mortality and improves the nutritional situation in
such circumstances [50, 51], and is to be continued until a stable, haemodynamic state is achieved [52, 53].
The lack of utilisation of the intestine in acute pancreatitis seems to worsen the metabolic stress situation,
lengthen the LOS and increase the risk of complications [33, 36, 42, 46, 54, 55]. Further evidence indicates that
not only enteral nutrition, but also specific nutritional components in enteral nutrition such as probiotics, arginine,
glutamine and antioxidants have a positive influence on LOS and the rate of complications [56, 57].
Energy Intake

The energy requirements lie in a range between 25 and 35 kcal/kg body weight/day [18] (A).
Substrate Intake





A standard solution including lipids can be administered in acute pancreatitis (C). Lipids can be
administered to meet energy requirements and should be subject to regular monitoring (triglycerides).
Carbohydrates are the most important energy source. Glucose administration (max. 4-5 g/kg body
weight/day) counteracts intrinsic gluconeogenesis, and prevents protein degradation. Administering
glucose instead of lipids, as an energy supplier, lowers the potential risk of hyperlipidemia, but lipid
administration cannot be avoided in most cases (B).
An even nitrogen balance can be achieved and maintained with amino acids. The intake of amino
acids should be about 1.2-1.5 g/kg body weight/day (A).
The additional enrichment of TPN with glutamine should be considered in severe, progressive forms of
pancreatitis, thereby improving the clinical progression (B).
The intravenous administration of lipid emulsions is safe, as long as triglyceride levels (<400 mg/dl) are
monitored (C). Statements on particularly beneficial fatty acid admixtures cannot be made regarding
pancreatitis.
Commentary
McClave et al. [45] carried out a study in 1997, in which 30 patients received either total PN or total enteral
nutrition. No differences between the two groups were observed with regards to mortality, level of pain in the
period until amylase levels normalised, serum albumin levels and the frequency of nosocomial infections.
Significantly more hyperglycaemia occurred in the total PN group [36].
Tests on fatty acid admixtures are at present only available for "Intralipid" solutions and are deemed safe for
administration [58].
The glucose admixture was modified in 2 studies [58, 59] based on the clinical picture of stress-induced
hyperglycaemia. In the study carried out by Wu [58], initial hyperglycaemia was reported in 64 % of patients,
which was easier to control with a lipid/glucose admixture than in a pure glucose admixture.
Hypertriglyceridaemia, or negative effects on the liver function, were not reported. Significant differences
regarding the glucose levels, cholesterol levels or uric acid levels were also not reported in Martinez' work [59].
De Beaux et al. [60] carried out a study of 14 patients with acute pancreatitis, where one group received
standardised PN and the other group received nutrition enriched with glutamine. The glutamine group showed
increased lymphocyte proliferation, an increase in T-cell DNA as well as a drop in an interleukin 8 concentration.
The administration of glutamine could be beneficial in preventing complications. A lower rate of complications
and significantly lower rates of pancreatic infections were also described with glutamine in the papers by
Ockenga et al. [61] and Xian et al. [62]. Patients with acute pancreatitis show an increased rate of cathetersepsis and metabolic dysfunctions. The administration of thiamine, folic acid, magnesium and zinc is
recommended in patients with a history of alcohol abuse [19, 63].
Patients with severe diseases and complications require early enteral nutritional therapy to prevent detrimental
effects caused by nutritional losses (especially proteins) [34, 38, 64]. Some authors recommend early jejunal
nutrition with an elementary diet and others recommend TPN combined with enteral nutrition [65]. PN should
5
only be used in complicated cases when ileus is present or probable with regular checks for glucose,
triglycerides and serum pH.
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Schulz RJ1, Bischoff SC2, Koletzko B3 *
1Clinic
for Geriatrics, St. Marien-Hospital, Cologne, 2Dept Nutritional Medicine and Prevention, University
Stuttgart-Hohenheim, 3Dept. Metabolic Diseases & Nutritional Medicine, Dr. von Hauner Children's Hospital,
University of Munich for the working group for developing the guidelines for parenteral nutrition of The German
Association for Nutritional Medicine
Erstellungsdatum:
04/2014
7
AWMF online - Guidelines on Parenteral Nutrition: Hepatology
1
AWMF online
Wissenschaftlichen
Medizinischen
Fachgesellschaften
Nr. 073-018e_16
Entwicklungsstufe:
3
Zitierbare Quelle:
Chapter 16: Hepatology
Kapitel 16: Hepatologie
Key words: Non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, liver cirrhosis, hepatic
encephalopathy, acute liver failure
Schlüsselwörter: Fettleberhepatitis, alkoholische Lebererkrankung, Leberzirrhose, hepatische
Enzephalopathie, akutes Leberversagen
Abstract
Parenteral nutrition (PN) is indicated in alcoholic steatohepatitis (ASH) and in cirrhotic patients with moderate or
severe malnutrition. PN should be started immediately when sufficientl oral or enteral feeding is not possible.
ASH and cirrhosis patients who can be sufficiently fed either orally or enterally, but who have to abstain from
food over a period of more than 12 hours (including nocturnal fasting) should receive basal glucose infusion (2-3
g/kg/d). Total PN is required if such fasting periods last longer than 72 h. PN in patients with higher-grade
hepatic encephalopathy (HE); particularly in HE IV° with malfunction of swallowing and cough reflexes, and
unprotected airways. Cirrhotic patients or patients after liver transplantation should receive early postoperative
PN after surgery if they cannot be sufficiently rally or enterally nourished. No recommendation can be made on
donor or organ conditioning by parenteral administration of glutamine and arginine, aiming at minimising
ischemia/reperfusion damage. In acute liver failure artificial nutrition should be considered irrespective of the
nutritional state and should be commenced when oral nutrition cannot be restarted within 5 to 7 days. Whenever
feasible, enteral nutrition should be administered via a nasoduodenal feeding tube.
Zusammenfassung
Bei Patienten mit Alkoholischer Steatohepatitis (ASH) oder Zirrhose mit mäßiger oder schwerer
Mangelernährung, die auf oralem oder enteralem Wege nicht ausreichend ernährt werden können, ist der
sofortige Beginn der PE (parenterale Ernährung) indiziert. ASH- oder Zirrhosepatienten, die auf oralem oder
enteralem Wege ausreichend ernährt werden können, aber aus medizinischen Gründen eine vorübergehende,
über 12 h hinausgehende Nahrungskarenz (nächtliche Nahrungskarenz mitrechnen) einhalten müssen, sollen
eine basale Glukosezufuhr (2-3 g.kg-1.d-1) erhalten. Dauert diese Karenz länger als 72 h, ist eine totale PE
indiziert. Bei höhergradiger hepatischer Enzephalopathie, insbesondere bei HE IV, ist bei gestörten
Schutzreflexen und ungeschützten Atemwegen der parenterale Zufuhrweg für die Ernährung in Betracht zu
ziehen. Des Weiteren sollten Zirrhosepatienten oder Patienten nach einer Lebertransplantation nach einem
operativen Eingriff eine frühe postoperative (zusätzliche) PE erhalten, wenn sie auf oralem oder enteralem
Wege nicht ausreichend ernährt werden können. Zur Frage der Spender- bzw. Organkonditionierung mit dem
Ziel der Minimierung eines Ischämie-/Reperfusionsschadens durch parenterale Gabe von Glutamin und Arginin
2
kann keine Empfehlung gegeben werden. Die Indikation zur künstlichen Ernährung bei akutem Leberversagen
ist unabhängig vom Ernährungszustand dann zu sehen, wenn eine orale Ernährung innerhalb von 5-7 Tagen
nicht wieder aufgenommen werden kann. Dabei ist in erster Linie die enterale Ernährung über eine
nasoduodenale Sonde anzustreben.
Alcoholic Steatohepatitis (ASH; alcoholic hepatitis + cirrhosis)
Indication and time of PN in ASH


PN is indicated in ASH and should be immediately started in ASH patients with moderate or severe
malnutrition, who cannot be sufficiently fed either orally or enterally (A).
ASH patients who can be sufficiently fed either orally or enterally, but who have to abstain from food
(including nocturnal fasting) for more then 12 hours should receive basal glucose infusion (2-3 g/kg/d)
(C). Total PN is required if fasting periods last longer than 72 h (C).
Commentary
The nutritional state of the patient carries a prognostic significance in patients with ASH (III) [1-3]. Simple
bedside methods like "subjective global assessment" or anthropometry are sufficient to identify at-risk patients,
and are, therefore, recommended [4].
PN supplementation to ad lib oral nutrition was studied in seven controlled trials using conventional amino acid
solutions. The parenteral intake provided approximately 200 - 3000 kcal/d, including 35 - 130 g amino acids per
day, and the oral intake ranged from 13 to 39 kcal/kg/d [5-13]. No change in mortality was observed with this
approach. This may be due to the inclusion of patients with low risk and only moderate disease severity.
Adverse effects of increased nitrogen intake were not observed, although sensitive methods, able to detect
minor degrees of hepatic encephalopathy, were not used. The majority of studies reported an improvement in
visceral protein compartment (serum prealbumin, transferrin, total protein, total lymphocyte count), used as a
measure of the nutritional state. An improvement in liver function (galactose elimination, serum bilirubin) was
also described.
A late evening carbohydrate snack resulted in an improvement in protein metabolism in cirrhotic patients [14-16].
Therefore, it is recommended that in the event of a long fasting duration, patients should receive a basal glucose
intake equal to the endogenous hepatic glucose production [14-16]. It is known that even an overnight fast in
cirrhotic patients results in depletion of glycogen stores and metabolic conditions similar to that after prolonged
starvation in normal individuals.
Energy Intake

In practice, an energy requirement equal to 1.3-times the basal metabolic rate, calculated by means of a
formula, can be safely assumed for patients with ASH (C).
Commentary
According to an older study [17], ASH patients are not different from healthy persons with regards to the
relationship between measured and predicted resting energy expenditure. ASH patients, however, show higher
energy consumption when correlated to their reduced muscle mass (creatinine excretion in 24 h urine).
When hydration status is normal, the actual weight should be used as body weight for the calculation of the
basal metabolic rate with the help of a formula [18]. In patients with ascites, the ideal weight according to the
body height should be used for calculations.
Substrate Intake with total PN




Carbohydrates should be provided exclusively by glucose and cover 50-60% of non-protein energy
requirements (C).
Lipids should be provided using emulsions with a reduced content of polyunsaturated fatty acids
compared to pure soybean oil emulsions and cover 40-50% of non-protein energy requirements (C).
The amino acid intake should amount to 1.2 g/kg/d in patients who are either not malnourished or
moderately malnourished, and 1.5 g/kg/d in severely malnourished patients (C).
Water-soluble and fat-soluble vitamins as well as minerals and trace elements should be administered
daily (cf. chapter "Water, electrolytes, vitamins and trace elements") (C).
Commentary
3
These recommendations are based on those for PN in liver cirrhosis, which is already present in many cases of
ASH. There are no systematic trials on the quantity and the formulation of PN for ASH.
Both water-soluble and fat-soluble vitamins should be administered daily in a standard TPN dosage. If
necessary, administration of pharmacological doses of vitamin B1, as a therapy/prophylaxis for Wernicke's
encephalopathy, or of vitamin K in cholestasis-related fat malabsorption or other vitamins may be additionally
required to correct deficiencies. Trace elements should be administered daily in a standard total PN dose. A
pragmatic recommendation is to routinely administer double the daily requirements of zinc (= 2 x 10 mg/d).
This patient group is at great risk of developing refeeding syndrome (cf. chapter "Complications and Monitoring")
because of their tendency to be chronically malnourished.
Liver Cirrhosis
Indication and Time of PN in Cirrhosis






Immediate commencement of PN is indicated in cirrhotic patients with moderate or severe malnutrition,
who cannot be sufficiently nourished either orally or enterally (C).
Cirrhosis patients, who can be sufficiently nourished either orally or enterally, but who have to abstain
temporarily from food (including nocturnal fasting) over a 12 hour period, should receive a basal glucose
infusion (2-3 g/kg/d). Total PN is required if this fast lasts longer than 72 h (C).
PN should be considered in patients with higher-grade hepatic encephalopathy (HE); particularly in HE
IV° with malfunction of swallowing and cough reflexes, and unprotected airways (C).
Cirrhosis patients should receive early postoperative (additional) PN after surgery, notwithstanding the
recommendations for other patients, if they cannot be sufficiently nourished either orally or enterally (A).
After liver transplantation, patients should receive early postoperative nutrition. PN is the option second to
enteral nutrition (C).
No recommendation can be made on the question of donor or organ conditioning, with the aim of
minimising ischemia/reperfusion damage, by parenteral administration of glutamine and arginine (C).
Commentary
Numerous descriptive studies have shown higher rates of complications and mortality in cirrhotic patients with
marked signs of protein malnutrition as well as a higher mortality rate when subjected to liver transplantation [1926].
Prevalence and severity of malnutrition are independent of the aetiology of liver disease [20, 27, 28], but
correlate positively with the severity of the illness. The prevalence of PEM increases from 20% in stage A, by
Child-Pugh criteria, to over 60% in stage C [27]. The daily food intake is of prognostic significance. Cirrhosis
patients with a low, spontaneous energy intake showed the highest mortality in controlled studies investigating
the efficiency of supplementary enteral nutrition [2, 29-32]. There are no systematic trials on PN in cirrhotic
patients without ASH.
Simple bedside methods like "Subjective Global Assessment" or anthropometry were able to sufficiently identify
malnutrition, and the use of more complex score systems was not superior in this identification [4].
The recommendation of basal glucose intake to be equal to endogenous hepatic glucose production in the event
of longer fasting is based on the findings that a late evening carbohydrate snack results in an improvement in
protein metabolism of cirrhotic patients [14-16]. After an overnight fast, in cirrhotic patients, glycogen stores are
depleted and metabolic conditions are similar to that after prolonged starvation in normal individuals.
Hepatic Encephalopathy (HE). In patients with hepatic encephalopathy, oral nutrition is often insufficient, even in
low-grade encephalopathy (HE I°-II°) due to somnolence and psycho-motor dysfunction, such that enteral
feeding is required to provide adequate nutrition. PN should be considered in patients with higher-grade
encephalopathy (HE), particularly in HE IV°, when there is malfunctioning of swallowing and cough reflexes in
the presence of unprotected airways. In clinical practice, enteral nutrition in patients with acute liver failure [33]
and the results of the study by Keohane et al. on malnourished patients with liver cirrhosis and acute
encephalopathy [34] demonstrate the feasibility of enteral nutrition in comatose cirrhotic patients. There are no
published systematic comparisons between enteral and parenteral nutrition in patients with liver cirrhosis and
encephalopathy.
In malnourished cirrhotic patients, the risk of postoperative complications, including mortality, is increased after
abdominal operations [35].
After visceral surgery, cirrhotic patients have a lower rate of complications when postoperative nutritional
therapy is given instead of just fluid and electrolytes [36, 37] (Ib).
Surgery and Transplantation. Postoperative nutrition of transplant patients confers the advantage of shorter time
on mechanical ventilation and shorter stay in the intensive care unit compared to just fluid and electrolyte
infusions [38] (Ib). In a direct comparison between parenteral and early enteral nutrition, both strategies were
equally efficient with regards to the maintenance of nutritional state [39]. However, lower incidence of viral
infections, and improved nitrogen retention were observed in patients who had been given early enteral nutrition,
12 hours after the transplantation [40].
4
At present, the value of donor or organ conditioning, by means of high doses of arginine intake, with the aim of
minimising ischemia/reperfusion damage is uncertain.
Energy Intake

The energy requirement of many patients with liver cirrhosis amounts to 1.3-times the basal metabolic
rate, calculated by means of a formula (B).
Commentary
Measured resting energy expenditure is higher than predicted by the Harris Benedict formula in up to 30-35% of
cirrhotic patients (hypermetabolism), and below the predicted value in 18% of the patients [41, 42]. Cirrhotic
patients can also have a hypermetabolic state [43], defined as measured basal metabolic rate versus value
calculated from measured body cell mass by regression analysis.
In order to classify patients according to metabolic rate, indirect calorimetry is required. Therefore, up to now
these findings remain without consequence in clinical practice. Furthermore, the few publications on total energy
expenditure in patients with liver cirrhosis indicate that the 24h energy requirement of cirrhotic patients is 130%
of the basal metabolic rate [44, 45]. Diet-induced thermogenesis [46-48] and energy requirements for physical
activity in stable cirrhosis patients [49-51] also show no deviation from those in healthy patients. Obviously, an
increased energy requirement in advanced illness is compensated for by diminished physical activity reflecting
poor physical condition [32, 51].
When hydration status is normal, the actual weight should be used as body weight for the calculation of the
basal metabolic rate according to a formula [18]. In patients with ascites, the ideal weight according to body
height should be used for calculations.
Patients with liver transplantations have average energy requirements similar to the majority of patients with
major abdominal surgery. In these patients too, an intake of non-protein energy of 1.3-fold the basal metabolic
rate is generally sufficient [52, 53]. In a longitudinal study, postoperative hypermetabolism peaked 10 days after
the transplantation at 124% of the predicted basal metabolic rate [54]. There was no difference between
measured and predicted basal metabolic rate at 6-12 months post transplantation [54,55]. Hyperalimentation
should be avoided.
Substrate Intake - General





If PN is used as the exclusive form of nutrition, all necessary macro- and micronutrients must be
administered with PN (C).
Carbohydrate intake should exclusively be provided by glucose and cover 50-60% of non-protein energy
requirements (cf. chapter "Carbohydrates") (C).
Lipid should be provided by using emulsions with a reduced content of polyunsaturated fatty acids, as
compared to pure soy bean oil emulsions, and cover 40-50% of non-protein energy requirements (C).
PN-related hyperglycaemia should be consequently avoided (A).
A reduction in carbohydrate intake to 2-3 g/kg/d and continuous insulin administration, if needed, should
be carried out in case of hyperglycaemia (C).
Commentary
Insulin resistance in Liver Cirrhosis. In the fasting state, substrate utilisation is characterised by an increased
rate of lipid oxidation and frequent occurrence of insulin resistance, even in Child-Pugh stage A of the illness
[41, 56-58]. Insulin resistance induces reduced glucose uptake and dysfunctional non-oxidative glucose
utilisation with reduced glycogen synthesis in skeletal muscles during fasting, while glucose oxidation and
lactate production return to normal after glucose administration [47, 59, 60]. Some 15-37% of cirrhotic patients
develop overt diabetes indicating an unfavourable prognosis [61 ,62].
There is growing evidence of a treatment advantage in various clinical conditions when euglycaemia is
maintained. It seems justified to also recommend this strategy for patients with liver cirrhosis who are receiving
PN (cf. chapter "Carbohydrates" and "Intensive Care Medicine").
In the early postoperative phase, a dysfunction of glucose metabolism associated with insulin resistance is often
prevalent. In this situation, hyperglycaemia should be treated by reducing the glucose intake, because higher
insulin doses do not improve glucose oxidation [63].
When tacrolimus is used for immunosuppression, its diabetogenic potential can be lowered by reducing the dose
and aiming for trough levels of 3-8 ng/ml without undue risk of rejection [64].
Lipid Tolerance and MCT/LCT. Only few data are available on the ideal composition of the main energysupplying substrates, carbohydrates and lipids. Plasma clearance and oxidation of infused lipids is normal in
cirrhotic patients [65, 66]. Glucose and lipids have been used as energy-supplying substrates in a caloric ratio of
40-50: 50-60 (G:L) in two trials [67, 68]. There are findings suggesting more favourable substrate and metabolite
concentrations when infusing both glucose and lipid compared to glucose as the sole energy substrate [69].
5
Improved functioning of the reticulo-endothelial system was observed (cf. chapter "Surgery and
Transplantation") when using MCT/LCT emulsions (with a lower content of polyunsaturated fatty acids as
compared to pure soy bean oil emulsions) after liver transplantation.
Substrate Intake - Amino Acids


Amino acids should be administered in a dose of 1.2 g/kg/d in compensated cirrhosis without severe
malnutrition, and in a dose of 1.5 g/kg/d in decompensated cirrhosis with severe malnutrition (A).
A standard solution should be given in encephalopathy ≤ grade II and a liver-adapted complete solution
should be given in encephalopathy grades III - IV. These solutions contain an increased amount of
branched-chain amino acids (BCAA) and lower content of aromatic amino acids, methionine and
tryptophan (A).
Commentary
Compensated Cirrhosis. For PN, these patients do not require an amino acid solution with a special "hepatic
formula" composition. In clinical studies, the protein or amino acid intake in patients with liver cirrhosis and
severe encephalopathy was between 0.6 and 1.2 g/kg/d [70]. In patients with alcoholic hepatitis or cirrhosis with
or without low-grade encephalopathy, the intake was between 0.5 and 1.6 g/kg/d [5-7, 9-13, 29-31, 71]. An
explicit and systematic determination of the protein requirement has, however, been carried out only in a few
studies. In these studies, patients with stable cirrhosis were found to have an increased protein requirement of
1.2 g/kg/d in contrast to the value of 0.8 g/kg/d in healthy humans [32, 44, 72, 73].
Cirrhosis with Encephalopathy. Liver-adapted amino acid solutions containing increased proportions of
branched-chain (35-45%) and a reduced proportion of aromatic amino acids as well as a reduced proportion of
methionine and tryptophan have been introduced for patients with liver diseases [74-76] (Tab. 1). These
solutions help to correct the amino acid imbalance existing in liver cirrhosis. "Coma solutions" are available in
some countries, which contain either exclusively BCAAs, or other additional substances supposed to be
effective in hepatic encephalopathy. The solutions are incomplete, and, therefore, should only be used to target
the pharmacological correction of an amino acid imbalance and not as the exclusive nitrogen source for PN.
The effectiveness of branched-chain amino acids in the treatment of hepatic encephalopathy has been tested in
seven controlled studies [77-81]; the results of which are, however, contradictory. It is extremely difficult to
detect a treatment effect on hepatic encephalopathy, when at the same time complications of cirrhosis are
present like gastrointestinal bleeding, sepsis or renal failure, which dominate the clinical results. A meta-analysis
of these studies shows a beneficial effect of the BCAA-enriched solutions with regards to mental state, but not
with regards to survival [70]. In a Cochrane analysis, a subgroup of the seven randomised controlled studies
was analysed, with a total of 397 patients with acute hepatic encephalopathy, who were treated with
intravenously administered BCAAs in the intervention group [82]. The parenteral BCAA administration had a
significant positive effect on the improvement of hepatic encephalopathy; the period of survival, however,
remained unchanged.
Surgery and Transplantation. After liver resection, oesophagus transection with splenectomy or splenorenal
shunt in patients with liver cirrhosis, no increased encephalopathy rate was observed when a conventional
amino acid solution (50 g/24 h) was used for postoperative nutrition instead of a BCAA-enriched amino acid
solution (40 g/24 h) [37]. No difference was observed between a standard or a BCAA-enriched amino acid
solution after liver transplantation either [38].
Transplanted patients exhibit a noteworthy nitrogen loss with a continuously negative nitrogen balance up to 28
days post surgery [52, 83], therefore protein or amino acid intake should be increased appropriately. A protein or
amino acid intake of 1.0-1.5 g/kg-/d was mostly used in studies [24, 38]. The determination of postoperative
urea-nitrogen excretion was helpful in ascertaining individual nitrogen requirements.
Conditioning of Organ Donors. Data mainly derived from experimental studies indicate that the balanced
nutrition of a "brain-dead" liver donor with moderate amounts of carbohydrates, lipids (long-chain fatty acids and
possibly fish oil) and amino acids is associated with an improved function of the transplanted organ [84]. The
value of donor or organ preconditioning against ischemia/reperfusion damage e.g. by means of high doses of
arginine is at present uncertain.
Table 1: Parenteral amino acid solutions with an increased content of branched-chain amino acids available in
Germany
Hepar
Aminofusin® Aminoplasmal® Aminosteril® 10%
PARENTAMIN® salviamin®
5% Hepar
Hepa 10%
n-Hepa 8%
hepar
Pfrimmer Hepa 10%
Electrolyte-free
Carbohydrate
(Xylitol)[g/l]
Total AA[g/l]
no
yes
yes
yes
no
yes
-
-
-
-
-
-
50
100
80
100
100
60
6
BCAA/total AA
[%]
45
33
42
35
33
35.6
Aromatic AA +
Trp + Met/ total
AA[%]
1.7
5
3.4
3.2
5
2.3
Isoleucine [g/l]
7.6
8.8
10.4
11.1
8.8
6.78
Leucine [g/l]
8.5
13.6
13.09
13.5
13.6
8.28
Valine [g/l]
6.4
10.6
10.08
10.4
10.6
6.3
Methionine [g/l]
0.5
1.2
1.1
1.2
1.2
0.45
Phenylalanine
[g/l]
0.25
1.6
0.88
1.2
1.6
0.6
Tryptophan [g/l]
0.1
1.5
0.7
0.8
1.5
0.38
Tyrosine [g/l]
-
0.7
-
-
0.7
-
Arginine [g/l]
4.9
8.8
10.72
9.6
8.8
4.5
Alanine [g/l]
2.1
8.3
4.64
9.2
8.3
5.48
Glutamic acid
[g/l]
1.0
5.7
-
-
5.7
-
Glycine [g/l]
0.7
6.3
5.82
11.0
6.3
6.75
Histidine [g/l]
0.6
4.7
2.8
3.0
4.7
1.88
Lysine [g/l]
4.1
7.51
6.88
7.5
7.51
5.55
L-Asparagine [g/l]
-
0.48
-
-
0.48
-
Aspartic acid [g/l]
4.03
2.5
-
-
2.5
-
Ornithine [g/l]
4.0
1.3
-
-
1.3
-
Proline [g/l]
1.2
7.1
5.73
9.8
7.1
6.0
Serine [g/l]
2.75
3.7
2.24
6.1
3.7
3.45
Threonine [g/l]
1.2
4.6
4.4
5.6
4.6
3.38
Cystein [g/l]
0.15
0.59
0.52
-
0.59
0.25
AA: amino acids; BCAA: branched-chain amino acids
Water, Electrolytes, Vitamins, Trace Elements

Water, electrolytes, water- and fat-soluble vitamins as well as trace elements should be administered
daily (cf. chapter "Water, Electrolytes, Vitamins and Trace Elements") (C).
Commentary
Patients with liver cirrhosis have profound alterations in body composition with an increase in total body water
already in Child-Pugh stage A [85]. This goes along with salt retention, which does not manifest in
hypernatraemia. In contrast, potassium, magnesium, phosphate and other intracellular minerals are frequently
depleted.
No recommendations on the requirements of micronutrients can be made on the basis of controlled studies. The
administration of micronutrients has no effect on the nutritional state other than in the adjustment of a deficiency.
Supplementations of zinc and vitamin A might indirectly improve the food intake and nutritional state by
improving dysgeusia [86, 87]. Zinc and selenium deficiencies were observed in alcoholic and non-alcoholic liver
disease [88-91]. A striking association between hepatic encephalopathy and zinc deficiency has been described
in case reports [92, 93]. Oral zinc supplementation, however, has shown no effectiveness in subclinical
encephalopathy in controlled studies [94-96]. Urea production capacity increased after oral zinc supply when the
previously lowered plasma levels were normalised [97].
A deficiency in water-soluble vitamins is common in cirrhosis, especially of alcoholic origin [98, 99]. Deficits in
fat-soluble vitamins are observed in cholestasis-related steatorrhoea, bile salt deficiency and in alcoholics [100,
101]. Supplementation with calcium and vitamin D is recommended for patients with osteopenia, although this
7
did not result in any improvement in bone density in patients with primary biliary cirrhosis, with oestrogen
substitution proving to be much more effective in female patients [100, 102].
In practice, liberal supplementation is recommended in the first two weeks of treatment as the laboratory
diagnosis of a specific trace element or vitamin deficiency may be more expensive. Due to high prevalence of
malnutrition in this group of patients, they are in danger of developing re-feeding syndrome (cf. chapter
"Complications and Monitoring").
After transplantation, the often chronic hyponatraemia should be corrected carefully in order to avoid the risk of
pontine myelinosis [103]. It is recommended to regularly check magnesium levels in order to determine
cyclosporine- or tacrolimus-induced hypomagnesaemia [104].
Some, but not all study groups, reported the risk of postoperative hypophosphataemia and its possible
connection with PN following right hemihepatectomy in a living donor [105-107].
Acute Liver Failure
Due to the massive loss of liver cell function, acute liver failure is a serious condition characterised by profound
metabolic dysfunctions and almost invariably complicated by multi-organ failure. Depending on the interval till
the onset of hepatic encephalopathy (HE), hyperacute (onset of jaundice till HE <8 days), acute (interval <29
days) and sub-acute liver failure (interval 29-72 days) are distinguished [108]. Prognosis is more favourable in
hyperacute LF (liver failure) than in acute or subacute LF.
Despite the clinical significance of metabolic derangements like hypoglycaemia or hyperammonaemia and
encephalopathy, there is only scarce animal-experiment or physiologically descriptive data, and no published
clinical studies, on which a metabolic intervention like nutritional therapy could be based.


In analogy to intensive care patients, in acute LF artificial nutrition should be considered irrespective of
the nutritional state and should be commenced when oral nutrition cannot be restarted within 5 to 7 days
(cf. chapter "Intensive Care Medicine")
Whenever possible, enteral nutrition should be administered via a nasoduodenal feeding tube (C).
Commentary
In the treatment of acute liver failure, measures to stabilize the metabolism and vital functions and the treatment
of brain oedema are of utmost importance. Nutritional therapy in this condition has two objectives:
1. ensuring the adequate provision of required energy, especially euglycaemia, by giving glucose, lipids,
vitamins and trace elements, and
2. ensuring optimal rates of protein synthesis by providing an adequate intake of protein or amino acids.
Energy Intake

In acute liver failure a hypermetabolic state can occur. The individual energy requirement should
preferably, be determined measuring energy expenditure with indirect calorimetry, or be estimated with a
formula (C).
Commentary
Surprisingly few liver units seem to measure, or at least calculate, the energy expenditure of patients with acute
liver failure [33] despite the well-known fact that hepatic energy expenditure amounts to 25% of the overall
energy expenditure [109]. A survey of 33 hepatology units in Europe showed that the resting energy expenditure
was measured by 12.5% of the centres by means of indirect calorimetry, and that 53 % usually used the HarrisBenedict formula; the energy requirements were not recorded in a third of centres.
In patients with acute liver failure, indirect calorimetry showed an increase in resting energy expenditure, in two
studies, by 18 or 30% in comparison with healthy controls [110, 111]. Obviously, patients with acute liver failure
are different from other critically ill patients regarding energy expenditure (cf. chapter "Intensive Care Medicine").
Substrate Intake


Sufficient glucose administration (2-3 g/kg/d) is mandatory for prophylaxis or treatment of hypoglycaemia
(C). Glucose substitutes are of no proven benefit in acute LF. Moreover, xylitol, sorbitol and fructose have
to be metabolised by the liver before they can be utilized.
Simultaneous infusion of glucose and lipid (0.8-1.2 g/kg/d) and offers benefits regarding insulin resistance

8
and should be used.
Amino acid administration is not necessary in hyper-acute LF. Amino acids (0.8-1.2 g/kg/d in PN) or
protein (0.8-1.2 g/kg/d in enteral nutrition) should be used in acute or sub-acute LF in order to support
protein synthesis.
Commentary
Glucose
In LF clinically significant hypoglycaemia [112] occure and results from a loss of hepatic gluconeogenetic
capacity, lack of glycogen and hyperinsulinism [113]. It is widely accepted to treat hypoglycaemia by infusing
1.5-2 g glucose/kg body weight [114, 115]. At the end of the 1990's, the administration of glucose doses of 6 to
10 g per kg body weight per day was practised: a blood glucose level of under 10 mmol/l was aimed for by only
39% of centres [33]. Meanwhile, the landmark study by v. d. Berghe showing that euglycaemic metabolic control
improved survival has likely been helpful in setting the standard also in acute liver failure [116].
As the progress of brain oedema mainly determines the prognosis of these patients, for pathophysiological
reasons, strict blood glucose control may be particularly advantageous. Increased ischemia-related damage of
neurons and glia cells [117], dysfunctional leukocyte function [118] or oxidative stress have been found to be
associated with hyperglycaemia. The aministration of up to 4 IU/h insulin is recommended in order to adjust
blood glucose levels and maintain euglycaemia (cf. chapter "Carbohydrates" and "Intensive Care Medicine").
Lipids
The oxidation of fatty acids and ketogenesis are the main energy-providing processes for hepatocytes [119].
Thus, adequate lipid administration would be a plausible, therapeutic objective provided there is sufficient
oxygen supply to the liver tissues. Some cases of acute liver failure are, however, caused by an impairment of
hepatic beta-oxidation. In these specific cases, exogenous lipid, e.g. even administering Propofol as a sedative,
cannot be metabolised and can become potentially harmful [120, 121]. Measurements of substrate turnover in a
study showed that there was no fatty acid absorption, but a release of free fatty acids from the splanchnic area
in patients with acute liver failure in comparison to septic patients [122].
There is no systematic data on the role of lipids as a nutrient. Exogenously administered lipids seem to be well
tolerated by most patients [123, 124]. A survey of hepatology centres also showed that two-thirds of the centres
administer parenteral lipids in patients with acute liver failure, mainly in the form of LCT/MCT emulsions [33].
Special attention should, however, be paid when giving lipids to patients with acute liver failure and
microvesicular steatosis, in whom mitochondrial dysfunction is predominant.
Monitoring should be carried out as described in the chapter on "Complications and Monitoring".
Amino Acids
The plasma levels of amino acids are raised 3 to 4 fold in acute liver failure. The amino acid pattern is altered,
and shows a relative decrease in branched-chain amino acids and a relative increase in tryptophan, aromatic
and sulphurous amino acids [125-127]. More recent data shows that the splanchnic organs cannot take up
amino acids in the event of liver failure while a net uptake of amino acids can be seen in healthy humans and
even in septic patients [127].
Amino acid infusion was not used as often in the past for fear of aggravating existing hyperammonaemia and
hyperaminoacidaemia, and causing brain oedema and encephalopathy. In the survey of hepatology centres,
more than half of the centres indicated, however, that amino acids are infused [33]. A few centres use standard
amino acid solutions, while the majority use incomplete solutions with branched-chain amino acids or complete
solutions enriched with branched-chain amino acids in order to correct the altered amino acid pattern and
optimise the nitrogen supply [74, 128, 129].
While pathophysiological considerations provide a rationale for the use of liver-adapted solutions with an
increased proportion of branched-chain amino acids, no advantage could, however, be proven in comparison to
standard solutions.
An adequate metabolic monitoring is necessary in order to ensure substrate supply, which is adjusted for
substrate utilisation, and to prevent substrate overload. Strict control of the plasma glucose levels (target: 5-8
mmol/L), lactate (target: 5.0 mmol/L), triglycerides (target: <3.0 mmol/L) and ammonia (target: <100 µmol/L) are
necessary for this purpose.
Patients with hypophosphataemia after acetaminophen-induced liver damage have a better prognosis. Severe
hypophosphataemia, however, results in respiratory insufficiency and dysfunction of the nervous system and
erythrocytes [130], and thus, serum phosphate levels should be controlled stringently and corrected in order to
support liver regeneration.
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659-665
Plauth M1, Schuetz T2
1Dept.
of Internal Medicine, Municipal Clinic Dessau, 2Medical Department, Division of Gastroenterologie,
Hepatology and Endocrinology, Charité Universitätsmedizin Berlin, for the working group for developing the
guidelines for parenteral nutrition of The German Association for Nutritional Medicine
Erstellungsdatum:
04/2014
12
AWMF online - Guidelines on Parenteral Nutrition: Parenteral Nutrition in Patients with Renal Failure
1
AWMF online
Wissenschaftlichen
Medizinischen
Fachgesellschaften
Nr. 073-018e_17
Entwicklungsstufe:
3
Zitierbare Quelle:
Chapter 17: Parenteral Nutrition in Patients with
Renal Failure
Kapitel 17: Parenterale Ernährung bei Nierenversagen
Key words: Acute renal failure, chronic renal failure, haemodialysis, peritoneal dialysis
Schlüsselwörter: Akutes Nierenversagen, chronisches Nierenversagen, Hämodialysetherapie, Peritonealdialyse
Abstract
Partial EN (enteral nutrition) should always be aimed for in patients with renal failure that require nutritional
support. Nevertheless PN (parenteral nutrition) may be necessary in renal failure in patient groups with acute or
chronic renal failure (ARF or CRF) and additional acute diseases but without extracorporeal renal replacement
therapy, or in patients with ARF or CRF with additional acute diseases on extracorporeal renal replacement
therapy, haemodialysis therapy (HD), peritoneal dialysis (PD) or continuous renal replacement therapy (CRRT),
or in patients on HD therapy with intradialytic PN. Patients with renal failure who show marked metabolic
derangements and changes in nutritional requirements require the use of specifically adapted nutrient solutions.
The substrate requirements of acutely ill, non-hypercatabolic patients with CRF correspond to those of patients
with ARF who are not receiving any renal replacement patients therapy (utilisation of the administered nutrients
has to be monitored carefully). In ARF patients and acutely ill CRF patients on renal replacement therapy,
substrate requirements depend on disease severity, type and extent/frequency of extracorporeal renal
replacement therapy, nutritional status, underlying disease and complications occurring during the course of the
disease. Patients under HD have a higher risk of developing malnutrition. Intradialytic PN (IDPN) should be used
if causes of malnutrition cannot be eliminated and other interventions fail. IDPN should only be carried out when
modifiable causes of malnutrition are excluded and enhanced oral (like i.e. additional energy drinks) or enteral
supply is unsuccessful or cannot be carried out.
Zusammenfassung
Patienten mit Nierenversagen sollten, wenn möglich, eine zumindest partielle enterale Ernährung erhalten.
Trotzdem kann bei bestimmten Patientengruppen mit Nierenversagen eine PE (parenterale Ernährung)
notwendig werden, wie z.B. bei Patienten mit akutem bzw. chronischem Nierenversagen (ANV bzw. CNV) und
zusätzlichen akuten Erkrankungen ohne extrakorporalen Nierenersatz, bei Patienten mit ANV und Patienten mit
CNV und zusätzlichen akuten Erkrankungen unter extrakorporaler Nierenersatztherapie, Hämodialysetherapie
(HD), Peritonealdialyse (PD) oder kontinuierlicher Nierenersatztherapie (CRRT) sowie bei Patienten unter HD
Therapie mit intradialytischer parenteraler Ernährung. Bei Patienten mit Nierenversagen machen umfangreiche
metabolische Störungen und Änderungen des Nährstoffbedarfes die Verwendung von spezifisch adaptierten
Nährlösungen notwendig. Bei akut-kranken nicht-hyperkatabolen Patienten mit CNV entspricht der
2
Substratbedarf dem der Patienten mit ANV ohne Nierenersatztherapie (die Verwertung der zugeführten
Nährstoffe muss sorgfältig überprüft werden). Bei Patienten mit ANV und akut-kranken Patienten mit CNV unter
Nierenersatztherapie wird der Substratbedarf vom Schweregrad der Erkrankung, Art und Dosis der
extrakorporalen Nierenersatzverfahren, dem Ernährungszustand, der Grunderkrankung und von im
Krankheitsverlauf auftretenden Komplikationen bestimmt. Patienten unter einer HD haben ein hohes Risiko, eine
Mangelernährung auszubilden. Eine IDPE sollte nur dann durchgeführt werden, wenn "beseitigbare" Ursachen
einer Mangelernährung ausgeschlossen wurden und wenn eine diätetische/orale (z.B. Trinknahrung) oder
enterale Therapie nicht vorgenommen werden kann bzw. nicht erfolgreich ist.
Preliminary Remark
In patients with renal failure, enteral nutrition (EN) should be the primary choice for nutrition therapy, and
administered whenever possible (see also recommendations by the German Society of Nutrition (DGEM) on
enteral nutrition [1]). However, patients with renal failure often have limitations in enteral intake, and therefore, the
administration of a quantitatively sufficient EN becomes impossible. Dysfunction of gastric and intestinal motility is
observed in patients even with moderately abnormal renal function and often restricts the a amount of EN
tolerated. Therefore, in clinical practice many acutely ill patients with renal failure require temporary and/or
supplementary parenteral nutrition (PN). Even if PN is required, one should always aim for establishind at least a
minimal enteral nutrition to enhance intestinal integrity [1].
The nutritional status has a massive impact on the prognosis of patients with renal failure [2]. In acutely ill
patients, however, the degree of malnutrition is not the only indication to start PN/EN, but also when the patient
can not be sufficiently orally/enterally nourished, and the degree of severity of the underlying illness and the
associated catabolism [3].
Only few systematic studies have performed on parenterally fed patients with renal failure, and only very few
controlled studies with an acceptable study design have been published. Therefore, recommendations for
practice for this patient group only reach the level of an expert opinion (C). General recommendations for nutrition
and nutritional requirements of patients with renal diseases have been published by the National Kidney
Foundation (NKF) [4], as well as by the European Society for Parenteral and Enteral Nutrition (ESPEN) [5, 6].
Parenteral Nutrition in Patients with Renal Failure




At least partial EN should always be aimed for in patients with renal failure that require nutritional support (C). PN
may be necessary in renal failure in the following patient groups (C).
Patients with acute or chronic renal failure (ARF or CRF) and additional acute diseases but without extracorporeal
renal replacement therapy.
Patients with ARF or CRF with additional acute diseases on extracorporeal renal replacement therapy,
haemodialysis therapy (HD), peritoneal dialysis (PD) or continuous renal replacement therapy (CRRT).
Patients on HD therapy with intradialytic PN.
Commentary
PN is administered almost solely to patients with acute (ARF) or chronic renal failure (CRF), or those on chronic
renal replacement therapy (HD or PD), who also have acute diseases. ARF or CRF is not a crucial factor for PN
administration in intensive care patients, but rather it is important whether the patient requires extracorporeal
therapy [HD] or continuous renal replacement therapy (CRRT), as well as the presence of hypercatabolism
depending on the severity of disease.
Aims of PN in Patients with Renal Failure
PN in patients with renal failure aims at reduction of the hypercatabolic state, and the prevention or elimination of
malnutrition and related functions, such as immunology, wound healing, antioxidative potential, inflammation.
While delaying the progress of CRF through protein or phosphate restriction is the aim of chronic dietary therapy,
this is not the goal of short-term PN, which is usually administered only in acute situations.
Metabolic Situation in Patients with Renal Failure

Patients with renal failure who show marked metabolic derangements and changes in nutritional requirements
require the use of specifically adapted nutrient solutions (C).
Commentary
Metabolism in patients with renal failure is not only influenced by abnormal renal function, but also by the
underlying disease, emerging complications and additional organ failure (Table 1). Metabolism and nutrient
3
balance are also influenced by the type and intensity of extracorporeal renal replacement therapy [7]. Distinctive
changes in metabolism and substrate requirements of renal failure patients make it necessary to adapt PN
according to their needs [7] (Table 1).
Energy metabolism is not markedly influenced by renal dysfunction but may be altered by underlying disease and
accompanying complications. In multiple organ failure, energy expenditure is only about 30% above the
calculated resting metabolic rate [8]. An increase in energy intake of more than 30 kcal/kg/day was not associated
with any further improvement in nitrogen balance, but resulted in increased metabolic complications [9].
The metabolic changes in ARF are mainly characterised by protein catabolism. There are alterations of the
metabolism of individual amino acids, including the utilisation of exogenously administered amino acids is altered,
and various non-essential amino acids, e.g. tyrosine, may become indispensible. Dysfunctions in carbohydrate
metabolism in ARF usually manifest clinically through hyperglycaemia. This is mainly caused by peripheral insulin
resistance, and in addition by an activation of hepatic gluconeogenesis that cannot be suppressed by exogenous
nutrient intake, other than in stable CRF and healthy persons ("obligatory" negative nitrogen balance).
Altered lipid metabolism is characterised by hypertriglyceridemia explained by the suppressed lipolysis. Fat
clearance is delayed after enteral or parenteral intake [10].
Patients with ARF or patients with CRF and acute diseases have a markedly reduced antioxidative potential [11].
Activation of vitamin D3 is also impaired in ARF resulting in secondary hyperparathyroidism [12].
Table. 1: Metabolic Disorders in Patients with Renal Failure
Peripheral insulin resistance
Impairment of lipolysis
Metabolic acidosis
Hyperparathyroidism
Dysfunction in vitamin D3 activation
Lower potassium tolerance/hyperkalaemia
Chronic inflammatory reaction
Activation of protein catabolism
Exuberant catabolism in intercurrent acute diseases (see below)
Influence of Renal Replacement Therapy on Metabolic and Nutrient Balances
Metabolic changes due to haemodialysis are shown in Table 2. Currently continuous renal replacement therapy
(CRRT), especially continuous venovenous haemofiltration (CVVH), is usually used in intensive care patients.
The continuous therapy mode and the usually high filtration rates result in significant influences on electrolyte and
nutrient balance, especially when losses are not sufficiently replaced [13]. The loss of amino acids is
approximately 0.2 g per litre of filtrate. Other substances such as water-soluble vitamins are also lost.
Complications can also occur through excessive lactate or citrate intake through the dialysate fluid
(hyperlactaemia, metabolic alkalosis)
Electrolyte metabolic disorders such as hypophosphataemia, hypomagnesaemia and/or hyponatraemia are
frequently observed due to the high fluid turnover required for CRRT [13] (Table 3).
Table 2: Effects of Haemodialysis
Loss of water-soluble molecules with low molecular weight
Amino acids
Water-soluble vitamins
L-carnitine etc.
Activation of protein catabolism through
loss of substrates (amino acids)
4
Release of cytokines (TNF-a etc)
Blood loss
Table 3: Effects of Continuous Renal Replacement Therapy
Decrease in "uraemic intoxication"
plus
Loss of heat (loss of energy)
Loss of substrates (e.g. amino acids, vitamins)
Intake of substrates (lactate, citrate, glucose)
Elimination of short-chained peptides (cytokines, hormones)
Activation of mediator-cascades (alexin etc.)
Stimulation of protein catabolism
Electrolyte disorders (sodium, potassium, magnesium, phosphate)
Induction of metabolic alkalosis
Parenteral Nutrition Substrates for Patients with Renal Failure
Amino Acid Solutions


Special amino acid solutions for patients with renal failure (so-called "nephro-solutions") show beneficial
effects on some surrogate parameters, but effects on clinical end points are not documented (IV).
Solutions providing exclusively essential amino acids should no longer be used (A).
Commentary
Renal failure influences the amino acid or protein metabolism, and changes the utilisation of intravenously
administered amino acids [14]. However, the question as to which parenteral amino acid solution should be used
in these patients remains controversial. Potential advantages of specially adapted amino acid solutions ("nephrosolutions") include assured intake of an adequate (higher) dose of amino acids without urea increase, partial/total
correction of imbalances in plasma aminograms and the intake of amino acids that become essential due to renal
failure (i.e. tyrosine as dipeptide) [15, 16]. Previously used solutions providing exclusively essential amino acids
should not be used [7].
Clinical advantages such as improved survival rates have not been documented with the use of "nephrosolutions" (cf. chapter "Amino Acids"). Benefits are most likely in patients who do not require dialysis and whose
urea increase can be reduced. In patients who require renal replacement therapy, the advantages are expeceted
to be less relevant because haemodialysis and haemofiltration have a "smoothing" effect on the plasma
aminogram. There are no advantages in using solutions enriched with branched-chain amino acids in intensive
care patients or patients with ARF [17].
In 1982 Mirtallo et al. administered either a standard amino acid solution (AA intake 33 g/day) or a solution
comprised exclusively of essential amino acids (AA intake 29 g/day) to patients with non-dialysis CRF. Various
parameters in the nitrogen balance tended to a slight improvement when the standard solution was used [18].
In a controlled study, Smolle et al. compared a conventional amino acid solution with a "nephro- solution" in
patients with ARF [16]. The modified solution resulted in a normalisation of plasma amino acid concentrations and
the phenylalanine/tyrosine ratio.
Lipid Emulsions

Patients with renal failure should receive lipid emulsions with a triglyceride dose of up to 1 g/kg body
5
weight/day in PN with regular montoring of plasma triglycerides (C).
Commentary
The first step in lipid utilisation is the lipolysis of the infused triglycerides which is reduced in renal failure, with
impaired fat clearance in patients with ARF and CRF [10]. Oxidation of the released fatty acids is not impaired.
Lipid emulsions can be used in PN but the dose should not exceed ~1 g/kg body weight/day. Regular monitoring
of plasma triglycerides should be performed. At present there are no studies documenting any advantages of
specific lipid emulsions over others in patients with renal failure (cf. chapter "Lipid emulsions").
Carbohydrates


Parenteral carbohydrates should be provided by glucose in patients with renal failure (C).
Normoglycaemia should be the goal during PN. Insulin is frequently required for maintaining
normoglycaemia in these patients who often show insulin resistance (A).
Commentary
Advantages of using parenteral glucose substitutes patients with renal failure are not shown, but their use might
be associated with significant disadvantages. Glucose substitutes are partly metabolised in the kidney and
increase renal oxygen consumption [19].
Normoglycaemia should be maintained in patients with renal failure when using PN [20]. Insulin is frequently
required to maintain normoglycaemia as these patients often show insulin resistance.
L-Carnitine

The administration of L-carnitine (500 mg/day) is justified in malnourished and critically-ill patients on renal
replacement therapy (and thus increased loss) (C).
Commentary
Whether L-carnitine should be regarded as an essential substrate in patients with renal failure has not yet been
clarified. "Carnitine responders" are mainly malnourished patients [4]. Good prospective studies and evidencebased dosing specifications are not available.
Vitamins
Fat-soluble Vitamins


Patients with chronic renal failure require an individually dosed pharmacological therapy with vitamin D3 or
its analogues in addition to the standard intake with fat-soluble vitamins in PN (C).
Patients with CRF and acute concomitant diseases as well as patients with ARF have an increased
requirement of vitamin E (C).
Commentary
Patients with renal failure have dysfunctional activation of vitamin D. For this reason activated vitamin D3 or its
analogues should be administered. The substitution of vitamin K exceeding daily basal requirements is not
necessary. In contrast to stable patients with CRF, the levels of vitamin E and vitamin A are lower in acutely ill
patients with renal failure, which results in the need for substitution [12]. Systematic substitution studies are,
however, not available.
Water-soluble Vitamins


Patients on renal replacement therapy and malnourished patients without renal replacement therapy
should receive approximately double the normal daily requirements of water-soluble vitamins with PN (C).
An increased intake of vitamin C (>250 mg/day) can be disadvantageous and result in increased oxalate
formation (B).
Commentary
6
Patients with renal failure require an increased dose of water-soluble vitamins. In patients on renal replacement
therapy, the dosage should amount to approximately 2-fold the daily requirements due to additional losses
through therapy [21-23].
The vitamin C supplementation should also be higher than the recommended daily intake of healthy persons, but
should not exceed 250 mg/day, in order to prevent possible secondary oxalosis. Excessive vitamin C
intake/supplementation can even cause ARF itself [24].
Trace elements


Patients on renal replacement therapy and malnourished patients without renal replacement therapy
should receive the recommended daily intake of trace elements in PN (C).
Selenium intake should be >200 µg/day in patients on renal replacement therapy (B).
Commentary
Renal balance studies of trace elementsare not available except for selenium, hence, in accordance with other
patient groups supplementation should correspond to the recommended daily intake of healthy persons [3].
Selenium is an exception, as approximately double the daily intake is lost through continuous renal therapy,
despite its high protein binding properties. Therefore, an increased supplementation should be given [21] (B).
Electrolytes

Electrolyte intake should be individually determined in patients with renal failure (C).
Commentary
Potassium and phosphate restriction is generally recommended in patients with renal failure. The requirements
are, however, extremely different for acutely ill patients. Hypokalaemia or hypophosphataemia may occur initially
in the disease course. A fast decline in potassium or phosphate levels may also occur in patients with renal failure
after commencing PN ("Refeeding hypophosphataemia or hypokalaemia"). The individual electrolyte requirement
can vary tremendously during the course of disease and is crucially influenced by residual diuresis.
PN in Patients with ARF/CRF without Renal Replacement Therapy


The substrate requirements of acutely ill, non-hypercatabolic with CRF correspond to those of patients with ARF
who are not receiving any renal replacement patients therapy (C) (Table 4).
In patients with renal failure, PN should be started slowly (approximately 50% of the requirements) in order to
monitor the utilisation of the administered nutrients and prevent metabolic imbalances (C).
Commentary
Patients with CRF or ARF, who do not require renal replacement therapy, are rarely catabolic, whereas dialysis is
necessary in increased catabolism due to the associated increase of urea. Only a few of these patients require
PN. The substrate requirements of acutely ill, non-hypercatabolic patients with CRF correspond to those of
patients with ARF without renal replacement therapy (Table 4).
Renal failure patients with uraemia develop malnutrition, related to the stage of the disease. The reasons for this
are manifold and comprise lower oral food intake, restrictive diet regime, the toxic effects of uraemia,
inflammation, metabolic acidosis, endocrine factors such as insulin resistance, hyperparathyroidism, altered leptin
levels, as well as gastroplegia, malassimilation and other gastrointestinal alterations [25].
Table 4: Recommended oarenteral nutrient intakes in ARF/CRF without Renal Replacement Therapy (see
[1,3-6])
Energy
20 - 25
Amino Acids
0.6 - 1.0*
Carbohydrates
3-5
Lipids
0.8 - 1.2**
L-carnitine
0.5***
g/day
Water-soluble vitamins Normal PN dosage
Fat-soluble vitamins:
Normal PN dosage
Trace elements:
Normal PN dosage
Electrolytes****.
Phosphate/potassium restriction often necessary
7
Fluid ****
* Depending on degree of catabolism and tolerance
** Monitoring of plasma triglycerides necessary
*** Optional
**** The individual requirements vary a great deal
PN in Patients with ARF/CRF and Renal Replacement Therapy

In ARF patients and acutely ill CRF patients on renal replacement therapy, substrate requirements depend on
disease severity, type and extent/frequency of extracorporeal renal replacement therapy, nutritional status,
underlying disease and complications occurring during the course of the disease (for recommendations for
medium substrate intake see Table 5) (C).
Table 5: Recommended parenteral substrate inatkes in Patients with ARF and in Acutely Ill Patients on
Renal Replacement Therapy
Energy
20 - 30
Carbohydrates
3 - 5 (max. 7) g/kg body weight/day
Lipids
0.8 - 1.2
Essential and Non-essential Amino Acids
Extracorporeal therapy 1.2 - 1.4
(in hypercatabolism up to 1.5 g/kg body weight/day)
Vitamins
Water-soluble vitamins 2 x usual PN dosage
Fat-soluble vitamins
Usual PN dosage
Trace elements
Usual PN dosage
(selenium potentially >200 µg/day)
Electrolytes
Adapt intake individually
Caution: Refeeding-hypophosphataemia after beginning of PN
Commentary
Critically ill patients with ARF are by far, the largest group of patients with renal failure who require parenteral
nutrition therapy. ARF is rarely a mono-organ failure; usually, additional complications like severe infections,
sepsis or multi-organ failure also occur. In these patients, ARF is only one factor that determines the need for and
type of nutritional therapy (cf. chapter "Intensive Care Medicine").
Altered water and electrolyte balance, specific metabolic disorders, gastrointestinal motility and influence of
extracorporeal therapies on metabolic and substrate balances should be considered during planning, execution
and monitoring of PN in renal failure patients.
Patients on intermittent haemodialysis therapy with accompanying acute diseases should be assessed
metabolically like patients with ARF, and treated similarly with regards to nutritional therapy. The specifications
made here for ARF can, therefore, be used for both these patient groups.
Indications for Nutritional Therapy
The same recommendations apply for PN therapy of patients with ARF as for other intensive care patients.
Nutritional state is a significant determinant of outcome in ARF patients, smilar to patients with other acute
diseases. PN is indicated in patients with ARF without pre-existing malnutrition who will not be able receive
8
sufficient oral or enteral nutrition for approximately 5 days. This often applies to ARF patients because underlying
diseases resulting in ARF tend to impair intestinal motility which often limits quantitatively sufficient enteral
nutrition [26]. In addition to duration of not meeting needs by oral or enteral supply, the extent of malnutrition and
the severity of underlying diseases are main determinants of the indication and timing for starting PN therapy.
Parenteral Substrate Requirements in Patients with ARF on Renal Replacement Therapy




The requirement of amino acids/protein is increased (A).
The requirement of water-soluble vitamins is increased (A).
The requirement of other micro nutrients (fat-soluble vitamins, trace elements) should be met (A).
Electrolyte intake should be dosed individually for patients with renal failure (C).
Commentary
The substrate requirements are determined less by presence or absence of ARF, but more by the severity of the
disease, type and dose of the extracorporeal renal replacement therapy, underlying diseases, and complications
occurring during the course of the disease. Tolerance to excessive substrate intakes (i.e. amino acids, trace
elements, vitamins) is reduced and overdoses should thus be avoided because the regulatory functions of the
kidneys are missing in ARF.
(See section on "Influence of renal replacement therapy on metabolism and nutrient balances" for vitamin and
trace element requirements.)
Amino Acid Requirements in Patients with ARF on Renal Replacement Therapy


The amino acid requirements of patients with ARF on renal replacement therapy depend on the extent of
the underlying disease and the intensity of renal replacement therapy (B).
Sufficient amino acid intake must be assured (B).
Commentary
The ideal amino acid intake in these patients is controversial and has not been properly clarified through studies.
There are no randomised studies with an adequate study design.
There is, however, consensus that protein restriction, which was previously recommended in analogy to CRF with
a minimal intake rate of approximately 0.6 g of AA/ kg/day, is not indicated in acutely ill patients.
Studies from the 1990s have dealt with the extent of catabolism or the optimal intake. In numerous studies a
"protein catabolic rate" of 1.4 to 1.75 g/kg/day was found in patients with ARF under CRRT [17, 27-29]. In these
studies, a protein intake of this magnitude was recommended which is consistent with the available information.
Taking into account the amino acid loss through CRRT of approximately 0.2 g/kg/day, this intake is similar to the
recommended intake of other intensive care patients (cf. chapter "Intensive Care Medicine").
Recent studies from Australia [30-32] have suggested that the amino acid/protein intake in intensive care patients
with ARF on CRRT should reach up to 2.5 g/kg/day. The authors found an increase in the plasma amino acid
levels and an enhanced nitrogen balance which correlated with an improves outcome. The study design,
however, did not permit any conclusions on causality regarding improved outcomes through increased amino acid
intake.
Protein catabolism cannot be suppressed by an increased amino acid intake in acute diseases. Potential dangers
of increased intake in patients with ARF are enhanced uraemic toxicity and increased requirements of
extracorporeal therapy. It unclear why patients with ARF should have much higher amino acid requirements than
other intensive care patients, after adjustment of therapy-related loss.
Admixture of Glutamine to PN in Critically Ill Patients with ARF


Glutamine intake should be avoided in non-dialysis patients due to its high nitrogen content (C).
In patients with ARF on renal replacement therapy, glutamine intake may be considered (C).
Commentary
The question of whether glutamine should be added to the PN solution in critically ill patients with ARF has not
been adequately answered. A post-hoc analysis of the study of Griffith et al. has determined that the benefits of
glutamine supplementation were particularly marked in patients with ARF on renal replacement therapy [33]. The
administration of glutamine should be calculated into the amino acid intake, and the dose of renal replacement
therapy adapted.
9
Metabolic Monitoring in Patients with ARF


Metabolic monitoring of nutritional therapy in ARF patients should be performed similar to monitoring in
other intensive care patients, but more stringently (C).
In particular electrolyte balance must be checked (frequent source of error!) (C).
Commentary
In patients with ARF there is a restricted tolerance to volume intake and electrolytes, and impairment in the
metabolism of various substrates resulting in a high risk of complications in nutrition therapy. More stringent
metabolic monitoring of nutrition therapy is, therefore, necessary for this patient group as compared to other
patients. Slow introduction of nutritional therapy reduces the risk of occurrence of metabolic complications.
Influence of Parenteral Nutrition on the Regeneration of Renal Function
Various nutrients can influence renal reparation and different aspects of renal function. Both parenterally and
enterally administered amino acids increase renal blood flow as well as creatinine clearance ("renal reserve").
However, amino acids have been found to be toxic for the kidney.
There are three aspects to consider:
An unfavourable effect of AA on renal function and the course of ARF ("AA paradox") has been described in
animal experiments [34]. This is only relevant when amino acids are infused in a higher dose at the time of the
insult, thus increasing renal oxygen requirements, but appears insignificant in the clinical situation. In contrast, it
has been shown that various amino acids like alanine, glycine, taurine and, particularly, arginine have a protective
effect on the kidneys, prevent ARF or may delay the progression of CRF [7]. The question as to what extent PN
improves renal reparation has not yet been determined. Abel et al. suggested an improvement but this has not
been confirmed in further studies [35]. However, experimentally substrate deficiency aggravates renal damage in
ARF.
Both parenterally and enterally administered amino acids increase renal blood flow and also creatinine clearance
("renal reserve"). An influence of this effect on renal function in ARF has only been studied in animal experiments
[36], whereas clinical observations have only been reported in abstract form.
Intradialytic Parenteral Nutrition (IDPN)

Patients under haemodialysis (HD) have a higher risk of developing malnutrition (A).
Commentary
The close connection between nutritional status and complications or outcome is well documented for patients
receiving chronic haemodialysis therapy. Malnutrition in dialysis patients has numerous causes; a significant
factor is anorexia leading to intakes below requirements [25, 37].
Light to moderate malnutrition is found in approximately 30% of dialysis patients, and severe malnutrition in 510% [38]. Dietary interventions alone seem to have only limited effect. Dialysis itself is a catabolic state caused
not only by losses of nutrients such as amino acids, but also by activation of protein catabolism which lasts for a
few hours after the end of dialysis. Isotops studies indicated that the catabolic state of HD can be converted to an
anabolic state through intradialytic nutrient supply (Table 2) [39, 40].
Strategies for the Treatment of Malnutrition in HD Patients
Strategies for the treatment of malnutrition are summarised in Table 6. In malnourished HD-patients with
inadequate oral food intake, attempts can be made to motivate the patients to accept energy drinks during the HD
therapy which leads to an increased nutrient intake in some patients (see recommendation in "Enteral Nutrition
Guidelines" [1]). Intradialytic PN (IDPN) should be used if causes of malnutrition cannot be eliminated and other
interventions fail.
Table 6: Malnutrition in HD patients - Possibilities for Intervention
Elimination of causes (dialysis quality, hyperparathyroidism, acidosis)
Treatment of intercurrent diseases (infections)
10
Dietary consultation/changes in diet
Nutrient supplements
Nocturnal gavage
Intradialytic Enteral nutrition (IDEN)
Intradialytic Parenteral Nutrition (IDPN)
Anabolic strategies: anabolic steroids, growth factors
Indications for Intradialytic PN (IDPN)

IDPN should only be carried out when modifiable causes of malnutrition are excluded and enhanced oral or
enteral supply is unsuccessful or cannot be carried out (C).
Commentary
The following international criteria for malnutrition have been suggested, even though they are not based on firm
evidence [41]:






Middle predialysis serum albumin <3.4 g/l for >3 months
Middle predialysis serum creatinine <8.0 mg/l for > 3months
Weight loss >10 % of ideal body weight or >20 % of normal body weight (no time limit)
Clinical examination indicates moderate to severe malnutrition
Dietary history indicating protein intake <0.8 g/kg, reduced calorie intake <25 kcal/kg
Subjective Global Assessment (SGA) "C"= severe malnutrition
IDPN should be considered when three of the above mentioned criteria are associated with the following
conditions:


Aborted attempts to increase oral/enteral food intake
Refusal of enteral gavage
Compounding and Completion of IDPN


The nutrient solution should be continuously infused into the venous drip chamber of the tube system
throughout the complete duration of dialysis (B).
Depending on the compounding of the nutrient solution, blood glucose, triglycerides and possibly even the
phosphate/potassium concentrations should be checked during the first treatment (C).
Commentary
In many studies, only amino acid solutions have been administered as IDPN, although some studies have infused
only slightly higher amounts than the 2 g/h loss due to dialysis. Recent studies have coinfused amino acids,
glucose and lipids together with pre-mixed solutions from the pharmacy or commercial ready-made solutions. In
some countries the concept of a complete nutrient solution is practised, where water-soluble vitamins, carnitine
and, if necessary, electrolytes are added to an all-in-one bag containing the three basic nutrients of amino
acids/glucose/lipids. Preparation of a nutrient solution on an individual basis, for every single patient, as occurs in
some countries, is extremely expensive and has no documented advantages compared to standardised
admixtures.
IDPN necessitates a compromise between the desire to infuse an adequate amount of nutrients and a limited
time-frame in which these can be infused. The following issues should be considered when deciding about the
infusion amount, even though evidence-based recommendations are not available as of now (C).
Amino Acids: Desirable intake >0.5 g/kg/dialysis. "Nephro" solutions have been used in more recent studies [42].
Glucose: Limits are set due to the short infusion time and the frequently existing glucose intolerance,
recommended intake 50-100 g/dialysis. Insulin must be given with higher doses of glucose or to diabetics.
11
Lipids: Limitations exist due to dysfunction in lipolysis. An intake between 20 and 40 g of lipids/dialysis appears
appropriate in order to prevent hypertriglyceridemia, in contrast to higher dose recommendations by French
authors.
Double the usual daily dose of water-soluble vitamins should be given, and in severely malnourished patients
carnitine should also be given.
The dialysis-related substrate loss is not considerably increased by the infusion [43].
Studies on IDPN
Approximately 25 studies have been published on IDPN, however, with very different indications, nutrient
solutions and nutrient inatkes, and lengths of therapy. Most studies were cohort studies without a control group;
some were retrospective and others used "run-in" periods prior to the intervention. Only the study by Cano et al.
was controlled but did not include a placebo [44].
Almost all studies have shown significant improvements in different parameters; including anthropometry (body
weight, mid arm circumference, triceps skinfolds), serum proteins, (albumin, total protein, transferrin, prealbumin),
plasma amino acid concentrations, lymphocyte cells and immune reactivity. An influence on survival was
determined only in two studies, but firm conclusions cannot be drawn because of limitaions in study design
[45,46]. A multicenter study from France is currently being completed [47].
Abbreviations
ARF
Acute Renal Failure
CAPD Chronic Ambulant Peritoneal Dialysis
CRF
Chronic Compensated Renal Failure
CRRT Continuous Renal Replacement Therapy
HD
Chronic Haemodialysis Therapy
IDPN
Intradialytic Parenteral Nutrition
MAC
Mid-arm circumference
TSF
Triceps skinfold
BW
Body weight
PN
Parenteral nutrition
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Druml W1, Kierdorf HP2*
1Clinical
Dept. of Nephrology and Dialysis, University of Vienna, Austria, 2Dept. Nephrology, Braunschweig for
the working group for developing the guidelines for parenteral nutrition of The German Association for Nutritional
Medicine
Erstellungsdatum:
13
04/2014
AWMF online - Guidelines on Parenteral Nutrition: Surgery and Transplantation
1
AWMF online
Wissenschaftlichen
Medizinischen
Fachgesellschaften
Nr. 073-018e_18
Entwicklungsstufe:
3
Zitierbare Quelle:
Chapter 18: Surgery and Transplantation
Kapitel 18: Chirurgie und Transplantation
Key words: Surgery, transplantation, fast track surgery, postoperative nutrition
Schlüsselwörter: Operation, Transplantation, fast-track-Chirurgie, postoperative Ernährung
Abstract
In surgery, indications for artificial nutrition comprise prevention and treatment of catabolism and malnutrition.
Thus in general, food intake should not be interrupted postoperatively and the re-establishing of oral (e.g. after
anastomosis of the colon and rectum, kidney transplantation) or enteral food intake (e.g. after an anastomosis in
the upper gastrointestinal tract, liver transplantation) is recommended within 24 h post surgery. To avoid
increased mortality an indication for an immediate postoperatively artificial nutrition (enteral or parenteral
nutrition (PN)) also exists in patients with no signs of malnutrition, but who will not receive oral food intake for
more than 7 days perioperatively or whose oral food intake does not meet their needs (e.g. less than 60-80%)
for more than 14 days. In cases of absolute contraindication for enteral nutrition, there is an indication for total
PN (TPN) such as in chronic intestinal obstruction with a relevant passage obstruction e.g. a peritoneal
carcinoma. If energy and nutrient requirements cannot be met by oral and enteral intake alone, a combination of
enteral and parenteral nutrition is indicated. Delaying surgery for a systematic nutrition therapy (enteral and
parenteral) is only indicated if severe malnutrition is present. Preoperative nutrition therapy should preferably be
conducted prior to hospital admission to lower the risk of nosocomial infections. The recommendations of early
postoperative re-establishing oral feeding, generally apply also to paediatric patients. Standardised operative
procedures should be established in order to guarantee an effective nutrition therapy.
Zusammenfassung
Die Indikationen für eine künstliche Ernährung sind auch in der Chirurgie die Prophylaxe und Behandlung von
Katabolie und Mangelernährung. Generell sollte deshalb postoperativ die Nahrungszufuhr nicht unterbrochen
werden. Ein oraler (z.B. nach Anastomosen an Kolon und Rektum, Nierentransplantation) bzw. enteraler
Kostaufbau (z.B. nach Anastomosen am oberen Gastrointestinaltrakt, Lebertransplantation) wird binnen 24 h
nach OP empfohlen. Zur Vermeidung einer erhöhten Letalität, besteht auch bei Patienten ohne Zeichen der
Mangelernährung, die perioperativ voraussichtlich mehr als 7 Tage keine orale Nahrungszufuhr oder mehr als
14 Tage oral eine nicht bedarfsdeckende Kost (weniger als 60-80%) erhalten, die Indikation zu einer
unverzüglichen postoperativen künstlichen Ernährung. Nur in Fällen einer absoluten Kontraindikation für eine
enterale Ernährung wie bei einer chronischen Darmobstruktion mit relevanter Passagestörung, z.B. einer
Peritonealkarzinose, besteht die Indikation zur totalen PE (TPE). Wenn der Energie- und Nährstoffbedarf durch
orale und enterale Zufuhr allein nicht gedeckt werden kann, ist eine kombinierte enterale und parenterale
2
Ernährung indiziert. Die Verschiebung einer Operation zur Durchführung einer gezielten Ernährungstherapie
(enteral und parenteral) ist nur bei schwerer Mangelernährung angezeigt. Bei mangelernährten Patienten sollte
die präoperative Ernährungstherapie möglichst prästationär durchgeführt werden, um das Risiko nosokomialer
Infektionen zu senken. Prinzipiell gelten die Empfehlungen des frühzeitigen postoperativen Kostaufbaus auch
für das Kindesalter. Zur Sicherung einer effektiven Ernährungstherapie sollten klinikintern standardisierte
Schemata erstellt werden.
Surgery and Transplantation
Introduction
In surgery, the importance of nutritional status for postoperative morbidity and mortality in various clinical
conditions is demonstrated by both retrospective [1-6] and prospective [7-22] studies.
The presence of malnutrition is often an expression of the underlying disease i.e. a tumour or chronic organ
insufficiency [22-31] (cf. appropriate chapter). Malnutrition is particularly relevant for outcome after organ
transplantation[32-41]. Nutritional status also has a significant influence on morbidity of older patients [42].
Enhanced recovery after surgery (ERAS) is a prerequisite for the desirable reduction of length of hospital stay.
This so-called "fast track" system has become a standard in postoperative management, especially after colon
operations. The principles of the multimodal process are perioperative limited volume supply, adequate pain
therapy (especially by means of epidural anaesthesia), and minimising the administration of opioids, antiemetics
and peristaltics. The objective is the re-establishing of oral food intake and full mobilisation of the patient at the
earliest possible time.
In surgery, the indications for artificial nutrition are prevention and treatment of catabolism and malnutrition. This
mainly affects the perioperative maintenance of nutritional state to prevent malnutrition. Criteria for the success
of the "therapeutic" indication for PN are the so-called "outcome" parameters of morbidity, length of hospital stay
and mortality, while taking into consideration economic implications. The improvement of nutritional status and
quality of life are most important in the postoperative period [43-55].
Postoperative Re-establishing of Food Intake





Generally, nutrient intake should not be interrupted postoperatively (A).
The postoperative re-establishing of oral food intake should be adjusted according to the patient's tolerance (C).
The re-establishing of oral or enteral food intake is recommended within 24 h post surgery (A).
Oral food intake can be reintroduced from the first postoperative day after an anastomosis of the colon and
rectum (A).
Enteral intake via a tube- with the tip distal to the anastomosis site is recommended for the first few days after
an anastomosis in the upper gastrointestinal tract (A).
Commentary
Early re-establishing of oral or enteral food intake lowers the risk of infection and reduces the length of the
hospital stay [56-58] (Ia), [59,60] (Ib), [61] (IIa).
Food intake can be reintroduced immediately after a cholecystectomy, because a latency period or
oesophagogastric decompression is of no advantage [62,63] (Ib). Early re-establishing of oral food intake, by
drinking from the first post operative day, after an anastomosis of the colon and rectum does not result in an
increased insufficiency rate or interruption in the healing process [56,63,64] (Ib), [65] (Ia). The speed at which
food is reintroduced should be guided by the gastrointestinal tract function and the patient's tolerance [57] (Ia),
[63-65] (Ib), [66-68] (IIa), [59,69] (IIb).
No comparable data are available for patients with an upper gastrointestinal tract anastomosis e.g. after a
gastrectomy or oesophageal resection. In these cases numerous controlled studies have shown the
practicability of enteral nutrition via a tube distal to the anastomosis site [70-73].
In comparison to conventional laparotomies, laparoscopic colonic surgery improves the tolerance to early reestablishing of oral food intake through faster establishment of peristalsis and intestinal passage [74] (Ib),
[68,75] (IIa).
Perioperative (pre and postoperative) Indications for Artificial Nutrition
General


Insufficient food intake for more than 14 days is associated with increased mortality (Ib).
Indications for artificial nutrition also exists in patients with no signs of malnutrition, but who will not



3
receive oral food intake for more than 7 days perioperatively or whose oral food intake does not meet
their needs (i.e. less than 60-80%) for more than 14 days. In these cases it is recommended that enteral
nutrition and, if required, also PN (B) is started immediately postoperatively.
Total PN (TPN) is indicated if there is an absolute contraindication for enteral nutrition, such as in chronic
intestinal obstruction with a relevant passage obstruction e.g. a peritoneal carcinoma (A).
If the energy and nutrient requirements cannot be met by oral and enteral intake alone, a combination of
enteral and parenteral nutrition is indicated (C).
Standardised operative procedures should be established to secure an effective nutrition therapy (C) (cf.
Advice and examples for postoperative PN on general wards, below).
Commentary
The prognostic influence of nutritional state on morbidity, mortality and length of hospital stay (LOS) is
prospectively documented for surgical patients, particularly after organ transplantation [1-22]. Insufficient food
intake over a period of more than 14 days is associated with increased mortality (Ib) [76].
The current guidelines of the American Society for Parental and Enteral Nutrition (ASPEN) recommend
postoperative PN for patients who cannot meet their energy needs orally within 7-10 days [77].
The effect of PN in comparison to oral/enteral standard nutrition with regards to the prognosis of surgical
patients has been discussed controversially [72,78-98] (Table 1). Twenty-one randomised studies of patients
with abdominal surgery, including patients after liver transplantation and trauma patients, are known to the
expert group. In these studies (total) PN was compared with enteral nutrition, or with crystalloid solutions or with
a normal hospital diet.
Enteral and parenteral nutrition was compared in 15 studies, of which 6 showed studies significant benefits of
enteral nutrition, mainly, a lower incidence of infectious complications, shorter length of stay, and lower costs
(Ib). No significant difference, was found in 8 of the 15 studies, which led most authors to favour enteral nutrition
because of its lower costs [72,92,93,95] (Ib).
Several authors have pointed out the possible advantages of PN when there is a limited tolerance of enteral
nutrition due to intestinal dysfunction especially in the early postoperative phase, which is associated with a
lower energy intake [78]. Strict attention, therefore, must be paid to the tolerance of enteral intake especially in
patients with severe polytrauma [88] (Ib). An adequate energy intake is better provided by PN when there is a
limited gastrointestinal tolerance [99] (IIa).
A meta-analysis by Braunschweig et al. [100] comparing enteral with parenteral nutrition incorporated the results
of 27 studies with 1,828 patients, (both surgical and non-surgical). It showed a significantly lower risk of infection
with oral/enteral nutrition. In malnourished patients, however, PN administration resulted in a significantly lower
mortality with a tendency towards lower rates of infection. Heyland et al. [101] incorporated 27 studies in a metaanalysis of PN in surgical patients. Clinical trials comparing enteral versus parenteral nutrition were excluded. An
influence of PN on the mortality of surgical patients was not shown. A lower complication rate, especially in
those with malnutrition, was observed in the parenterally nourished patients These results lead to the
recommendation not to enforce a dietary intake covering energy requirements during the first 7-10 postoperative
days in well-nourished patients.
Table 1: Randomised controlled studies on perioperative PN
Author
Year N
MuggiaSullam et
al. [78]
Type
Start
Results
Evaluation
1985 19 Visceral
EN vs.
TPN
1.-10. days,
FNCJ
No difference
+-
Adams et
al. [79]
1986 46 Trauma
EN vs.
TPN
1-14 days
No difference in rate of
complications and Nbalance
+-
Bower et
al. [80]
1986 20 Visceral
EN vs.
TPN
1-7 days - FNCJ Lower costs
Moore et
al. [81]
1989 59 Trauma
EN vs.
TPN
12h, FNCJ,
Less severe infections, no +
50ml/h
difference in N-balance
isocaloric TPN,
1.3-1.5xBEE HB
Reilly et al. 1990
[82]
VA [83]
OP
Visceral - Liver
transplantation
1991 395 Malnutritioned
before
+
TPN+BCAA
versus
controls
Better N-balance and
shorter LOS in intensive
care with TPN - no
difference for enrichment
with BCAA
+
7 days
preop. and
Significantly less non+infectious complications in
laporotomy or
non-cardiac
thoractomy
3 days
postop.
TPN
versus
controls
4
severe malnutrition otherwise no difference
Kudsk et al. 1992 98 Trauma
[84]
EN vs.
TPN
24h FNCJ
EN less infections
Von
1992 101 Visceral
Meyenfeldt
et al. [85]
Preop. EN
versus
TPN
versus
controls
At least 10 days
with malnutrition
(NI), nasogastr.
or oral 150%
BEE according
to Harris &
Benedict
Less intraabdom.
+
abscesses with weight
loss > 10 % in comparison
to the malnourished
control group, however
TEN versus TPN
comparable
Sandstrom 1993 300 Visceral
et al. [76]
TPN
versus
glucose
solution
Iovinelli et
al. [86]
EN versus PEG after 24h, Weight, TSF, MAC, alb.,
TPN
energy: Harris & TFN, no difference,
Benedict. + 40 shorter LOS
%
+
TPN
versus
controls
No benefit - significantly
more complications in
TPN
-
Dunham et 1994 37 Severe
al. [88]
polytrauma (ISS
> 15)
EN versus approx. 24h
TPN
versus
PN/EN
No difference in mortality, but increased mortality of
enteral nutrition in
intestinal dysfunction
Fan et al.
[89]
Oral
1 day
versus oral
+ PN
Low rate of complications +
in PN
Wicks et al. 1994 24 Visceral - liver
[90]
transplantation
EN vs.
TPN
No difference in
+anthropometric
parameters, intestinal
function and infection rate
Jauch et al. 1995 44 Visceral
[91]
Hypocal.
OP day
glucose or
xylite
versus
NaCl 0.9 %
Hypocal. metabolically
more favourableNo
difference between
glucose and xylite
+
Baigrie et
al. [92]
1996 97 Visceral
EN versus 3 days, FNCJ
TPN
Tendency towards less
complications
+ - safe
Reynolds
et al. [93]
1997 67 Visceral
EN versus 1 day, FNCJ
TPN
No difference in
complications
+-
Sand et al. 1997 29 Gastrectomy
[94]
EN versus 1. day, FNCJ
TPN
More economical
+
Shirabe et
al. [95]
1997 26 Liver resection
EN vs.
TPN
2 days, nasojejunal
No significant difference in +outcome
Hu et al.
[96]
1998 40 Orthopaedics spine
TPN
versus
controls
1. day
Significantly lower drop in +
albumin and prealbumin,
lower albumin and
prealbumin correlates with
the increased risk of
pneumonia and urinary
tract infections, no
significant difference in
the rate of wound
infections
Pacelli et
al. [72]
2001 241 Malnutrition visceral
EE versus FNCJ or
PN
nasojejunal on
1993 48 Laryngectomy
Brennan et 1994
al. [87]
Visceral pancreas
resection
1994 124 Visceral liver
resection
within 18h
No difference in the rate
of complication and
+
+-
1st day 30 ml/h
Bozzetti et
al. [73]
2001 317 Malnutrition visceral
EE versus FNCJ or
PN
nasojejunal on
1st day
isocaloric
Braga et al. 2001 257 Visceral stomach EN versus Target 25
[98]
(121) pancreas - PN
kcal/kg/day
(110 oesophagus
approx. (26)
BCAA = Branched-chain Amino Acids
EN = Enteral Nutrition
FNCJ = Fine Needle Catheter jejunostomy
LOS= Length of Hospital Stay
QL= Quality of Life
PEG = Percutaneous Endoscopic Gastrostomy
PN = Parenteral Nutrition
TPN = Total Parenteral Nutrition
5
mortality
Enteral: significantly less
complications and lower
LOS
+
No difference in the rate
+of complications, LOS and
mortality, EN 4x more
economical
Combined Enteral/Parenteral Nutrition
Indication


Combined enteral/parenteral nutrition should always be carried out when artificial nutrition is indicated
and the energy requirements cannot be adequately met because of limited enteral tolerance. This is
particularly applicable when the energy intake amounts to <60% of the calculated caloric requirements
and a central venous catheter for PN is already available (C).
When insertion of a central venous catheter is required for the purpose of artificial nutrition, this indication
must be critically considered in relation to the expected time period of PN. Combined nutrition is not
necessary if expected time period of PN is <4 days. If the expected PN period is expected to last between
4-7 days, nutrition can be hypocaloric with 2 g carbohydrates and 1 g amino acids/kg body weight
administered via a peripheral catheter, and if it is likely to last more than 7-10 days, it is recommended
that a central venous catheter should be inserted (C).
Commentary
Combined enteral/parenteral nutrition has not yet been evaluated in prospectively controlled clinical trials with
patients undergoing elective surgery. Heyland et al. [102] and Dhaliwal et al. [103] analysed the studies carried
out on critically ill patients. Two of these studies from the 80's came from the same study group, and were
carried out on patients with bad burns and severe trauma respectively. In the meta-analysis of these studies no
advantage was found of combined nutrition regarding mortality, infection, LOS and length of artificial ventilation.
Heyland et al. [102], therefore, recommend not to begin with combined enteral and parental nutrition in critically
ill patients without signs of malnutrition. They further recommend to decide on parental substrate intake on an
individual basis in case of poor tolerance to enteral nutrition.
In major elective surgeries, placement of a central venous catheter is usually a routine. It is the opinion of this
expert group that in the presence of a suitable indication this access should be used for PN, especially in
malnourished patients, and if necessary also as a part of hypocaloric regime. A randomised controlled study has
shown that a hypocaloric PN of 25 kcal/kg and 1.5 g/kg protein presents no increased risk of hyperglycaemia
and infectious complications, but results in a significant improvement in nitrogen balance [104] (Ib). Insertion of a
central venous catheter exclusively for artificial nutrition should be carefully considered. An increase in energy
intake can be achieved in the short-term by lipid administration using peripheral venous access. An increase in
enteral intake is the main objective in combined enteral/parenteral nutrition.
A possible approach to combined PN and to tapering PN when reintroducing enteral feeding is shown in plan IV.
Preoperative Indications for PN




Delaying surgery for a systematic nutrition therapy (enteral and parenteral) is only indicated if severe
malnutrition is present (A).
Preoperative PN is indicated in patients where energy requirement cannot be adequately met by enteral nutrition
(C).
An intravenous administration of 200 g glucose preoperatively during the night is recommended in patients who
cannot be enterally fed (B).
In malnourished patients, preoperative nutrition therapy should preferably be conducted prior to hospital
6
admission to lower the risk of nosocomial infections (C).
Commentary
Positive effects of PN for 7-10 days were observed postoperatively with regards to the rate of complications
[83,97] and the drop in mortality [83] (Ib). The early postoperative release of cytokines such as IL-6 and IL-8 is,
however, significantly higher when PN is administered [105] (Ib). Furthermore, parenteral infusion involves the
risk of expanding the extracellular space, thus lowering the albumin concentration and thereby, increasing the
risk of pulmonary complications [106] (Ib). Positive effects on postoperative stress adaption were reported after
parenteral infusion of 1.5-2 g/kg glucose and 1 g/kg amino acids preoperatively (16-20 h) [107].
There is insufficient data available on the comparison of enteral and parenteral nutrition preoperatively.
Therefore oral or enteral feeding should be preferred whenever possible. If parenteral nutrition is necessary to
meet energy needs e.g. in stenosis of the upper gastrointestinal tract, it should be combined with oral nutrition
(e.g. oral nutritional supplements) whenever possible. The benefits of preoperative PN over 7-10 days are only
evident in patients with severe malnutrition (weight loss >15%) prior to major gastrointestinal surgery [83,97].
When PN is continued for 9 days postoperatively the rate of complications is 30% lower and there is a reduction
in mortality (Ib). Questions regarding the type of preoperative nutritional intake have not been clearly resolved in
malnourished patients. Preoperative parenteral and enteral nutrition has been compared in one prospective
study. Clear advantage of preoperative PN could not be shown [85]. The results of the meta-analysis by
Braunschweig [100], however, do favour PN. A significantly lower mortality with a tendency towards lower rates
of infection was found in malnourished patients receiving PN.
Glutamine
Indication for Glutamine Administration


Currently, there is only an indication for postoperative parenteral supplementation of glutamine
dipeptide solutions in severely malnourished patients who cannot be adequately fed enterally and,
therefore, require PN (C).
A lack of sufficient evidence-based studies deter the expert group from making a general
recommendation for parenteral use of glutamine in surgical patients (C).
Commentary
The parenteral supplementation of glutamine dipeptide in 9 controlled randomised trials (Ib) with non-enterally
fed surgical patients was reviewed by the working group with regards to the end-points morbidity and outcome
(two as abstracts, see Table 2 in the attachment [108-116]). In eight of these studies, the patients were to
undergo elective surgery and in one after emergency visceral surgery. All studies showed significant benefits of
glutamine supplementation, seven with respect to postoperative LOS and two with respect to postoperative
morbidity. This correlates with the results of an earlier meta-analysis examining elective surgical patients [117]
(Ia). A systematic analysis of European and Asian non-enterally nourished surgical patients resulted in 10
studies with the end point of infectious complications and 8 studies of postoperative LOS. Significant benefits of
glutamine supplementation were also seen [118] (Ia). Significantly improved regeneration of the postoperative
immune function was shown in two current studies with immunological end points [119-122] (Ib).
Based on the current understanding, exclusive PN over 5-7 days is not indicated in surgical patients particularly
after elective colorectal surgery with an uncomplicated course [58,123]. To what extent does parenteral
glutamine intake, with oral/enteral nutrition, may have a positive effect, cannot be answered at present due to
lack of available data. The possible significance of a short-term perioperative glutamine infusion for a total
duration of 72 hours, beginning 24 hours before elective surgery, needs to be further clarified [119].
Table 2: Randomised controlled studies on glutamine supplementation in the PN of surgical patients
Author
Year N
Patients
Glutamine dosage
Results
Evaluation
Morlion et
al. [108]
1998 28
Visceral-colorectal
0.3g/kg/day alanineglutamine versus
standard isonitrogen,
isocaloric for 5 days
postop.
Significantly shorter
LOS, improved Nbalance and
regeneration of
immune defence
+
Fürst et al.
[109,110]*
1999 126 Multicentervisceral,
thorax
0.5 g/kg d alanineglutamine versus
standard isonitrogen for 5
days postop.
Significantly lower
LOS, no difference
in rate of
complications
+
Jacobi et al.
[110]
1999 34
Visceral
(oesophagus,
stomach)
Jiang et al.
[111]
1999 120 Multicentervisceral
7
0.4 g/kg/day for 5 days
postop.
Lower rate of
complications, no
clear advantage in
postop. immune
function
+
0.5 g/kg/day alanineglutamine versus
standardisonitrogen,
postop.
Significantly lower
LOS
+
Powell-Tuck 1999 168 Mixed - also visceral
et al. [112]
Suppl. of 20 g / day
versus standard for the
whole period of PN
Significantly lower
+
LOS only in surgical
patients
Mertes et al. 2000 37
[113]
Visceral
postop.
Significantly lower
LOS
+
Karwowska
et al. [114]*
2000 30
Abdominal aorta
surgery
postop.
LOS, significantly
better N-balance,
improved
regeneration of
immune function
+
Neri et al.
[115]
2001 33
Viseral
postop.
LOS, significantly
better N-balance
+
Fuentes
Orozco et
al. [116]
2004 33
Visceral - secondary
peritonitis
postop.
Significantly less
infectious
complications
+
Albers et al.
[128]
2005 80
Newborns and
children with OP on
intestinal tract
0.4g/kg/d L-glutamine in
2.5% solution,
isonitrogen, isocaloric
No significant
difference in
intestinal
permeability, Nbalance and
outcome
+-
* Abstract; LOS = Length of Hospital Stay
Specific aspects in Paediatric Surgery

The recommendations on early postoperative re-establishing of oral feeding generally apply also to
infants, children and adolescents (C).
Commentary
In neonates and premature infants, early re-establishing of food (even with the smallest amounts of EN) result in
a lower risk of sepsis due to an increase in immune competence [124]. Numerous studies have shown that
postoperative energy expenditure increases in newborns after major surgery by 20%, and is normal again within
the first 12 to 24 hours [125]. Postoperatively, infants tend to retain water during the first 24 hours due to
increased ADH levels and, therefore, fluid intake should be restricted whereas sodium should be given in higher
doses [126,127].
No benefits have been observed when PN is supplemented with glutamine in newborns and children undergoing
gastrointestinal surgery [128] (Ib).
Children with short bowel syndrome due to genetic or acquired loss of resorptive surface are dependent on longterm PN. Liver damage and complications like thromboses, embolism and sepsis associated with intravenous
8
nutrition determine the prognosis [129]. An assessment by a intestinal transplantation centre should be
considered for PN-dependent paediatric patients with short bowel syndrome who suffer from hyperbilirubinaemia
(total bilirubin >3 mg/dl) for more than three-months despite adequate therapy [130]. A formula is available to
calculate the anticipated duration of PN-dependency in order to determine an early indication of transplantation
[131]. An isolated small intestine transplantation is strived for in children with reversible liver damage. PN may
usually be terminated over medium-term after the small intestine transplantation has been successful.
Organ Transplantation
PN in Patients after Organ Transplants





An early re-establishing of oral feeding should be strived for after successful, uncomplicated heart,
liver, and kidney transplantation procedures (C).
Early EN, combined with PN if necessary, is recommended within 24 hours after liver or pancreas
transplantations (C).
EN should be increased very carefully within the first week of a small intestine transplantation.
Enteral/parenteral nutrition should be combined as well. (C)
No recommendation can be made for parenteral supplementation of immune-modulatory substrates
due to the lack of data available (C).
No recommendation can be made regarding the parenteral supplementation of glutamine and arginine
to precondition against ischemia/reperfusion damage (C).
Commentary
Early oral or enteral feeding should also be strived for in transplantation patients [132,133].
Absorption and blood levels from tacrolism are not impaired by EN [134] (IIb). EN and PN are equally important
in patients after liver transplantations [90] (Ib).
Benefits have been reported with administration of MCT/LCT lipid emulsions compared to LCT emulsions, with
more favourable regeneration of the function of the reticuloendothelial system after liver transplantation [135].
The metabolism of both lipid solutions shows no difference [136] (Ib).
Advantages of EN are evident when the incidence of viral infections is considered [137] (Ib). In comparison to a
standard enteral diet in combination with selective intestinal contamination, a significant drop in the rate of
infection was also shown through the use of a high-fibre diet enriched with Lactobacillus plantarum [138] (Ib).
The placement of a fine needle catheter jejunostomy is also feasible in liver transplanted patients [139] (IIb).
After small intestine transplantation EN is more difficult because of increased intestinal secretion [140].
The role of pre-conditioning the organ donor or the donor organ i.e. through high-dosage arginine intake for the
production of NO and its conversion into glutamine and glutathione is a still open-ended question.
There are no clinical trials on parenteral immunonutrition. Data resulting from animal experiments on parenteral
supplementation with glutamine after transplantation of the small intestine show beneficial trophic effects with
low mucosa permeability and a low rate of bacterial translocation [141].
Attachment
Advice and examples for postoperative PN on general wards
See also "Safe Practices of PN" [126]










Multi-chamber bags must be mixed according to instructions prior to administration.
Attention should be paid to expiry date, precipitation etc.
Careful labelling of infusion bags (admixtures, patient`s name)
Solutions with high osmolarity (>800 mosm/l) should only be infused via central venous access.
The infusion is administered via infusion pumps when feeding paediatric patients and when using
hypercaloric nutrition.
Regular checks of the infused solutions should be made during every shift in order to recognise and
correct irregularities.
Replacement of the whole infusion system including the three-way valve should take place every 3rd day.
For drug infusion via piggy-bag a separate intravenous line should be used.
Attention should be paid to hygiene rules when injecting admixtures, penetrating a vein or changing the
infusion system, or during manipulations at the access etc.
Replacement of additional fluid losses (fever, drainages, diarrhoea, vomiting, stomach tube, etc.).


9
Exact documentation in the chart (length of infusion, signature)
Regular laboratory tests.
Postoperative Infusion and Nutrition Therapy
Plan 1: Fast track with immediate re-establishing of oral food
Indication: Patients who are not suffering from malnutrition and who may receive sufficient oral or enteral
nutrition within 4 days, do not require PN irrespective of the type and size of surgery.
Principle: Exclusively electrolyte, fluids and glucose administration irrespective of body weight. Peripheral
venous administration is possible. The electrolyte solution can serve as a carrier solution for drugs.
Simultaneous increase in oral fluid intake and gradual re-establishing of food.
Application: Peripheral venous, crystalloids - preferred solution: balanced electrolyte solution, NaCl 0.9% in
case of increase in serum potassium (dialysis patients).
Example:
Body weight OP day
irrespective
1st postoperative day 2nd postoperative day
1000 ml
1000 ml
electrolyte solution electrolyte solution
as in day 1 in case ofinsufficient oral fluid intake
Plan II: Short-term hypocaloric PN
Indication: Patients who are not malnourished and who probably will not be able to receive sufficient oral or
enteral nutrition within 4 days of surgery. Principle: Hypocaloric PN, e.g. adequate amino acid substitution with
limited carbohydrate infusion, only meeting the basic requirements.
Application: Peripheral venous administration is possible. However, it could lead to vein irritation especially with
the additional administration of electrolytes, drugs (i.e. antibiotic infusion etc.), complete solutions or twochamber bags.
Example:
Body weight OP day
irrespective
1st postoperative day
as of 2nd postoperative day
2500 ml
1000 ml glucose(10 - 12 %)
electrolyte solution 1000 ml
amino acids (10 %)
+ electrolytes
500 ml
electrolyte solution
1000 ml glucose
(10 - 12 %) 1000 ml
amino acids (10 %)
+ electrolytes
500 ml
electrolyte solution
Plan III: PN to meet energy and nutritional requirements
Indications: All patients who are suffering from malnutrition, and those who are not suffering from malnutrition
but will not be able to receive sufficient oral or enteral nutrition within 7 days, or those who are not suffering from
malnutrition but where it is not anticipated that adequate oral or enteral nutrition can be administered within 14
days.
Principle: Required calorie intake taking into account all substrates as well as adequate substitutions of
vitamins and trace elements (total PN). Lipid intake is started on the third day.
There is marked interindividual variance in energy needs for newborns and infants under severe postoperative
conditions. Jaksic et al. [142] was not able to detect any increased energy expenditure as a result of massive
postoperative stress in newborns. In infants, weight development and fluid balance should be observed to
evaluate energy intake. Additionally CO2 production may be measured.
Application: Central venous (catheter via the vena jugularis or vena subclavia), mixed or two-chamber and
three-chamber bags. The electrolyte solution can serve as a carrier solution for drugs.
Example:
Body
weight
OP day
Irrespective 1000 ml
electrolyte
solution
1st postoperative day
2nd postoperative day
as of 3rd postoperative day
2000 ml
two-chamber bag
500 mlelectrolyte
2000 ml
two-chamber bag
500 mlelectrolyte
2000 ml
"all-in-one"three-chamber
bag
solution
solution
10
500 mlelectrolyte solution
Plan IV: Combined Enteral and Parenteral Nutrition
Indications: All patients, with indications for artificial nutrition, who are unlikely to meet caloric requirements
through EN.
Principle: The parenteral substrate intake is adjusted as enteral intake is tolerated with the objective of
gradually meeting caloric requirements enterally.
Application: Enteral tube/needle catheter jejunostomy or peripheral venous access, two and three-chamber
bags
Example:
Level * Enteral
Parenteral
1a
10 - 25 ml/h over 20 - 24h 1000 ml glucose 10 - 12 %
approx. 200 - 500 kcal
(100 - 120 g = 400 - 480 kcal)
+ electrolytes
500 ml amino acids 10 %
(50 g)**
1b
10-25 ml/h over 20 - 24h
1000 ml glucose 20 - 25 %
(200 - 250 g = 800-1000 kcal)
+ electrolytes
1000 ml amino acids 10 % (100 g)
**possibly 250 ml lipids 20 %
(50 g approx. 500 kcal)
2
50 ml/h over 20h
approx. 1000 kcal
1000 ml glucose 20 - 25 %
(200 - 250 g = 800-1000 kcal)
+ electrolytes
(100 g)**
3
75 ml/h over 20h
approx. 1500 kcal
500 ml glucose 10 - 12%
(100 - 120 g = 400 - 480 kcal)
+ electrolytes
(100 g)**
4
100-125 ml/h over 20h
*The increase in levels is according to the enteral tolerance of the patient. Substitution with water-soluble and
fat-soluble vitamins and trace elements is recommended, provided that Level 1 cannot be exceeded for several
days.
**Amino acids are not included in this example for the calculation of the calorie intake
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Kuse ER, Kotzerke J, Muller S, Nashan B, Luck R, Jaeger K. Hepatic reticuloendothelial function during parenteral nutrition including an MCT/LCT or
LCT emulsion after liver transplantation - a double-blind study. Transpl Int 2002; 15: 272-277
Delafosse B, Viale JP, Pachiaudi C et al. Long- and medium-chain triglycerides during parenteral nutrition in critically ill patients. Am J Physiol 1997;
272: E550-E555
Hasse JM, Blue LS, Liepa GU et al. Early enteral nutrition support in patients undergoing liver transplantation. JPEN J Parenter Enteral Nutr 1995;
19: 437-443
Rayes N, Seehofer D, Theruvath T et al. Supply of pre- and probiotics reduces bacterial infection rates after liver transplantation--a randomized,
double-blind trial. Am J Transplant 2005; 5: 125-130
Pescovitz MD, Mehta PL, Leapman SB, Milgrom ML, Jindal RM, Filo RS. Tube jejunostomy in liver transplant recipients. Surgery 1995; 117: 642-647
Rovera GM, Graham TO, Hutson WR et al. Nutritional management of intestinal allograft recipients. Transplant Proc 1998; 30: 2517-2518
Li YS, Li JS, Jiang JW et al. Glycyl-glutamine-enriched long-term total parenteral nutrition attenuates bacterial translocation following small bowel
transplantation in the pig. J Surg Res 1999; 82: 106-111
Jaksic T, Shew SB, Keshen TH, Dzakovic A, Jahoor F. Do critically ill surgical neonates have increased energy expenditure? J Pediatr Surg 2001;
36: 63-67
Weimann A1, Ebener Ch2, Holland-Cunz S3, Jauch KW4, Hausser L5, Kemen, M6, Kraehenbuehl L7, Kuse
ER8, Laengle F9 *
1Dept.
of General und Visceral Surgery, St. George's Hospital, Leipzig, 2Dept. of General, Visceral and
Children's Surgery, Heinrich-Heine-University of Dusseldorf, 3Dept. of Paediatric Surgery, University of
Tuebingen, 4Dept Surgery Grosshadern, University Hospital, Munich, 5Dept. of General and Visceral Surgery,
Augsburg, 6Dept. Surgery, Lutheran Hospital Herne, 7Dept. of Surgery, Canton Hospital Fribourg, Switzerland,
8Central Clinic for Anaesthetics, Operative Intensive Medicine and Pain Therapy, Hospital of Salzgitter, 9Dept.
14
General Surgery, University of Vienna, Austria for the working group for developing the guidelines for parenteral
nutrition of The German Association for Nutritional Medicine
Erstellungsdatum:
04/2014
AWMF online - Guidelines on Parenteral Nutrition: Non-surgical Oncology
1
AWMF online
Wissenschaftlichen
Medizinischen
Fachgesellschaften
Nr. 073-018e_19
Entwicklungsstufe:
3
Zitierbare Quelle:
Chapter 19: Non-surgical Oncology
Kapitel 19: Nichtchirurgische Onkologie
Key words: Tumour, radiotherapy, chemotherapy, stem cell transplantation
Schlüsselwörter: Tumor, Radiotherapie, Chemotherapie, Stammzelltransplantation
Abstract
Reduced nutritional state is associated with unfavourable outcomes and a lower quality of life in patients with
malignancies. Patients with active tumour disease frequently have insufficient food intake. The resting energy
expenditure in cancer patients can be increased, decreased, or remain unchanged compared to predicted
values. Tumours may result in varying degrees of systemic pro-inflammatory processes with secondary effects
on all significant metabolic pathways. Therapeutic objectives are to stabilise nutritional state with oral/enteral
nutrition and PN and thus to prevent or reduce progressive weight loss. The maintenance or improvement of
quality of life, and the increase in the effectiveness and a reduction in the side-effects of antitumor therapy are
further objectives. Indications for PN in tumour patients are essentially identical to those in patients with benign
illnesses, with preference given to oral or enteral nutrition when feasible. A combined nutritional concept is
preferred if oral or enteral nutrition are possible but not sufficient. There are generally no accepted standards for
ideal energy and nutrient intakes in oncological patients, particularly when exclusive artificial nutrition is
administered. The use of PN as a general accompaniment to radiotherapy or chemotherapy is not indicated, but
PN is indicated in chronic severe radiogenic enteritis or after allogenic transplantation with pronounced mucositis
or GvH-related gastrointestinal damage for prolonged periods, with particular attention to increased risk of
bleeding and infection. No PN is necessary in the terminal phase.
Zusammenfassung
Ein reduzierter Ernährungszustand ist mit einer eingeschränkten Prognose und verminderter Lebensqualität
assoziiert. Patienten mit aktiver Tumorerkrankung haben häufig eine unzureichende Nährstoffaufnahme. Der
Ruhe-Energieumsatz kann im Vergleich zum Erwartungswert unverändert, gesteigert oder vermindert sein. Bei
manifesten Tumorerkrankungen kommt es in unterschiedlichem Ausmaß zu systemischen proinflammatorischen
Prozessen mit sekundären Auswirkungen auf alle wesentlichen Stoffwechselwege. Durch eine PE soll der
Ernährungszustand stabilisiert und ein fortschreitender Gewichtsverlust verhindert oder reduziert werden.
Weitere Ziele sind der Erhalt oder eine Verbesserung der Lebensqualität und eine Erhöhung der Effektivität
sowie eine Reduktion von Nebenwirkungen der antitumoralen Therapie. Prinzipiell sind die Indikationen für eine
PE bei Tumorpatienten identisch mit den Indikationen bei Patienten mit gutartigen Erkrankungen, wobei bei
Tumorpatienten eine orale oder enterale Nahrungszufuhr immer vor einer PE eingesetzt werden sollte. Bei
möglicher oraler oder enteraler Zufuhr ergibt sich ein kombiniertes Ernährungskonzept. Für die optimale
2
Energie- und Nährstoffzufuhr onkologischer Patienten, besonders für die ausschließliche künstliche Ernährung,
gibt es keine allgemein akzeptierten Standards. Der generelle Einsatz einer PE begleitend zum
Strahlentherapieverfahren oder zur Chemotherapie ist nicht sinnvoll, ist jedoch indiziert bei chronischer
schwerer radiogener Enteritis oder nach allogener Transplantation wegen einer ausgeprägten Mukositis und
GvH-bedingten Gastrointestinalschäden mit besonderer Rücksicht auf das erhöhte Blutungs- und
Infektionsrisiko. In der Sterbephase ist keine PE erforderlich.
The Nutritional State Influences the Clinical Outcome

Reduced nutritional state is associated with unfavourable outcomes and a lower quality of life in patients with
malignancies (IIa).
Commentary
Adult tumour patients who have lost weight or are malnourished show an unfavorable outcome in longitudinal
studies. The response to antitumor treatment is decreased while treatment-associated side effects are more
frequent; physical performance and quality of life are compromised; overall survival is significantly shorter than
in patients without weight loss [1-11]. Cachexia is the most common cause of death in tumour patients other
than sepsis [12].
In a recent study body nitrogen content was found to be the strongest predictor for protection against bone
marrow toxicity during chemotherapy in patients with breast cancer [13].
The effect of malnutrition on the rate of cure in children with cancer is controversial. While a significantly lower
rate of healing is reported in malnourished patients (Ib) [14-18], there appears to be no influence on patients'
survival (IIa) [19-22]. These differences depend on the various definitions of malnutrition, the type and extent of
the tumour, tumour therapy, supportive measures and the socio-economic status of the family. Malnutrition is
known to decrease immunocompetence (IIa) [23,24], decrease the tolerance to chemotherapy (IIa) [25] and
increase the rate of infection (IIa) [26,27]. Information on organ dysfunction as a result of malnutrition in children
with cancer is scarce. In malnouruished children there is an increased risk of cardiomyopathy after the
administration of anthracyclines (IV) [28].
Influence of Malignancies on Energy Expenditure


Patients with active tumours frequently have insufficient food intake (II).
The resting energy expenditure in cancer patients can be increased, decreased, or remain unchanged in
comparison to the predicted value (II).
Commentary
Food intake is lower than the usual even in patients with early stage tumour disease, and there is often a large
discrepancy between the actual energy and protein intake and the calculated requirements in advanced tumour
stages [10,29].
In approximately 25% of patients with active tumours, resting energy expenditure (REE), as measured by
indirect calorimetry, is more than 10% above, and in another 25% more than 10% below the predicted value. A
prediction as to the direction and extent of the deviation is not possible [30,31]. The mean value of total energy
expenditure in cancer patients is similar to that of a healthy reference group [31,32,32]. Studies in patients with
various tumour entities showed a normal REE in people with stomach or colorectal carcinomas, and an
increased REE in patients with pancreatic or bronchial carcinomas [33-36]. More detailed investigations in
patients with advanced bronchial and pancreatic carcinomas revealed an increased REE coupled with
diminished physical activity and a slightly lower overall energy expenditure when compared to healthy subjects
[35,36].
Therefore, in adult patients normal energy expenditure should be assumed if the actual resting energy
expenditure cannot be measured in individual cases. Formulae (i.e. Harris Benedict, cf. chapter "Energy
Expenditure and Energy Intake") may be used to calculate the normal resting energy expenditure. In patients,
the overall energy requirement is also determined by physical activity and may be estimated as 100-120% of
REE (cf. chapters "Energy Expenditure and Energy Intake" and "Neonatology/Paediatrics" for children's energy
expenditure).
Studies have shown that children with leukaemia have a near normal resting energy expenditure at diagnosis
and during anti-cancer treatment [24,37-40]. Resting energy expenditure, however, is increased in leukaemic
children with large tumour mass [38], and in children with solid tumours [24,41]. However, the data are
inconsistent.
Malignancies May Influence Metabolic Parameters
3
Clinically-relevant Metabolic Changes
Manifest tumours result in varying degrees of systemic pro-inflammatory processes with secondary effects on all
significant metabolic pathways [42]. A large body of data suggests that the primary reaction of the tumourbearing host is to release cytokines, catabolic hormones and other regulatory peptides locally and systemically
[42-44].
The resulting systemic inflammatory reaction contributes significantly to the loss of appetite [45,46] and weight
[47-50]. These cytokine-induced metabolic changes prevent a recovery of body cell mass [51], and are
associated with reduced life expectancy [52] in cachectic patients [52,53].
Effects on Carbohydrate Metabolism

Insulin resistance and increased glucose production can often be detected in tumour patients (II).
Commentary
Impaired glucose tolerance due to insulin resistance is common in tumour patients [54]. The plasma ratio of
insulin to catabolic hormones is abnormal with typical findings of increased cortisol secretion and a decreased
insulin-cortisol ratio [44,55]. This results in increased glucose turnover and gluconeogenesis [43]. Concomitant
medication with high-dose glucocorticoids intensifies these changes.
Effects on Lipid Metabolism

Weight loss in cancer patients is accompanied by a loss of lipid stores and increased serum triglycerides.
The ability to oxidise lipids is normal to increased (II).
Commentary
The reasons for changes in lipid metabolism have not yet been clearly determined [44] although increased
lipolysis is often observed [56,57]. Increased [57-59] or at least normal [60], lipid oxidation is often detectable at
the same time, while glucose oxidation is compromised. These observations may support the recommendation
to increase the lipids to glucose ratio when composing nutrition for cancer patients.
Effects on Protein Metabolism

Protein expenditure is usually increased, resulting in a loss of muscle mass and an increased production
of acute phase proteins (II).
Commentary
While the underlying processes are complex, usually increases in overall body protein turnover and in
proteolysis are measured [43,61]. The ATP consuming and ubiquitin-dependent proteolysis system of
proteasomes is activated at an early stage [62-64]. These changes are triggered by inflammatory mediators and,
possibly, additional substances released by the tumour [65,66].
Treatment aims for Parenteral Nutrition (PN) in Cancer Patients



PN should stabilise the nutritional state and prevent or reduce progressive weight loss (C)
PN should maintain or improve the quality of life (C)
PN might increase the effectivity and reduce the side-effects of anti-cancer therapies (C).
Commentary
After curative antitumour treatment, PN can enhance survival chances in patients with severe gastrointestinal
defects e.g. with radiation enteritis [67]. Due to the accompanying non-specific inflammatory processes in
patients with active cancers anabolism usually cannot be achieved by only supplying energy and substrates
[44,50,51]. According to data collected on body compartments, artificial nutrition results in a stabilisation of or an
increase in body weight [68-71] and body fat mass, while an improvement in lean body or muscle mass is
observed only rarely. [72].
Numerous studies reported a median overall survival of 50 to 150 days [69-71,73-78] when using PN in patients
4
with advanced cancer and chronic small bowel defects. In the majority of these patients weight [69-71], and
parameters to measure quality of life may be stabilized [69-71,75]. The rate of PN-associated infectious
complications is between 0.34 and 2.68 per 1000 catheter days [74,76-78].
Orreval et al. reported that the provision of home PN was perceived as a positive alternative to progressive
weight loss due to the inability to eat in a small group of patients with advanced tumours [79]. Meta-analyses
indicate that PN may reduce postoperative complications in malnourished, but not in normally nourished,
patients after extensive abdominal surgery [80]. In contrast, only few studies have evaluated the influence of PN
on the therapeutic effects of non-surgical oncology. Parenteral nutrition in orally nourished patients undergoing
chemotherapy may increase body weight [68] (Ib), but does not improve anticancer treatment [68,81] (Ib). The
quality of these few studies, however, is restricted by the inhomogeneity of the patient groups and by the
inclusion of patients without malnutrition or patients who were able to eat normal amounts of food [81].
Indication for Parenteral Nutrition in Cancer Patients
Indications for PN in tumour patients are essentially identical to those in patients with benign illnesses.
Considering the limited data available in this area [82-88] the following recommendations are given:
 PN is indicated if oral and enteral food intake [83,84] provide <500 kcal per day and this is expected to
continue for >5 days, or for between 3 and 5 days in case of severe malnutrition, or if oral and enteral
food intake reach <60 % of calculated requirement and this is expected to last for 10-14 days in adult
patients (C).
 PN should be commenced immediately when indicated, and increased to target dosages over 2-4 days if
considered necessary (C).
 The amount of PN should supplement oral or enteral nutrition, providing full nutritional requirements in
combination (C).
 PN in children is indicated (C):
 in severe malnutrition
 in borderline malnutrition and high risk for malnutrition through therapy, etc.
 when oral food intake is <60 % of the energy and protein requirements and there is a high risk for
treatment-induced malnutrition, etc.
 PN is used in children if digestion or absorption of food is impaired and it is expected that the patient will
require nutritional therapy for at least 7 days. PN should be commenced as soon as possible and
continued until the gastrointestinal tract is fully functioning. Regular checks should be carried out if it is
expected that the patient will require a nutrition therapy for less than 7 days (C).
Commentary
In tumour patients, who are not able to eat, digest or absorb foods, the nutritional state may be maintained or
improved by PN [71,75,89-91]. This includes situations with severe intestinal defects caused by radiation
enteritis, chronic ileus, severe adhesions, short bowel syndrome, peritoneal carcinosis or the occurrence of
chylothorax.
In 1994 Klein and Koretz analysed several prospective randomised-controlled studies on the effects of PN
regimes in tumour patients, including 22 studies on perioperative nutrition, 18 studies using PN during the
course of chemotherapy, and 4 studies using PN during radiotherapy [81]. They found no general advantage of
PN regarding morbidity or mortality, but an increased rate of infection in patients receiving chemotherapy.
Definitive conclusions on the role of PN in the three treatment modalities, however, were not possible due to
major flaws in most studies. Most studies had included only few subjects of heterogeneous patient groups
undergoing various antitumor therapies. Individual studies were not comparable as they had used different
criteria for initiation of artificial nutrition as well as different nutrition regimens and different treatment durations.
In addition, patients in these studies were treated despite having a normal, or only a slightly impaired, nutritional
state [85,86].
PN increases tumour cell proliferation [92-97] and sensitivity to chemotherapy [94,97] in in-vitro models. In
malnourished patients with gastric cancer, concomitant administration of PN with preoperative chemotherapy
improved nutritional state, reduced post-operative complications, but did not influence the pre-operative tumour
cell proliferation [97].
Using PN during tumour therapy improved the nutritional state of children (Ib) [23,98-100]. Several studies
indicate that chemotherapy is better tolerated when accompanied by PN, resulting in fewer therapy delays, dose
reductions and shorter myelosuppression (Ib) [15,100-103]. However, other data suggest that the use of PN
does not lower the incidence of therapy-related complications (IIa) [98,104]. In addition, there is no evidence that
targeted nutritinal therapy might increase the chance of healing [105] (UICC 34). On the contrary, PN is
associated with an increased rate of infection (Ia) [106,107]. Therefore, in nutritional therapy whenver possible
preference should be given to the oral or enteral route [108].
Volume and Substrate Quantities in Parenteral Nutrition of Cancer
Patients






5
Energy expenditure is usually comparable to that of healthy subjects; only rarely is it necessary to supply daily
energy exceeding 35 kcal per kg body weight (C) (for children's intake, cf. chapter "Neonatology/Paediatrics").
A daily amino acid supply of 1.2 to 1.5 g per kg body weight is usually appropriate in cancer patients (C) (for the
appropriate dose for children, cf. chapter Neonatology/Paediatrics).
There is no agreement on an ideal ratio of lipids and carbohydrates; the proportion of lipids can be above 35%
of the overall energy intake without disadvantages (C).
Glucose should be the preferred parenteral carbohydrate (B).
Micronutrients should be supplied in sufficient amounts; this should not be less than the iv doses
recommended for healthy persons (C).
Monitoring of PN should be carried out following the usual protocol for all PN patients (C).
Commentary
There are generally no accepted standards for the optimal energy and nutrient intake in oncological patients,
particularly when artificial nutrition is administered exclusively.
The energy intake should be adapted to the potentially increased energy requirements and the level of physical
activity. Total energy expenditure of cancer patients was measured to be comparable to that of healthy subjects,
even though REE was incresed in cancer patients [30]. The cause of this is perhaps an adaptive decrease in
physical activity in metabolically altered cancer patients [36].
The basis for dosing macro- and micronutrients currently remains the same as for healthy persons. There is no
indication that an intake of protein above the normal dose (max. 1.5 g protein/kg body weight) has an
anticatabolic effect in oncological patients [109].
Tumour patients show increased lipid oxidation and utilisation of exogenously administered lipids [58]. Tumour
cells preferentially utilise glucose for their energy requirements while healthy tissues display high lipid oxidation
[110]. Therefore, it is recommended to increase the proportion of lipids to over 35% of the total energy supply in
the nutrition of oncological patients [58]. More recent studies, however, showed that post-absorptive glucose
turnover of malignant tissues is high and does not increase during an intravenous glucose infusion [111]; thus,
the theoretical benefit of lipid over glucose solutions may be clinically irrelevant.
Metabolic and immunological effects of various lipid solutions (LCT, MCT) have been compared mainly in
surgical environments. The postulated benefit of medium-chained triglycerides (MCT) over long-chained
triglycerides (LCT) could not be established in various clinical studies [112,113]. There are no data in cancer
patients undergoing radiotherapy or chemotherapy substantiating benefits of more recently developed
parenteral lipid emulsions, with increased contents of n-9 or n-3 fatty acids.
Attention should be given to providing a sufficient supply of micronutrients. The recommendations for intake in
other patient population should be followed (cf. chapter "Water, Electrolytes, Vitamins and Trace Elements").
There are no data supporting a clinical advantage of very high doses of micronutrients.
Special Substrates

The provision of special substrates such as glutamine, arginine, taurine, branched-chain amino acids or n-3 fatty
acids is not recommended due to lack of convincing data supporting their use (C).
Commentary
Glutamine has been studied as a possible oral supplement to reduce toxic side-effects of radiation or
chemotherapy [114]. Parenteral glutamine has been used in haematopoietic stem cell transplantations (HSCT).
Findings to date are inconsistent.
In a randomized study of patients after allogeneic HSCT Ziegler et al. showed a significantly improved nitrogen
balance, reduced infection rate and shorter length of stay (LOS) for patients supplemented with glutamine (0.57
g/kg/d) compared a control group on an isonitrogenic and isocaloric diet (Ib) [115]. In a randomized follow-up
study these data, however, could only be repeated with respect to a reduction in LOS (Ib) [116]. In a later study,
the same working group was not able to document any advantage of parenteral glutamine (0.57 g/kg/d) in a
similar clinical situation [117] (Ib).
In a further randomised study patients after HSCT receiving 3-4 weeks of glutamine-enriched PN showed
significant increases in total lymphocyte counts, T-lymphocytes, CD4 and CD8 cells, while the clinical outcome
was unchanged [118] (Ib). In a randomised study in patients after autologous HSCT, high daily doses of
intravenous alanyl-glutamine dipeptide (30 g glutamine) resulted in increased relapse and mortality rates as well
as increased costs [119] (Ib).
One randomised study, which highlighted the possible protective role of glutamine infusions on hepatic functions
during HSCT justifies further studies, especially with a focus on the prevention of veno-occlusive disease [120]
(Ib).
In hematological patients undergoing intensive chemotherapy supplementation with glutamine dipeptide had no
effect on hematological parameters or clinical toxicity; the glutamine group, however, showed significantly more
weight gain during the study period [121].
In a randomised study of patients with acute myeloid leukaemia requiring PN supplementation with glutamine
6
(20 g) resulted in a more rapid recovery of neutrophils after myelosuppressive chemotherapy, but no reduction in
the incidence of neutropenic fever and no improvement in other immunological parameters [122] (Ib)
According to the current ASPEN guidelines [123], there is no indication for the administration of pharmacological
doses of glutamine in patients after HSCT. Other recent recommendations agree with this [124].
There is only scarce evidence concerning other special substrates; particularly, there are no relevant data on the
parenteral use of n-3 fatty acids.
Indications for Parenteral Nutrition during Radiotherapy


PN should not be used as a general accompaniment of radiotherapy (B), but PN is indicated if sufficient enteral
intake cannot be achieved (B).
PN is indicated in chronic severe radiation enteritis (C).
Commentary
During the last 10 years no prospective randomised studies have been published on the use of PN as an
accompaniment to radiotherapy. So far it has not been demonstrated that routine PN during radiotherapy or
radio-chemotherapy improves prognosis [81,125,126]. During radiation treatment, especially when treating head
and neck areas, whenever possible, sufficient enteral nutrition should be supplied including the use of sip feeds
or enteral tube feeding [109,125,127,128].
PN is indicated if sufficient enteral nutrition is not possible, e.g. as a result of acute radioation enteritis; if
nutritional deficits exist and radiation is intended to cover the upper gastrointestinal tract such that an intended
PEG would need to be placed within the radiation field; and during neoadjuvant treatment, if insertion of a PEG
system is not recommended, e.g. in oesophageal resections and planned gastric interposition. Chronic radiation
enteritis develops in approx. 5 % of cases subjected to abdominal radiation; this may be accompanied by
intestinal failure, fistulae, perforation or chylous ascites and these cases frequently require long-term PN
[67,129-132].
No benefit of special parenteral substrates such as glutamine has been established for radiotherapy procedures.
Indications for Parenteral Nutrition during Chemotherapy

The indications for PN during chemotherapy are not different from general indications in malignant diseases.
Routine PN therapy as an accompaniment to chemotherapy is not indicated (B).
Commentary
In 1990 McGeer et al. published a meta-analysis on the use of PN during chemotherapy (Ia) [133]. They
reported that PN is associated with a trend towards shorter survival and reduced tumour response. They
concluded that routine PN is not advisable in patients undergoing chemotherapy. Klein and Koretz analysed 18
randomised studies with clinically relevant end points on the effect of PN in patients treated with chemotherapy.
They concluded that there were no evident advantages of PN with regards to overall survival, tumour responses
and toxicity of chemotherapy, but there was an increased rate of infection in those receiving PN (Ib) [81].
It is difficult to draw reliable conclusions from the existing data due to serious flaws in most study designs, such
as insufficient number of patients treated, inclusion of extremely inhomogeneous patient groups, large variability
of the nutrient solutions used, large variability of antitumor therapies, and inclusion of patients who were not
suffering from malnutrition as well as patients who maintained normal oral food intake [81]. Randomised studies,
i.e. by De Cicco et al, which differentiated between normal and malnourished patients undergoing
chemotherapy, were able to detect an improvement in the nitrogen balance in severely malnourished patients
while no effect was seen in patients without malnutrition [134] (Ib).
Recent recommendations by the American Gastroenterological Association (AGA) and the American Society for
Parenteral and Enteral Nutrition (ASPEN) have come to similar conclusions. The AGA report reviewed 19
randomised studies and concluded that PN had no influence on the survival of patients who were treated with
chemotherapy or radiation treatment, although a positive influence may be possible after bone marrow
transplants. Accompanying PN has an unfavourable effect on other parameters in patients treated for
chemotherapy, radiotherapy or bone marrow transplants, mainly an increase in infectious complications and a
decrease of the response to chemotherapy (Ib) [85].
The ASPEN recommendations specify that PN as routine accompaniment of chemotherapy is not justified and
potentially dangerous due to the increased risk of infection. It is pointed out, however, that PN should be offered
to patients who are malnourished and who are unable to absorb sufficient nutrients over a long time period
[135].
Regarding all published recommendations it is important to note that all randomised studies on which they are
based were performed more than 10 years ago and that many are flawed as mentioned above. More recent
studies report fewer complications of long-term PN [67,76-78,136,137], suggesting that the benefits and risks of
PN administration during chemotherapy should be reviewed again in the near future.
7
Indications for Parenteral Nutrition during Autologous/Allogeneic Stem Cell
Transplantion


PN is required only in selected patients after autologous transplantations, while after allogeneic transplantation
PN is usually required in most patients and for prolonged time periods due to the development of pronounced
mucositis and GvH-related gastrointestinal damage (C).
Particular attention must be paid to the increased risk of bleeding and infection associated with PN (C).
Commentary
In patients after autologous transplantations impaired food intake is usually of short duration (2-3 weeks).
Nutritional problems in allogenic transplant patients usually are more severe and prolonged. Thus, there is no
need for routine PN after autologous transplantations, but PN may be necessary if complications develop such
as prolonged mucositis [138]. After allogenic transplantations, PN is routinely administered in most
transplantation centres [138]. In 1987 Weisdorf et al. showed that prophylactic standardised PN significantly
improved survival three years after HSCT [106]. The control group received only minerals and vitamins
intravenously until a reduced nutritional state was detected. Because patients receiving early PN had a lower
relapse rate, it was speculated that the better overall survival observed might have been caused by a possible
positive effect of PN on transplant function, resulting e.g. in an increased graft versus leukaemia effect.
Enteral nutrition is not well tolerated in most cases after complete conditioning regimens [139]; if tolerated,
however, enteral nutrition in patients with a functioning gastrointestinal tract has effects on nutritional status that
are comparable to those of PN [124,140,141] (Ib). The French Federation of Cancer Centres, as well as the
authors of a review of relevant randomised studies recommend enteral nutrition as the primary approach in nonmyeloablative conditioning, and PN only in cases of gastrointestinal complications [141]. It has been
recommended to initiate PN when oral or enteral food intake provides less than 50-60% of calculated
requirements [67,141].
American and French panels on gastroenterology and nutrition emphasize that all HSCT patients carry a high
nutritional risk and should, therefore, be monitored regularly for nutritional deficits before and after
transplantation [123,141]. A small randomised study has observed that a high dose of lipid [lipid:glucose ratio
80:20] after allogenic transplantation lowered the incidence of lethal acute graft-versus-host disease and
hyperglycaemia [142]. This study has yet to be confirmed.
Certin et al. [143] reported that supplying total rather than partial PN after autologous transplantation resulted in
a delyed rise in thrombocytes.. At the same time, there were more cases of infection and hyperglycaemia
associated with total PN as compared to partial PN, whilst a drop in the level of albumin was prevented. The
study was not randomized and patients receiving total PN may have been more severely ill. The observation,
however, may support the recommendation not to provide total PN as a standard treatment after autologous
transplantations.
In children an autologous blood stem cell transplantation usually has only a low impact on nutritional status (III)
[144,145]. Thus, a targeted nutritional therapy should be based primarily on the above-mentioned criteria (see:
Indication for PN in Cancer Patients) or be initiated if a conditioning therapy is chosen, which is associated with
a high risk for severe mucositis.
In allogenic transplantations the criteria for using PN are usually given, and PN has been shown to have positive
effects on maintaining the body weight [146,147] (Ib). Enteral nutrition is possible in many cases and then is as
effective as PN. In a study by Hopman et al., enteral tube feeding was possible during 60% of the study period,
although it could be used as the sole form of nutrition only in 3 of 12 children [148] (Ib). In a retrospective
analysis, Langdana et al. reported on their positive experiences and the high patient acceptance rate for a
similar concept with the preferrential use of enteral nutrition [149] (III). In all cases the risks of enteral tube
feeding (aspiration, bleeding, diarrhoea, sinusitis, intestinal perforation) should be weighed against the risks of
PN (catheter sepsis and metabolic complications).
In most cases it appears to be sufficient to restrict the amount of energy provided to be slightly more than the
resting energy expenditure (see: Influence of Malignancies on Energy Expenditure) [150-152].
There are no generally accepted indications for the use of glutamine (see: Special Substrates).
Indications for Parenteral Nutrition Independent ofAntitumor Therapies in
Incurable Cancer Patients


If food intake is insufficient survival of patients in advanced cancer stages may be compromised more by
inadequate nutrition than by the underlying illness (C).
Long-term PN should be initiated if intestinal absorption is severely impaired and if allof the following 4 criteria
are fulfilled (C):
1. enteral nutrition is insufficient to maintain nutritional state
2. the expected survival is more than 4 weeks
3. PN is expected to stabilise or improve quality of life
8
4. the patient explicitely wishes to receive PN
Commentary
Oncological treatments today may allow patients with incurable cancer disease to survive up to a point at which
further survival is significantly affected the nutritional state [153]. An inadequate oral or enteral intake results in
progressive weight loss and impaired clinical outcome (see: The nutritional state influences the clinical
outcome). Randomised studies on the value of PN appear unethical in these situations [87].
Despite a lack of effective antitumor treatment options, patients with advanced cancers may have a life
expectancy of several weeks or months. If the expected survival exceeds 2 to 3 months (e.g. the period of
survival in total starvation [154-156]), it can be reasonably assumed that PN will lengthen the survival of a
patient who does not tolerate enteral nutrition [87]. In this situation PN, by providing essential nutrition,
constitutes a basic care rather than a medical therapy [87,157].
Specialised centres providing long-term PN to patients with advanced cancer disease report a median survival
period of 2-5 months [69-71,73-78]. This means that a large proportion of patients cared for in this manner have
a longer period of survival than that assumed for conditions of complete starvation. Weight stabilisation was
successful in a majority of patients [69-71]. Quality of life scores are poorer in parenterally nourished cancer
patients than in healthy subjects undergoing PN; cancer patients are further burdened by accompanying
depressions and opoid requirements [158]. PN, however, may stabilise parameters determining quality of life
[69-71]. Orreval et al. reported that the provision of PN was perceived as a positive alternative to progressive
weight loss by a small group of patients with advanced tumours and their relatives [79].
Since the benefits of PN can only have an impact when life expectancy is impaired more by insufficient food
intake than by the tumour itself, several expert groups recommend considering PN when the expected survival is
at least 4 weeks [135] or 2-3 months depending on the tumour [85,87,159,160]. No advantage of PN should be
expected when survival is shorter.
It is extremely difficult to estimate the life expectancy of a cancer patient and, hence, the possible advantages of
artificial nutrition. These patients should, therefore, be seen and evaluated cooperatively by their consultant
oncologist, the nutrition specialist and the palliative care consultant in order to design a treatment plan that is in
agreement with the patients expectations and wishes.
Parenteral Nutrition in Terminally Ill Patients


No PN is necessary in dying patients (B).
The occurrence of agitated confusion induced by dehydration can be controlled by parenteral infusion of saline
solutions (or the appropriate paediatric solutions, respectively) (B).
Commentary
During the phase of dying the most important aims of treatment and care are the alleviation of agonising
discomfort and the feelings of thirst and hunger. Fluids and nutrition are part of the basic care; however, the
patient needs to consent to such offers [157]. Most patients do not feel hungry in the terminal phase of life and
only require minimal quantities of fluid [161]. It is counterproductive since it may strain the patient severely and
thus it should be avoided at all cost to continue standardised infusion regimens into the terminal phase without
further consideration [162].
Regulation of fluid balance should be observed closely. Both dehydration, induced by diuretics or limited
drinking, and hyperhydration caused by infusions can have adverse affects on a person's well-being. The "dry
mouth" is one of the main symptoms of the dying [163]. However, thirst and "dry mouth" do neither correlate with
the degree of hydration [164] nor with the volume of intravenous infusion [165]. Terminal patients appear to
receive too much fluid in general [162], increasing the risks for peripheral oedema, ascites, pleural effusions and
the development of a pulmonary oedema.
Dehydration can result in drying of the mucous membranes with subsequent injuries and infections [163], it
reduces alertness and promotes the occurrence of restlessness and confusion [166], thus contributing to the
burden of the patients and their relatives [167]. Retrospective studies provided evidence that intravenous flids
may reduce neuropsychiatric symptoms like sedation, hallucinations, myoclonus and agitation [168,169]. A
randomised trial in dehydrated terminal cancer patients could show that subjective discomfort was significantly
improved with the infusion of 1000 ml per day as compared to no infusions and only minimal oral fluid intake of
100 ml per day [170].
Recommendations for terminal care, therefore, emphasize that fluid intake should always be prescribed on an
individual basis and should target the prevention of intolerable symptoms. Fluid quantities of 1000 ml per day
are recommended in symptomatic dehydration [170,171]; in children this corresponds to supplying approx. 50%
of the daily fluid requirements.
9
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Arends J1, Zuercher G2, Dossett A1, Fietkau R3, Hug M4, Schmid I5, Shang E6, Zander A7
1Dept.
of Medical Oncology, Tumour Biology Center, University of Freiburg, 2Dept. of Internal Medicine I,
University of Freiburg, 3Depts. Paediatric Surgery and Radiation Therapy, University of Rostock, 4Pharmacy,
University Hospital Freiburg, 5Dept. Metabolic Diseases & Nutritional Medicine, Dr. von Hauner Children's
Hospital, University of Munich, 6Dept Surgery, University Hospital of Mannheim, 7Dept. of Oncology and
Haematology, University of Hamburg for the working group for developing the guidelines for parenteral nutrition
of The German Association for Nutritional Medicine
Erstellungsdatum:
04/2014
13

AWMF - Deutsche Diabetes Gesellschaft

Transcription

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