C Feeding critically ill patients: What is the optimal amount of energy?

Feeding critically ill patients: What is the optimal amount of
energy?
Renee D. Stapleton, MD, MSc; Naomi Jones, RD, MSc; Daren K. Heyland, MD, MSc
Hypermetabolism and malnourishment are common in the
intensive care unit. Malnutrition is associated with increased
morbidity and mortality, and most intensive care unit patients
receive specialized nutrition therapy to attenuate the effects of
malnourishment. However, the optimal amount of energy to deliver is unknown, with some studies suggesting that full calorie
feeding improves clinical outcomes but other studies concluding
that caloric intake may not be important in determining outcome.
In this narrative review, we discuss the studies of critically ill
patients that examine the relationship between dose of nutrition
and clinically important outcomes. Observational studies suggest
that achieving targeted caloric intake might not be necessary
since provision of approximately 25% to 66% of goal calories may
be sufficient. Randomized controlled trials comparing early aggressive use of enteral nutrition compared with delayed, less
aggressive use of enteral nutrition suggest that providing in-
C
ritically ill patients are often
hypermetabolic and can become malnourished (1). Malnutrition has been associated
with increased morbidity and mortality in
acutely ill patients, particularly in the
surgical population (2). Therefore, the
generally accepted goals of nutritional
delivery in critically ill patients are to
provide nutritional therapy consistent
with the patient’s condition, prevent nutrient deficiencies, avoid complications
related to delivering nutrition, and improve patient outcomes (3). However,
many questions about the appropriate assessment of nutritional status and the
appropriate substrate, timing, route, and
From the Division of Pulmonary and Critical Care
Medicine, Department of Medicine, School of Medicine, University of Washington, Seattle, WA (RDS); and
the Clinical Evaluation Research Unit, Department of
Medicine, Queen’s University, Kingston, Ontario, Canada (NJ, DKH).
Drs. Stapleton and Heyland and Ms. Jones have
not disclosed any potential conflicts of interest.
For information regarding this article, E-mail:
rstaplet@u.washington.edu
Copyright © 2007 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/01.CCM.0000279204.24648.44
Crit Care Med 2007 Vol. 35, No. 9 (Suppl.)
creased calories with early, aggressive enteral nutrition is associated with improved clinical outcomes. However, energy provision
with parenteral nutrition, either instead of or supplemental to enteral
nutrition, does not offer additional benefits. In summary, the optimal
amount of calories to provide critically ill patients is unclear given the
limitations of the existing data. However, evidence suggests that
improving adequacy of enteral nutrition by moving intake closer to
goal calories might be associated with a clinical benefit. There is no
role for supplemental parenteral nutrition to increase caloric delivery
in the early phase of critical illness. Further high-quality evidence
from randomized trials investigating the optimal amount of energy
intake in intensive care unit patients is needed. (Crit Care Med 2007;
35[Suppl.]:S535–S540)
KEY WORDS: nutrition; critical illness; feeding; hypocaloric feeding; enteral; parenteral; calories; intensive care unit; caloric debt;
caloric deficit
amount of nutritional support in critically ill patients remain understudied,
particularly in medical patients. One important unanswered question that has recently become more prominent in the
critical care literature pertains to dose or
amount of nutrition. There is a general
consensus that excessive hypocaloric or
hypercaloric feeding should be avoided,
but controversy exists over what the feeding target should be. Some authors advocate for the provision of energy below
actual requirements to avoid accentuating the metabolic adaptive response to
injury or stress (4, 5). In clinical practice
in the intensive care unit (ICU), patients
commonly fail to receive adequate calories to meet prescribed targets, with studies reporting average energy intakes of
49% to 70% of calculated requirements
(6 –12). Reasons for failing to achieve adequate intake include fasting for procedures and gastrointestinal intolerance
(13). Consequently, we are faced with a
question: Is struggling to achieve goal
calories during the course of critical illness a worthwhile strategy that will affect
clinically important outcomes? It is the
intent of this review to discuss the evidence for and against the practice of hy-
pocaloric feeding in clinical care. Given
the heterogeneity of studies providing evidence on this topic with regard to route
of delivery (enteral vs. parenteral), timing
(early vs. delayed initiation), and dose
(full vs. partial feedings), it is difficult to
interpret the literature. However, with a
systematic approach to the available data,
one can arrive at conclusions about the
evidence and the obvious need for further
research. Although our goal is to determine the optimal amount of energy to
feed the critically ill, we will not discuss
the relationship between protein intake
and outcomes. In contrast to the purported benefits of energy restriction, protein restriction is associated with worse
clinical outcomes in both animal models
and clinical studies (14, 15).
Observational Studies on
Hypocaloric Nutrition in
Critically Ill Patients
Over the past decade, several observational studies have examined the association between caloric intake and clinically important outcomes in critically ill
patients. A recent prospective cohort
study in Switzerland followed 48 critiS535
cally ill patients for the duration of their
ICU stay (16). Their weekly caloric balance (defined as calories received minus
calories targeted) was calculated. After
adjustment for Simplified Acute Physiology Score II (17), Sequential Organ Failure Assessment score (18), body mass index, and age, cumulative energy deficit
was associated with longer ICU length of
stay (p ⫽ .0001), more days on mechanical ventilation (p ⫽ .0002), and more
complications (p ⫽ .0003). As a sensitivity analysis, the authors examined cumulative energy debt during the first week of
the patients’ ICU stay and found the same
associations of an increasing caloric debt
and worse clinical outcomes.
These associations were further examined in another study exploring the link
between caloric intake and increased risk
of bloodstream infection (12). This was a
prospective observational cohort study of
138 medical ICU patients who had not
had any food intake by mouth for ⱖ96
hrs after medical ICU admission, 92% of
whom were receiving mechanical ventilation. Daily caloric intake was recorded
during the entire medical ICU stay, and
patients were grouped into quartiles
based on percentages of caloric need as
recommended by the American College of
Chest Physicians in its 1997 guidelines
(3). Simple Kaplan-Meier analyses found
that patients in the lowest quartile of
caloric intake (less than approximately 6
kcal/kg/day) had a higher risk for bloodstream infection than all other patients.
After multivariable Cox proportional hazards analysis adjusting for severity of illness (Simplified Acute Physiology Score
II) at medical ICU admission, patients
who received an average of ⱖ25% of their
recommended caloric intake had a significant reduction in the risk of bloodstream
infection (relative hazard 0.27, 95% confidence interval [CI] 0.11– 0.68). It is difficult to infer causality since patients who
cannot tolerate greater caloric intake
might be the same patients who are more
ill and at higher risk of infections. Alternatively, receiving ⬍25% of prescribed
energy requirements may put patients at
high risk of infectious complications.
Krishnan et al. (10) performed a prospective cohort study of 187 critically ill
patients who were categorized into tertiles according to percentage of American
College of Chest Physicians-recommended levels of caloric intake (3)
achieved during the ICU stay of ⱖ4 days
in duration. The authors found that patients in the highest tertile (receiving
S536
ⱖ66% of recommended calories) were
less likely to be discharged from the hospital alive and to achieve spontaneous
ventilation before ICU discharge compared with patients in the lowest tertile.
Patients in the middle tertile (33% to
65%), however, were more likely than
patients in the lowest tertile to be discharged from the ICU breathing spontaneously.
We performed a similar analysis (19)
using cross-sectional survey data from
the follow-up phase of a previous cluster
randomized trial of dissemination of Canadian Clinical Practice Guidelines for
nutrition support (20). According to
mean daily caloric intake from enteral
nutrition (EN) as a percentage of calories
prescribed, 669 patients from 59 Canadian ICUs were divided into tertiles. After
adjustment for confounding variables
(age, admission category and diagnosis,
gender, body mass index, timing of initiation of EN, and presence of the acute
respiratory distress syndrome), we found
that caloric intake was not associated
with risk of death. Greater caloric intake
was associated with longer lengths of stay
in the ICU and hospital. Compared with
the lowest tertile, patients in the middle
and highest tertiles stayed in the ICU an
average of 4.8 days (p ⫽ .01) and 8.2 days
(p ⬍ .001) longer, respectively. Patients
in the middle and highest tertiles also
stayed in the hospital a mean of 4.5 days
(p ⫽ .02) and 8.0 days (p ⬍ .001) longer,
respectively. However, one probable interpretation of these results is that higher
rates of EN were achieved in patients with
longer length of stay because there were
more days in the ICU or hospital to meet
goal intake.
Finally, in a recent nonrandomized
trial, 150 mechanically ventilated patients in a medical ICU were assigned to
treatment groups on alternating days
(rather than by random allocation) to
evaluate early aggressive EN compared
with delayed EN (21). Patients in the
early group were scheduled to receive
their targeted amount of EN on day 1
after enrollment, while patients in the
delayed group were scheduled to receive
20% of their caloric needs on days 1–5,
with full calorie EN starting on day 5.
During the first 5 days of mechanical
ventilation, patients in the early group
received 28% of their estimated caloric
needs (average of 474 kcal/day), while patients in the delayed group received 7% of
their caloric needs (126 kcal/day). Enteral
nutrition in this trial was given using
gastric bolus feeding delivered every 4
hrs. Patients in the early-feeding group
had a statistically greater incidence of
ventilator-associated pneumonia (49.3%
vs. 30.7%; p ⫽ .02), longer ICU length of
stay (13.6 days vs. 9.8 days; p ⫽ .043), and
longer hospital length of stay (22.9 days
vs. 16.7 days; p ⫽ .023). Hospital mortality was not different between the two
groups. Since both these groups were
truly underfed and were near or below
the 25% goal calorie threshold set by the
previous analysis (12), it is difficult to
interpret these findings. The use of bolus
feedings, which may increase risk of regurgitation and aspiration, further limits
the inferences that can be drawn from
this study.
Integrating across all these aforementioned studies, it would seem that the
optimal dose of EN would be ⬎25% but
⬍66% of goal calories. However, as acknowledged by many of their authors,
these observational studies have an obvious and common bias in the critical care
nutrition literature: Sicker patients are
more likely to stay longer in the ICU and
more likely to be difficult to feed enterally, and longer exposure to the ICU increases the chances of complications.
Thus, observational research cannot reliably answer our question: Does achieving
goal calories during the course of critical
illness affect clinically important outcomes? Many unmeasured factors likely
play a role in clinicians’ decisions to deliver nutritional support to individual
critically ill patients (such as the patient’s
expected length of stay and perceived nutritional status), and even the most carefully performed observational study
might still be limited by residual confounding.
To truly find the answer, we need to
seek evidence from randomized controlled trials (RCTs). One group of RCTs
to consider includes those trials comparing EN with parenteral nutrition (PN)
(22–34). In these trials, patients in the PN
groups achieve target caloric intake rapidly after initiation while patients in the
EN group usually have a substantial caloric debt. Four meta-analyses—two in
critically ill patients (35, 36) and two that
also included hospitalized patients (37,
38)—all concluded there is no difference
in mortality rates between patients receiving EN or PN, but fewer complications are associated with EN than with
PN. If we accept that EN is the preferred
route of delivery, despite the fact that it
usually underdelivers calories compared
Crit Care Med 2007 Vol. 35, No. 9 (Suppl.)
with PN, then two important additional
questions arise: Are greater amounts of
EN more beneficial than less EN? Is providing supplemental PN to EN in order to
meet caloric goals beneficial? Close inspection of additional RCTs providing evidence in three different areas can help
answer these questions: 1) RCTs comparing higher vs. lower doses of EN; 2) RCTs
comparing early vs. delayed EN; and 3)
RCTs comparing EN alone vs. EN plus
supplemental PN.
RCTs Comparing Early
Aggressive vs. Early Lower
Dose Enteral Nutrition
Three RCTs have linked increased caloric intake from EN begun early in the
course of critical illness with improved
patient-centered outcomes. The first was
an RCT by Taylor et al. (39) that investigated the effects of early enhanced EN on
clinical outcomes in patients with severe
head injury who were receiving mechanical ventilation. Eighty-two head-injured
patients with Glasgow Coma Scale score
⬎3 were randomized to receive either
standard early EN or enhanced early EN.
Enteral feeding was started within 24 hrs
of the injury in both groups. In the control group, patients received EN starting
at 15 mL/hr, which was increased incrementally as tolerated according to a predefined protocol. In the intervention
group, patients received EN starting at
the rate that would meet their full caloric
needs. During the first week after head
injury, patients in the enhanced EN
group received significantly more calories than patients in the control group
(59.2% vs. 36.8% of caloric goal, p ⬍ .001).
There was no difference in mortality between the two groups (12.2% in the intervention group and 14.6% in the control group). There was a trend toward
improved neurologic outcome 3 months
after injury in the intervention group
(proportion with good neurologic recovery 61% vs. 39%, p ⫽ .08), but this difference was not apparent at 6 months,
thus suggesting that the aggressively fed
group had a faster time to recovery. Patients in the intervention group also had
fewer overall complications, including infections, up to 6 months after the initial
injury (37% vs. 61%, p ⫽ .046).
The second RCT evaluating “dose” of
nutritional support was a multicenter
cluster-randomized clinical trial of algorithms for critical care enteral and parenteral therapy (ACCEPT) (40). This clusCrit Care Med 2007 Vol. 35, No. 9 (Suppl.)
ter-randomized trial at 14 Canadian
hospitals investigated the impact of the
implementation of evidence-based feeding algorithms on nutrition practices and
patient outcomes in the ICU. Patients
ⱖ16 yrs of age who were expected to stay
in the ICU ⱖ48 hrs were enrolled in the
study (n ⫽ 499). At the sites assigned to
the intervention group, in-service education sessions, reminders, and academic
detailing (i.e., one-to-one education)
were performed to implement the evidence-based nutrition support recommendations. Hospitals assigned to the
control group did not receive any of the
interventions. Patients at both the intervention (n ⫽ 248) and control (n ⫽ 214)
sites were similar with the exception that
more patients at the intervention hospitals were admitted from the operating
room. Although not statistically different,
patients at the intervention hospitals received more calories per day than those at
the control sites (1264 kcal vs. 998 kcal;
p ⫽ .25) and received significantly more
days of EN per 10 days (6.7 vs. 5.4;
p ⫽ .042). This increased amount of EN
translated into a large improvement in
clinical outcomes as patients in the intervention hospitals had a significantly
shorter length of hospital stay (25 vs. 35
days; p ⫽ .003) and trended toward reduced mortality (27% vs. 37%; p ⫽ .058).
However, length of ICU stay was not different between the two groups (10.9 vs.
11.8 days; p ⫽ .7). Admittedly, it is difficult to understand how such a small difference in dose of EN is associated with
such large changes in clinical outcomes.
Nevertheless, the observations are consistent with the message that it is worthwhile to try to increase EN delivery.
The third RCT in this group, published
only in abstract form (41), randomized 53
critically ill mechanically ventilated patients to receive tight caloric balance
control or standard diet prescribed using
the Harris-Benedict equation for energy
expenditure (42). Patients in the tight
caloric balance control group had their
resting energy expenditure measured
daily and their nutritional support adjusted according to the results. The tight
caloric balance control patients had less
cumulative energy debt (⫺1353 kcal vs.
⫺9199 kcal, p ⬍ .01) and significantly
fewer complications, including less renal
failure and need for dialysis. However,
length of stay, duration of ventilation,
and mortality were not different between
the two groups.
Summarizing these three studies,
there appears to be some evidence, albeit
weak, that increased amounts of EN or
less energy deficit is associated with improved clinical outcomes.
RCTs Comparing Early vs.
Delayed Enteral Nutrition
Since the mid-1970s, 19 RCTs of early
vs. delayed EN in critically ill patients
have been performed (39, 43– 60). Eight
of these trials were in elective surgery
patients (43–50); the remainder were in
trauma, head injury, and burn patients
(39, 51– 60). In these trials, patients in
the early EN groups generally received
more total calories (average of 1713 kcal)
than patients in the delayed groups (average of 910 kcal) since their EN was
initiated earlier. These RCTs have undergone two meta-analyses. The first metaanalysis included only mechanically ventilated patients (35) and concluded that
early EN is associated with trends toward
a reduction in both mortality (risk ratio
[RR] 0.65, 95% CI 0.41–1.02, p ⫽ .06)
and infectious complications (RR 0.78,
95% CI 0.60 –1.01, p ⫽ .06) (Figs. 1 and 2).
The second meta-analysis included all trials (61) and found that early EN was not
associated with mortality but was associated with a significantly lower risk of
infectious complications (RR 0.45, 95%
CI 0.30 – 0.66, p ⬍ .001) and reduced hospital length of stay (mean reduction of
2.2 days, 95% CI 0.81–3.63, p ⫽ .004).
Consistent with the observations from
the randomized trials presented earlier,
these data support the notion that more
aggressive initiation of EN with increased
amounts of EN provided is associated
with improved clinical outcomes.
None of the previously mentioned
studies that achieved greater success with
EN achieved 100% of goal calories.
Rather, they increased the provision of
goal calories from the 25% to 66% range
toward 100% of goal calories. How close
to 100% of goal calories from EN or how
much above 66% represents a shift from
benefit toward harm is unknown.
RCTs Comparing Enteral
Nutrition Alone vs. Enteral
Nutrition Plus Supplemental
Parenteral Nutrition
Five RCTs have compared combined
EN and PN vs. EN alone, all of which
started both regimens simultaneously
(25, 62– 65). Patients in the groups supS537
Figure 1. The effect of early vs. delayed enteral nutrition (EN) on infectious complications in critically ill patients. Reproduced with permission from
www.criticalcarenutrition.com. RR, risk ratio; CI, confidence interval.
Figure 2. The effect of early vs. delayed enteral nutrition (EN) on mortality in critically ill patients. Reproduced with permission from www.criticalcarenutrition.com. RR, risk ratio; CI, confidence interval.
plemented with PN likely achieved full
caloric intake more rapidly and thus had
less caloric debt. However, caloric debt
can only be calculated from one of these
studies (65) where the prescribed calories
were 25 kcal/kg/day, the combined EN
and PN group reached 98% of goal calories with 24.6 kcal/kg/day, and the ENonly group received 57% of prescribed
calories with 14.2 kcal/kg/day. A metaanalysis of these five trials found that the
combination of EN and PN has no benefit
with regard to mortality (RR 1.27, 95% CI
0.82–1.94, p ⫽ .3), infectious complications (RR 1.14, 95% CI 0.66 –1.96, p ⫽ .6),
length of hospital stay, or days on mechanical ventilation (66). Therefore, although some observational data suggest
S538
that a caloric deficit may be associated
with poor outcomes, there is no evidence
that minimizing caloric deficit with supplemental PN in addition to EN will improve clinical outcomes.
CONCLUSIONS
Observational studies examining the
association between amount of caloric intake and clinical outcomes suggest that
providing somewhere in the range of 25%
to 66% of calculated energy requirements
is optimal. These observations are supported by animal studies showing that
restrictive energy intake is associated
with decreased inflammatory cytokines,
improved metabolic profiles, and better
survival compared with more liberal
amounts of energy (67). However, stronger inferences can be made from existing
RCTs comparing different routes of delivery and timing of feeding. Evidence from
these RCTs suggests that early aggressive
EN, with increased amounts of EN provided, is associated with improved clinical outcomes, and that using PN in preference to EN, or supplementing EN with
PN, does not confer any additional benefits. Consequently, given the inadequate
provision of energy to critically ill patients in our ICUs, strategies to achieve
goal calories with EN should be adopted.
Improving adequacy of EN from 25% to
66% to closer to goal calories may be
associated with a clinical benefit. HowCrit Care Med 2007 Vol. 35, No. 9 (Suppl.)
ever, high-quality evidence from randomized trials investigating the optimal
amount of energy intake in ICU patients
is still needed.
15.
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