Fever in the ICU* Paul E. Marik, MD, FCCP

Fever in the ICU*
Paul E. Marik, MD, FCCP
Fever is a common problem in ICU patients. The presence of fever frequently results in the
performance of diagnostic tests and procedures that significantly increase medical costs and
expose the patient to unnecessary invasive diagnostic procedures and the inappropriate use of
antibiotics. ICU patients frequently have multiple infectious and noninfectious causes of fever,
necessitating a systematic and comprehensive diagnostic approach. Pneumonia, sinusitis, and
blood stream infection are the most common infectious causes of fever. The urinary tract is
unimportant in most ICU patients as a primary source of infection. Fever is a basic evolutionary
response to infection, is an important host defense mechanism and, in the majority of patients,
does not require treatment in itself. This article reviews the common infectious and noninfectious
causes of fever in ICU patients and outlines a rational approach to the management of this
problem.
(CHEST 2000; 117:855– 869)
Key words: cytokines; fever; ICU; sinusitis; urinary tract infection; ventilator-associated pneumonia
Abbreviations: CDC ⫽ Centers for Disease Control and Prevention; CFU ⫽ colony-forming units; ELISA ⫽ enzymelinked immunosorbent assay; IL ⫽ interleukin; TNF ⫽ tumor necrosis factor; UTI ⫽ urinary tract infection;
VAP ⫽ ventilator-associated pneumonia
is a common problem in ICU patients. The
F ever
presence of fever frequently results in the per-
Pathogenesis of Fever
primarily involved in the development of fever include interleukin (IL) 1, IL-6, and tumor necrosis
factor (TNF)-␣.2–13 The interaction between these
cytokines is complex, with each being able to upregulate and down-regulate their own expression as
well as that of the other cytokines. These cytokines
bind to their own specific receptors located in close
proximity to the preoptic region of the anterior
hypothalamus.2,3 Here, the cytokine receptor interaction activates phospholipase A2, resulting in the
liberation of plasma membrane arachidonic acid as
substrate for the cyclo-oxygenase pathway. Some
cytokines appear to increase cyclo-oxygenase expression directly, leading to liberation of prostaglandin
E2. This small lipid mediator diffuses across the
blood brain barrier, where it acts to decrease the rate
of firing of preoptic warm-sensitive neurons, leading
to activation of responses designed to decrease heat
loss and increase heat production.2,14 In a small
proportion of hospitalized patients, hyperthermia
may result from increased sympathetic activity with
increased heat production.
Cytokines released by monocytic cells play a central role in the genesis of fever. The cytokines
Significance of Fever
*From the Department of Internal Medicine, Section of Critical
Care, Washington Hospital Center, Washington, DC.
Manuscript received May 11, 1999; revision accepted October
25, 1999.
Correspondence to: Paul E. Marik, MD, Department of Internal
Medicine, Washington Hospital Center, 110 Irving St NW,
Washington, DC 20010-2975; e-mail: pem4@mhg.edu
Fever appears to be a preserved evolutionary
response within the animal kingdom.15–20 With few
exceptions, reptiles, amphibians, and fish, as well as
several invertebrate species, have been shown to
manifest fever in response to challenge with microorganism.15–19 Increased body temperature has been
formance of diagnostic tests and procedures that
significantly increase medical costs and expose the
patient to unnecessary invasive diagnostic procedures and the inappropriate use of antibiotics. The
main diagnostic dilemma is to exclude noninfectious
causes of fever and then to determine the site and
For editorial comment see page 627
likely pathogens of those with infections. ICU patients frequently have multiple infectious and noninfectious causes of fever,1 necessitating a systematic
and comprehensive diagnostic approach. This article
reviews the common infectious and noninfectious
causes of fever in ICU patients and outlines a
rational approach to the management of these patients.
CHEST / 117 / 3 / MARCH, 2000
855
shown to enhance the resistance of animals to infection.21,22 Although fever has some harmful effects,
fever appears to be an adaptive response that has
evolved to help rid the host of invading pathogens.
Temperature elevation has been shown to enhance
several parameters of immune function, including
antibody production, T-cell activation, production of
cytokines, and enhanced neutrophil and macrophage
function.23–26 Furthermore, some pathogens such as
Streptococcus pneumoniae are inhibited by febrile
temperatures.27
It has long been known that increasing body
temperature is associated with improved outcome
from infectious diseases. The preantibiotic era provides abundant, although uncontrolled data, on the
deliberate use of elevated body temperature to treat
infections. The beneficial effects of hot baths and
malarial fevers in syphilis were noted as early as the
15th century.28 In mammalian models, increasing
body temperature results in enhanced resistance to
infection.29 –32 In a retrospective analysis of 218
patients with Gram-negative bacteremia, Bryant and
colleagues33 reported a positive correlation between
maximum temperature on the day of bacteremia and
survival. Similarly, Weinstein and colleagues34 reported that a temperature ⬎ 38°C increased survival
in patients with spontaneous bacterial peritonitis.
Dorn and colleagues35 reported that children with
chickenpox who were treated with acetaminophen
had a longer time to crusting of lesions than when
treated with placebo.
An elevated body temperature may, however, also
be associated with a number of deleterious effects,
most notably an increase in cardiac output, oxygen
consumption, carbon dioxide production, and energy
expenditure.36 Oxygen consumption increases by
approximately 10% per degree Celsius.36 These
changes may be poorly tolerated in patients with
limited cardiorespiratory reserve. In patients who
have suffered a cerebrovascular accident or traumatic head injury, moderate elevations of brain
temperature may markedly worsen the resulting
injury.37 Maternal fever has been suggested to be a
cause of fetal malformations or spontaneous abortions.38,39 However, this association has not been
rigorously tested.
Definitions and Measurement of Fever
Accurate and reproducible measurement of body
temperature is important in detecting disease and in
monitoring patients with an elevated temperature. A
variety of methods are used to measure body temperature, combining different sites, instruments, and
techniques. The mixed venous blood in the pulmo856
nary artery is considered the optimal site for core
temperature measurement; however, this method
requires placement of a pulmonary artery catheter.40 – 42 Infrared ear thermometry has been demonstrated to provide values that are a few tenths of a
degree below temperatures in the pulmonary artery
and brain.43– 46 Rectal temperatures obtained with a
mercury thermometer or electronic probe are often
a few tenths of a degree higher than core temperature.40 – 42 Rectal temperatures are perceived by patients as unpleasant and intrusive. Furthermore,
access to the rectum may be limited by patient
position, with an associated risk of rectal trauma.
Oral measurements are influenced by events such as
eating and drinking and the presence of respiratory
devices delivering warmed gases.43 Axillary measurements substantially underestimate core temperature
and lack reproducibility.43 Body temperature is
therefore most accurately measured by an intravascular thermistor, but measurement by infrared ear
thermometry or with an electronic probe in the
rectum is an acceptable alternative.47 Normal body
temperature is generally considered to be 37.0°C
(98.6°F) with a circadian variation of between 0.5 to
1.0°C.2,14 The definition of fever is arbitrary and
depends on the purpose for which it is defined. The
Society of Critical Care Medicine practice parameters define fever in the ICU as a temperature
⬎ 38.3°C (ⱖ 101°F).47 Unless the patient has other
features of an infectious process, only a temperature
⬎ 38.3°C (ⱖ 101°F) warrants further investigation.
Fever Patterns
Attempts to derive reliable and consistent clues
from evaluation of a patient’s fever pattern is fraught
with uncertainly and not likely to be helpful diagnostically.2,14,48 Most patients have remittent or intermittent fever that, when due to infection, usually
follow a diurnal variation.48 Sustained fevers have
been reported in patients with Gram-negative pneumonia or CNS damage.48 The appearance of fever at
different time points in the course of a patient’s
illness may however provide some diagnostic clues.
Fevers that arise ⬎ 48 h after institution of mechanical ventilation may be secondary to a developing
pneumonia.49,50 Fevers that arise 5 to 7 days postoperatively may be related to abscess formation.51
Fevers that arise 10 to 14 days postinstitution antibiotics for intra-abdominal abscess may be due to
fungal infections.52–54
Causes of Fever in the ICU
As outlined above, any disease process that results
in the release of the proinflammatory cytokines IL-1,
Reviews
IL-6, and TNF-␣ will result in the development of
fever. While infections are the commonest cause of
fever in ICU patients, many noninfectious inflammatory conditions cause the release of the proinflammatory cytokines with a febrile response.55– 61 Similarly, it is important to appreciate that not all patients
with infections are febrile. Approximately 10% of
septic patients are hypothermic and 35% are normothermic at presentation. Septic patients who fail to
develop a temperature have a significantly higher
mortality than febrile septic patients.62– 64 The reason
that patients with established infections fail to develop a febrile response is unclear; however, preliminary evidence suggests that this aberrant response is
not due to diminished cytokine production.65
The presence of fever in an ICU patient frequently triggers a battery of diagnostic tests that are
costly, expose the patient to unnecessary risks, and
often produce misleading or inconclusive results. It
is therefore important that fever in ICU patient be
evaluated in a systematic, prudent, clinically appropriate, and cost-effective manner.
Noninfectious Causes of Fever in the ICU
A large number of noninfectious disorders result
in tissue injury with inflammation and a febrile
reaction. Those noninfectious disorders that should
Table 1—Noninfectious Causes of Fever in the ICU
Noninfectious Causes
Alcohol/drug withdrawal
Postoperative fever (48 h postoperative)
Posttransfusion fever
Drug fever
Cerebral infarction/hemorrhage
Adrenal insufficiency
Myocardial infarction
Pancreatitis
Acalculous cholecystitis
Ischemic bowel
Aspiration pneumonitis
ARDS (both acute and late fibroproliferative phase)
Subarachnoid hemorrhage
Fat emboli
Transplant rejection
Deep venous thrombosis
Pulmonary emboli
Gout/pseudogout
Hematoma
Cirrhosis (without primary peritonitis)
GI bleed
Phlebitis/thrombophlebitis
Adrenal insufficiency
IV contrast reaction
Neoplastic fevers
Decubitus ulcers
be considered in ICU patients are listed in Table
1.1,55,66 – 68 For reasons that are not entirely clear,
most noninfectious disorders usually do not lead to a
fever ⬎ 38.9°C (102°F); therefore, if the temperature increases above this threshold, the patient
should be considered to have an infectious etiology
as the cause of the fever.67 However, patients with
drug fever may have a temperature ⬎ 102°F.69 –71
Similarly, fever secondary to blood transfusion may
be ⬎ 102°F.72,73
Most of those clinical conditions listed in Table 1
are clinically obvious and do not require additional
diagnostic tests to confirm their presence. However,
a few of these disorders require special consideration. Although drug-induced fever is commonly
cited as a cause of fever,74 ⬍ 300 cases of this
condition have been reported in the literature.70
Furthermore, only a single case of drug fever has
been reported in an ICU patient population.1 However, on the basis of the number of medications
administered to patients in the ICU, one would
expect drug fever to be a relatively common event.
Although the true incidence of this disorder is
unknown, drug fever should be considered in patients with an otherwise unexplained fever, particularly if they are receiving ␤-lactam antibiotics, procainamide, or diphenylhydantoin.70 Drug fever is
usually characterized by high spiking temperatures
and shaking chills.70 It may be associated with a with
leukocytosis and eosinophilia. Relative bradycardia,
although commonly cited, is uncommon.67,70,74
Atelectasis is commonly implicated as a cause of
fever. Standard ICU texts list atelectasis as a cause of
fever, although they provide no primary source.51,75
Indeed a major surgery text states that “fever is
almost always present [in patients with atelectasis].”51 However, Engeron76 studied 100 postoperative cardiac surgery patients and was unable to
demonstrate a relationship between atelectasis and
fever. Furthermore, when atelectasis is induced in
experimental animals by ligation of a mainstem
bronchus, fever does not occur.77,78 However, Kisala
and coworkers79 demonstrated that IL-1 and TNF-␣
levels of macrophage cultures from atelectatic lungs
were significantly increased compared with the control lungs. The role of atelectasis as a cause of fever
is unclear; however, atelectasis probably does not
cause fever in the absence of pulmonary infection.
Febrile reactions complicate about 0.5% of blood
transfusions, but may be more common following
platelet transfusion.72,80,81 Antibodies against membrane antigens of transfused leukocytes and/or platelets are responsible for most febrile reactions to
cellular blood components.72 Febrile reactions usually begin within 30 min to 2 h after a blood-product
transfusion is begun. The fever generally lasts beCHEST / 117 / 3 / MARCH, 2000
857
tween 2 h and 24 h and may be preceded by chills.73
An acute leucocytosis lasting up to 12 h commonly
occurs following a blood transfusion.82
Patients with the ARDS may progress to a “chronic” stage characterized by pulmonary fibroproliferation and fevers. Meduri and coworkers1,83 have
demonstrated that fever and leukocytosis may result
from the inflammatory-fibrotic process present in
the airspace of patients with late ARDS in the
absence of pulmonary infection. Corticosteroids appear to be associated with an improvement in lung
injury and reduced mortality.83,84 Some authors recommend an open lung biopsy prior to commencing
corticosteroid therapy, in order to obtain histologic
evidence of the fibroproliferative phase of ARDS
and to exclude infection.
Acalculous cholecystis occurs in approximately
1.5% of critically ill patients.85,86 While relatively
uncommon, acalculous cholecystitis is an important
“noninfectious” cause of fever in critically ill patients,
as it is frequently unrecognized and therefore potentially life threatening.85,86 The pathophysiology of
acalculous cholecystitis is related to the complex
interplay of a number of pathogenetic mechanisms,
including gallbladder ischemia, bile stasis with inpissation in the absence of stimuli for emptying of the
gallbladder, positive-end expiratory pressure, and
parenteral nutrition.87–92 Bacterial invasion of the
gallbladder appears to be a secondary phenomenon.89
The diagnosis of acalculous cholecystitis is often
exceedingly difficult and requires a high index of
suspicion. Pain in the right upper quadrant is the
finding that most often leads the clinician to the
correct diagnosis, but it may frequently be absent.85,86,89 Nausea, vomiting, and fever are other
associated clinical features. The clinical findings and
laboratory workup in patients with acalculous cholecystitis are, however, often nonspecific. The most
difficult patients are those recovering from abdominal sepsis who deteriorate again, misleadingly suggesting a flare-up of the original infection. Rapid
diagnosis is essential because ischemia may progress
rapidly to gangrene and perforation, with attendant
increase in the already high morbidity and mortality.89 The diagnosis should therefore be considered in
every critically ill patient who has clinical findings of
sepsis with no obvious source.
Radiologic investigations are required for a presumptive diagnosis of acalculous cholecystitis. Ultrasound is the most common radiologic investigation
used in the diagnosis of acalculous cholecystitis;
features include increased wall thickness, intramural
lucencies, gallbladder distension, pericholecystic
fluid, and intramural sludge.93,94 Wall thickness ⱖ 3
mm is reported to be the most important diagnostic
858
feature on ultrasound examination, with a specificity
of 90% and a sensitivity of 100%.93,94 In ICU
patients, hepatobiliary scintigraphy has a high falsepositive rate (⬎ 50%), limiting the value of this
test.95 However, a normal scan virtually excluded
acalculous cholecystitis. CT scanning has been reported to have a high sensitivity and specificity;
however, no prospective studies have been performed comparing ultrasonography with CT scanning in the diagnosis of acalculous cholecystitis.96
The management of acalculous cholecystitis is
somewhat controversial.85,89,97 However, with the
development of more advanced radiologic imaging
techniques, percutaneous cholecystostomy may be
the procedure of choice. Kiviniemi and coworker98
demonstrated diminution of pain in 94% of patients,
with normalization of fever in 90% and leukocyte
count in 84% of patients treated by percutaneous
cholecystostomy. The procedure is associated with
few complications and is the definitive therapy in
most patients.99 Open cholecystectomy is, however,
recommended should the abdominal signs, fever,
and leucocytosis not improve within 48 h of percutaneous cholecystostomy.85,89,97
While fever may occur in patients with deep
venous thrombosis, in patients suspected of deep
venous thrombosis, the predictive value of fever is
poor.100 Furthermore, in critically ill ICU patients,
fever without other features of ileofemoral thrombosis is uncommon and does not warrant routine
venography as part of the initial diagnostic workup of
pyrexia in ICU patients.1,101
Infectious Causes of Fever
The prevalence of nosocomial infection in ICUs
has been reported to vary from 3 to 31%.102–108 Data
from the National Nosocomial Infection Surveillance
system database from 1986 to 1990 documented
nosocomial infection in 10% of the 164,034 patients,
with a strong correlation between ICU length of stay
and the development of infection.103 In a point
prevalence study conducted in 1992, The EPIC
Study Investigators104 reported on the prevalence of
nosocomial infections in 10,038 patients hospitalized
in 1,417 European ICUs. In this study, 20.6% of
patients had an ICU-acquired infection, with pneumonia being the most common (46.9%), followed by
urinary tract infection (17.6%) and blood stream
infection (12%). This data must, however, be interpreted with some caution. The presence and type of
infection in these studies was documented according
to the “standard definitions” of the Centers for
Disease Control and Prevention (CDC).109,110 The
definitions of nosocomial infection published by the
Reviews
CDC may, however, not be applicable to ICU
patients.109,110 For example, according to the most
recent definitions published in 1988, the presence of
rales and purulent sputum or the presence of new
chest radiographic findings and change in sputum
character were used to diagnose pneumonia.110 In
patients receiving mechanical ventilation, less than a
third of patients with these features would be considered to have pneumonia using invasive diagnostic
methods.111–114 Similarly, fever and a urine culture
of ⱖ 105 colony-forming units (CFU)/mL was considered diagnostic of urinary tract infection. As is
discussed below, the presence of these two finding in
catheterized critically ill ICU patients does not represent infection of the urinary tract.
The most common infections reported in ICU patients are pneumonia, followed by sinusitis, blood
stream infection, and catheter-related infection.1,102–108
Table 2 lists the most important sites of infection in
ICU patients. As is discussed below, urinary tract
infection is probably unimportant in most ICU patients.
Ventilator-Associated Pneumonia
Ventilator-associated pneumonia (VAP) occurs in
approximately 25% of patients undergoing mechanical ventilation.49,115–118 The impact of VAP on patient outcome has been much debated117,119,120;
however, Fagon and colleagues121 reported an attributable mortality of 27%. The optimal management of
patients with suspected VAP requires confirmation
of the diagnosis and identification of the responsible
pathogen(s) in order to provide appropriate antimicrobial therapy. The diagnosis of VAP remains one of
the most difficult clinical dilemmas in critically ill
patients receiving mechanical ventilation.49 Clinical
criteria alone have been shown to be unreliable in
the diagnosis of this condition.113,115,122 A number of
invasive and minimally invasive techniques have
been reported to aid in the diagnosis of VAP. The
number of methods currently available attest to the
fact that no single method is ideal.49,112,120,123–132
Table 2—Common Infectious Causes of Fever in the
ICU
Infectious Causes
VAP
Sinusitis
Catheter-related sepsis
Primary Gram-negative septicemia
C difficile diarrhea
Abdominal sepsis
Complicated wound infections
The optimal technique(s) for diagnosis of VAP remains unclear as a uniformly agreed on “gold standard,” for the diagnosis is lacking.111,118,124,133–135
The impact that diagnostic tests for VAP have on
patient outcome is controversial. Using a decision
analysis method, Sterling and coauthors136 demonstrated that invasive or semi-invasive microbiological
diagnostic techniques improved the outcome of patients with suspected VAP. However, Luna and
colleagues137 and Rello and coworkers138 have demonstrated that the most important factor affecting
outcome in patients with VAP is the early initiation
of appropriate antibiotic therapy. In the study by
Luna et al,137 the mortality of patients who were
changed from inadequate antibiotic therapy to appropriate therapy based on the results of the BAL
was comparable to the mortality of those patients
who continued to receive inadequate therapy. Kollef
and Ward,139using noninvasive mini-BAL to diagnose VAP, confirmed these findings. It should however be noted that patients who have clinical features
of VAP and in whom VAP is “excluded” based on
quantitative culture of lower respiratory tract secretions and in whom antibiotics are stopped have a
significantly lower mortality than those patient who
are culture positive.121,139 Invasive or noninvasive
sampling of lower respiratory tract sections with
quantitative culture therefore allows for the safe
discontinuation of antibiotics in the “culture negative” patients.123,125,140 –145 Furthermore, as the initial empiric antibiotic regimen must be broad and
cover both Gram-positive and negative organisms,
these techniques allow for narrowing of the spectrum once a pathogen has been isolated in those
patients with confirmed pneumonia. This approach
to suspected VAP will result in significant cost savings
and reduce the selection of resistant organisms.113
Sinusitis
Because paranasal sinusitis is usually clinically
silent in intubated patients, it is not widely appreciated that nosocomial sinusitis is an important source
of infection and fever in critically ill patients. Furthermore, many ear, nose, and throat surgeons are of
the belief that paranasal sinusitis in intubated patients receiving mechanical ventilation does not
cause fever or systemic signs of infection. Nosocomial sinusitis is particularly common following nasal
intubation, with an incidence of up to 85% after a
week of intubation.146 –151 The incidence of nosocomial sinusitis appears to be lower in patients in
whom both the endotracheal and gastric tubes are
placed orally.146 –151 The diagnosis of sinusitis requires a CT scan and cannot be accurately assessed
CHEST / 117 / 3 / MARCH, 2000
859
using standard radiography or echography.152 Sinusitis is diagnosed by total opacification or the presence
of an air fluid level within any of the paranasal
sinuses. The maxillary sinus is most commonly involved; however, most patients with radiologic maxillary sinusitis have abnormalities of the ethmoid and
sphenoid sinuses.148 Since radiologic abnormalities
of the paranasal sinuses do not necessarily imply
infection, diagnosis of infectious maxillary sinusitis
requires transnasal puncture following appropriate
disinfection of the nares.146,148,150,153 When the ethmoid or sphenoid sinuses only are involved, bacteriologic specimens can be obtained by an open ethmoidectomy/sphenoidotomy.146 Sinus infection is
diagnosed by the presence of pus associated with
high quantitative cultures of implicated pathogens.
Rouby and colleagues148 reported that only 38% of
patients with radiologic maxillary sinusitis had true
infectious sinusitis. In the series reported by Rouby
et al,148 there was normalization of the core temperature and WBC count following removal of all nasal
tubes, followed by transnasal puncture and drainage
in the patients with infectious maxillary sinusitis.
These authors did not use IV antibiotics. Similarly, in
the series reported by Grindlinger and colleagues146
and by Deutschman and coworkers,147 resolution of
sinusitis was associated with normalization of the
temperature and WBC count. Paranasal sinusitis is
best treated by removal of all nasal tubes together
with drainage of the maxillary sinuses. Broad-spectrum antibiotics are generally recommended.146,147
Catheter-Associated Sepsis
Catheter-associated sepsis is defined as blood
stream infection due to an organism that has colonized a vascular catheter. Approximately 5% of
patients with indwelling vascular catheters (uncoated) will develop blood stream infection (⬇ 10 infections/1,000 catheter days).154 –158 The incidence of
catheter-associated sepsis increases with the length
of time the catheter is in situ, the number of ports,
and increases with the number of manipulations.
Approximately 25% of central venous catheters become colonized (⬎ 15 CFU), and approximately 20
to 30% of colonized catheters will result in catheter
sepsis.154 –158 Staphylocuccus aureus and coagulasenegative staphylococci are the most common infecting (and colonizing) organisms, followed by enterococci, Gram-negative bacteria, and Candida
species.154 –158
A number of methods of reducing catheter colonization and blood stream infection have been studied, including topical antibiotics, antimicrobial flush
solutions, subcutaneous tunneling of catheters, and
860
silver-impregnated subcutaneous cuffs.156,159 –162
These studies have generally shown poor or inconsistent results. It has been suggested that antimicrobial bonding of central venous catheters may be the
most effective method of reducing the rate of catheter colonization and catheter-related sepsis.163,164
Several types of antiseptic or antimicrobial coatings
have been developed, including catheters coated
with chlorhexidine gluconate and silver sulfadiazine,
as well as with minocycline and rifampin. While a
number of studies have demonstrated the incidence
of catheter-related sepsis to be lower with chlorhexidine/sulfadiazine-coated catheters,165–167 not all
studies have duplicated these findings.168 –170 Furthermore, Darouiche and colleagues154 have demonstrated that central venous catheters impregnated
with minocycline and rifampin are associated with a
significantly lower rate of catheter colonization and
blood stream infection than catheters coated with
chlorhexidine and silver sulfadiazine.
Central venous catheterization via the femoral and
internal jugular veins are reported to have a similar
infection rates, which are higher than that for catheters inserted via the subclavian approach.154,163,165,171
Replacement of a colonized catheter over a guidewire is associated with rapid recolonization of the
replacement catheter.172 If catheter sepsis is suspected, the catheter should be changed to a new site,
with culture (quantitative or semiquantitative) of the
catheter tip.154,172–176 In patients with limited venous
access or in patients in whom catheter sepsis is less
likely, the catheter can be changed over a guidewire;
however, withdrawal blood cultures and culture of
the catheter tip should be performed and the catheter removed if the cultures are positive.
Urinary Tract Infection
Urinary tract infections (UTIs) have been reported
to be common in ICU patients, where they are
reported to account for between 25 to 50% of all
infections.102–108 However, it is likely that most of
these patients had “asymptomatic bacteriuria” rather
than true infections of the urinary tract. The use of
antibiotics in patients with asymptomatic bacteriuria
is based on a single study performed in the early
1980s that may not be applicable today.177 Platt and
colleagues177 demonstrated that in hospitalized patients bacteriuria with ⱖ 105 CFUs of bacteria per
milliliter of urine during bladder catheterization was
associated with a 2.8-fold increase in mortality.
Based on this study, thousands of ICU patients with
urinary tract colonization have been treated with
antibiotics.
Most ICU patients require an indwelling urinary
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catheter for monitoring fluid balance and renal
function. The patients’ colonic flora rapidly colonizes
the urinary tract in these patients.178 Stark and
Maki179 have demonstrated that in catheterized patients, bacteria in the urinary system rapidly proliferate to exceed 105 CFU/mL over a short period of
time. Bacteriuria, defined as a quantitative culture of
ⱖ 105 CFU/mL, has been reported in up to 30%
of catheterized hospitalized patients.180 The terms
“bacteriuria” and “UTI” are generally although incorrectly used as synonyms. Indeed, most studies in
ICU patients have used bacteriuria to diagnose a
UTI. Bacteriuria implies colonization of the urinary
tract without bacterial invasion and an acute inflammatory response.181 UTI implies an infection of the
urinary tract.181 Criteria have not been developed for
differentiating asymptomatic colonization of the urinary tract from symptomatic infection. Furthermore,
the presence of white cells in the urine is not useful
for differentiating colonization from infection, as
most catheter-associated bacteriurias have accompanying pyuria.182 It is therefore unclear how many
catheterized patients with ⬎ 105 CFU/mL actually
have UTI.
While catheter-associated bacteruria is common in
ICU patients, data for the early 1980s indicates that
⬍ 3% of catheter-associated bacteriuric patients will
develop bacteremia caused by organisms in the
urine.183 Therefore, the surveillance for and treatment of isolated bacteruria in most ICU patients is
currently not recommended.184 Bacteriuria should,
however, be treated following urinary tract manipulation or surgery, in patients with kidney stones, and
in patients with urinary tract obstruction.
CLOSTRIDIA DIFFICILE Colitis
C difficile, the agent that causes pseudomembranous colitis and antibiotic-associated diarrhea, has
become a common nosocomial pathogen.185–187 Approximately 20% of all hospitalized patients become
“infected” with C difficile, of whom only about a
third develop diarrhea.185–187 The majority of hospital inpatients infected with C difficile are asymptomatic.188,189 C difficile infection commonly presents
with mild to moderate diarrhea, sometimes accompanied by lower abdominal cramping. Symptoms
usually begin during or shortly after antibiotic therapy but are occasionally delayed for several weeks.
Severe colitis without pseudomembrane formation
may occur with profuse, debilitating diarrhea, abdominal pain, and distension. Common systemic
manifestations include fever, nausea, anorexia, and
malaise. A neutrophilia and increased numbers of
fecal leukocytes are common.188,189 Pseudomembra-
nous colitis is the most dramatic manifestation of C
difficile infection; these patients have marked abdominal and systemic signs and symptoms and may
develop a fulminant and life-threatening colitis.
Stool assay for toxins A or B are the main clinical
tests used to diagnose C difficile infection.190 –192 The
“gold standard” test is the tissue culture cytotoxicity
assay. This test has a high sensitivity (94 to 100%)
and specificity (99%). The major disadvantages of
this test are its high expense and the time needed to
complete the assay (2 to 3 days). For these reasons,
this test is no longer routinely performed. Toxin
enzyme-linked immunosorbent assay (ELISA) tests
are less sensitive (70 to 90%) than the cytotoxicity
test, but demonstrate excellent specificity (99%) and
can be rapidly processed, and have largely replaced
the cytotoxicity assay.190 –192 It is suggested that two
stool specimens be examined for leukocytes and
toxin ELISA test.190 Should the ELISA be negative
and a high index of suspicion for C difficile exist, the
following are recommended: (1) sigmoidoscopy,
and/or (2) cytotoxicity assay, and/or (3) CT scan of
abdomen looking for thickened colonic wall.
Candida Infections
Candida species are important opportunistic
pathogens in the ICU. The CDC National Nosocomial Infection Study reported that 7% of all nosocomial infections were due to candidal species.193 In
the EPIC study,104 17% of nosocomial ICU infections were due to fungi. Candida infections should
be considered in febrile ICU patients who have been
in the ICU for ⬎ 10 days and have received multiple
courses of antibiotics.53 Candida species are particularly important pathogens in patients with ongoing
peritonitis.52–54 It is important to realize that Candida species are constituents of the normal flora in
about 30% of all healthy people. Antibiotic therapy
increases the incidence of colonization by up to
70%.53 It is probable that most ICU patients become
colonized with Candida species soon after admission.
Not all patients colonized with Candida will become
infected with Candida. Nonneutropenic patients
with isolation of Candida species from pulmonary
samples (tracheal aspirates, bronchoscopic or blind
sampling methods), even in high concentrations, are
unlikely to have invasive candidiasis.194,195 Indication
for initiation of antifungal therapy in these patients
should be based on histologic evidence or identification from sterile specimens. Similarly, isolation of
Candida species from the urine in ICU patients with
indwelling catheters usually represents colonization
rather than infection. Although candiduria may be
CHEST / 117 / 3 / MARCH, 2000
861
observed in up to 80% of patients with systemic
candidiasis, candidemia from a urinary tract source is
extremely rare.54
Other Infections
Nosocomial meningitis is exceedingly uncommon
in hospitalized patients who have not undergone a
neurosurgical procedure.196,197 Lumbar puncture,
therefore, need not be performed routinely in ICU
patients (nonneurosurgical) who develop a fever
unless they have meningeal signs or contiguous
infection.196,197 In patients who have undergone
abdominal surgery and develop a fever, intra-abdominal infection must always be excluded. CT scanning
of the abdomen is indicated in these patients. Similarly, in patients who have undergone other operative procedures, wound infection must be excluded.
Diagnostic Evaluation
It is important that blood cultures as well as other
appropriate cultures be performed before the initiation of antibiotic therapy. The impact of antibiotic
therapy on culture positivity is illustrated in patients
with suspected VAP, where a number of studies have
demonstrated that both prior and current antibiotic
therapy reduces the predictive accuracy of invasive
diagnostic testing. 198,199
blood cultures should not be obtained through intravascular catheters unless the catheter has been recently placed.207
The volume of blood drawn in adult patients is the
single most important factor governing the sensitivity
of blood cultures.180,206,208,209 Therefore, it is recommended that a minimum of 10 mL and preferably 20
mL of blood be removed per draw divided among
the minimum number of blood culture containers
as recommended by the manufacturer.180,206,208,209
Resin-containing medium offers little clinical benefit
to the majority of ICU patients.210 Once bloodstream
infection is identified, repeated or follow-up cultures
are not necessary in most cases. Subsequent blood
cultures may be justified in patients who deteriorate
clinically or those who fail to improve despite therapy. However in some cases bacteremia may be
prolonged, necessitating further blood cultures during treatment (eg, staphylococcal bacteremia).
Scintigraphy, CT Scanning, and Ultrasound
Examinations
Scintigraphic scanning techniques have a low sensitivity and specificity in ICU patients and are therefore not recommended.1,211,212 The advantages of
CT scanning and/or ultrasound over scintigraphy is
that the results of the test can be obtained immediately with superior anatomic resolution, which can
be used to guide drainage procedures.
Blood Cultures
Bacteremia and candidemia have been documented in up to 10% of ICU patients and are an
important cause of morbidity and mortality in the
ICU.200 –203 Blood cultures are therefore indicated in
all febrile patients. Surveillance blood cultures, however, are expensive and add very little to the management of patients in the ICU.204
Bennett and Beeson205 reported that the presence
of microorganisms in the blood is the initiating event
leading to fever and chills 1 to 2 h later, and that
blood cultures are frequently negative at the time of
the temperature spike. Thus blood cultures are
ideally drawn prior to the onset of a temperature
spike. In reality, this is not possible; therefore,
spreading out the collection of blood cultures increases the likelihood of blood collection during
bacteremia. It is therefore recommended that at
least two and no more than three sets of blood
cultures should be obtained by separate needle sticks
from different venipuncture sites.206 Colonization of
the lumen of central venous catheters occurs within
a short period of time after placement. Therefore,
862
An Approach to the Critically Ill Patient
With Fever
From the forgoing information, the following approach is suggested in ICU patients who develop a
fever (see Fig 1). Due to the frequency and excess
morbidity and mortality associated with bacteremia,
blood cultures are recommenced in all ICU patients
who develop a fever. A comprehensive physical
examination and review of the chest radiograph is
essential. Noninfectious causes of fever should be
excluded. In patients with an obvious focus of infections (eg, purulent nasal discharge, abdominal tenderness, profuse green diarrhea), a focused diagnostic workup is required. If there is no clinically
obvious source of infection and unless the patient is
clinically deteriorating (falling BP, decreased urine
output, increasing confusion, rising serum lactate
concentration, falling platelet count, or worsening
coagulopathy), or the temperature is ⬎ 39°C
(102°F), it may be prudent to perform blood cultures
and then observe the patient before embarking on
further diagnostic tests and commencing empiric
Reviews
Figure 1. Fever diagnostic algorithm. Dx ⫽ diagnostic; ABx ⫽ antibiotics; Rx ⫽ therapy.
antibiotics. However, all neutropenic patients with
fever and patients with severe (as outlined above) or
progressive signs of sepsis should be started on
broad-spectrum antimicrobial therapy immediately
after obtaining appropriate cultures.
In patients whose clinical picture is consistent with
infection and in whom no clinically obvious source
has been documented, removal of all central lines
⬎ 48 h old (with semiquantitative or quantitative
culture) is recommended as well as stool for WBC
count and C difficile toxin in those patients with
loose stools, and CT scan of the sinuses with removal
of all nasal tubes. Urine culture is indicated only in
patients with abnormalities of the renal system or
following urinary tract manipulation. If the patient is
at risk of abdominal sepsis or has any abdominal
signs (tenderness, distension, unable to tolerate enteral feeds) CT scan of abdomen is indicated. Patients with right upper quadrant tenderness require
an abdominal ultrasound.
Reevaluation of the patient’s status after 48 h
using all available results and the evolution of the
CHEST / 117 / 3 / MARCH, 2000
863
patients clinical condition is essential. If fever persists despite empiric antibiotics and no source of
infection has been identified, empiric antifungal
therapy may be indicated if the patient has risk
factors for candidal infection. Additional diagnostic
tests may be appropriate at this time, including
venography, a differential blood count for eosinophils (diagnosis of drug fever), and abdominal
imaging.
Treatment of Fever in the ICU
Almost all febrile ICU patients are treated with
acetaminophen and external cooling methods to
render the patients “afebrile.” However, fever is a
basic evolutionary response to infection and may be
an important host defense mechanism. The preponderance of evidence suggests that temperature in the
range of the usual fever renders host defenses more
active and many pathogens more susceptible to these
defenses. Therefore, it seems illogical to treat fever
per se. In addition, temperature is an important
physical sign, allowing the physician to monitor the
response to treatment. Furthermore, acute hepatitis
may occur in ICU patients with reduced glutathione
reserves (alcoholics, malnourished, etc.) who have
received regular therapeutic doses of acetaminophen. Based on this data, it is recommenced that
febrile episodes not be routinely treated with antipyretic therapy; an evaluation of the relative benefits
and risks of antipyretic treatment should be evaluated in each individual case. Fever should, however,
be treated in patients with acute brain insults, patients with limited cardiorespiratory reserve (ie, ischemic heart disease), and in patients in whom the
temperature increases above 40°C (104°F).2,14,37,213–217
Hypothermia blankets are frequently used in ICU
patients with febrile episodes.218 However, studies
have demonstrated that hypothermia blankets are no
more effective in cooling patients than are antipyretic agents.218 Furthermore, the use of hypothermia
blankets is associated with large temperature fluctuations and rebound hyperthermia.218 In addition,
there is a fundamental illogic to the use of external
application of cold to lower temperature in a patient
with true fever. Because of the altered hypothalamic
set point, the patient is already responding as if to a
cold environment. External cooling may result in
augmented hypermetabolism and a persistent fever.
Indeed, Lenhardt and colleagues219 demonstrated
that active external cooling in volunteers with induced fever increased oxygen consumption by 35 to
40% and was associated with a significant increase in
epinephrine and norepinephrine levels.
864
References
1 Meduri GU, Mauldin GL, Wunderink RG, et al. Causes of
fever and pulmonary densities in patients with clinical
manifestations of ventilator-associated pneumonia. Chest
1994; 106:221–235
2 Mackowiak PA. Concepts of fever. Arch Intern Med 1998;
158:1870 –1881
3 Saper CB, Breder CD. The neurologic basis of fever. N Engl
J Med 1994; 330:1880 –1886
4 Dinarello CA, Cannon JG, Mancilla J. Interleukin-6 as an
endogenous pyrogen: induction of prostaglandin E2 in brain
but not peripheral blood mononuclear cells. Brain Res 1991;
562:199 –206
5 Dinarello CA, Wolff SM. The role of interleukin-1 in
disease. N Engl J Med 1993; 328:106 –113
6 Dinarello CA, Cannon JG, Mier JW, et al. Multiple biological activities of human recombinant interleukin 1. J Clin
Invest 1986; 77:1734 –1739
7 Dinarello CA. Interleukin-1 and the pathogenesis of the
acute-phase response. N Engl J Med 1984; 311:1413–1418
8 Fontana A, Weber E, Dayer JM. Synthesis of interleukin
1/endogenous pyrogen in the brain of endotoxin-treated
mice: a step in fever induction? J Immunol 1984; 133:1696 –
1698
9 Gourine AV, Rudolph K, Tesfaigzi J, et al. Role of hypothalamic interleukin-1 beta in fever induced by cecal ligation
and puncture in rats. Am J Physiol 1998; 275(3 Pt 2):R754 –
R761
10 Leon LR, White AA, Kluger MJ. Role of IL-6 and TNF in
thermoregulation and survival during sepsis in mice. Am J
Physiol 1998; 275(1 Pt 2):R269 –R277
11 Kluger MJ, Kozak W, Leon LR, et al. The use of knockout
mice to understand the role of cytokines in fever. Clin Exp
Pharmacol Physiol 1998; 25:141–144
12 Klir JJ, McClellan JL, Kluger MJ. Interleukin-1 beta causes
the increase in anterior hypothalamic interleukin-6 during
LPS-induced fever in rats. Am J Physiol 1994; 266(6 Pt
2):R1845–R1848
13 Klir JJ, Roth J, Szelenyi Z, et al. Role of hypothalamic
interleukin-6 and tumor necrosis factor-alpha in LPS fever
in rat. Am J Physiol 1993; 265(3 Pt 2):R512–R517
14 Mackowiak PA, Bartlett JG, Borden EC, et al. Concepts of
fever: recent advances and lingering dogma. Clin Infect Dis
1997; 25:119 –138
15 Kluger MJ, Kozak W, Conn CA, et al. The adaptive value of
fever. Infect Dis Clin N Am 1996; 10:1–20
16 Kluger MJ, Vaughn LK. Fever and survival in rabbits
infected with Pasteurella multocida. J Physiol 1978; 282:
243–251
17 Bernheim HA, Kluger MJ. Fever and antipyresis in the
lizard Dipsosaurus dorsalis. Am J Physiol 1976; 231:198 –203
18 D’Alecy LG, Kluger MJ. Avian febrile response. J Physiol
1975; 253:223–232
19 Vaughn LK, Bernheim HA, Kluger MJ. Fever in the lizard
Dipsosaurus dorsalis. Nature 1974; 252:473– 474
20 Covert JB, Reynolds WW. Survival value of fever in fish.
Nature 1977; 267:43– 45
21 Bernheim HA, Kluger MJ. Fever: effect of drug-induced
antipyresis on survival. Science 1976; 193:237–239
22 Kluger MJ, Ringler DH, Anver MR. Fever and survival.
Science 1975; 188:166 –168
23 Jampel HD, Duff GW, Gershon RK, et al. Fever and
immunoregulation: III. Hyperthermia augments the primary in vitro humoral immune response. J Exp Med 1983;
157:1229 –1238
24 van Oss CJ, Absolom DR, Moore LL, et al. Effect of
Reviews
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
temperature on the chemotaxis, phagocytic engulfment,
digestion and O2 consumption of human polymorphonuclear leukocytes. J Reticuloendothel Soc 1980; 27:561–565
Biggar WD, Bohn DJ, Kent G, et al. Neutrophil migration in
vitro and in vivo during hypothermia. Infect Immunol 1984;
46:857– 859
Azocar J, Yunis EJ, Essex M. Sensitivity of human natural
killer cells to hyperthermia. Lancet 1982; 1:16 –17
Styrt B, Sugarman B. Antipyresis and fever. Arch Intern
Med 1990; 150:1589 –1597
Dennie CC. A history of syphilis. Springfield, IL: Charles C.
Thomas, 1962
Small PM, Tauber MG, Hackbarth CJ, et al. Influence of
body temperature on bacterial growth rates in experimental
pneumococcal meningitis in rabbits. Infect Immunol 1986;
52:484 – 487
Sande MA, Sande ER, Woolwine JD, et al. The influence of
fever on the development of experimental Streptococcus
pneumoniae meningitis. J Infect Dis 1987; 156:849 – 850
Anderson KJ, Kuhn RE. Elevated environmental temperature enhances immunity in experimental Chagas’ disease.
Infect Immunol 1989; 57:13–17
Carmichael LE, Barnes FD, Percy DH. Temperature as a
factor in resistance of young puppies to canine herpesvirus.
J Infect Dis 1969; 120:669 – 678
Bryant RE, Hood AF, Hood CE, et al. Factors affecting
mortality of gram-negative rod bacteremia. Arch Intern Med
1971; 127:120 –128
Weinstein MR, Iannini PB, Stratton CW, et al. Spontaneous
bacterial peritonitis: a review of 28 cases with emphasis on
improved survival and factors influencing prognosis. Am J
Med 1978; 64:592–598
Dorn TF, DeAngelis C, Baumgardner RA, et al. Acetaminophen: more harm than good for chickenpox? J Pediatr
1989; 114:1045–1048
Manthous CA, Hall JB, Olson D, et al. Effect of cooling on
oxygen consumption in febrile critically ill patients. Am J
Respir Crit Care Med 1995; 151:10 –14
Ginsberg MD, Busto R. Combating hyperthermia in acute
stroke: a significant clinical concern. Stroke 1998; 29:529 –
534
Badawi N, Kurinczuk JJ, Keogh JM, et al. Intrapartum risk
factors for newborn encephalopathy: the Western Australian
case-control study. BMJ 1998; 317:1554 –1558
Quinn M, Matthews TG. Does maternal pyrexia embarrass
the fetus? Irish Med J 1984; 77:218 –219
Schmitz T, Bair N, Falk M, et al. A comparison of five
methods of temperature measurement in febrile intensive
care patients. Am J Crit Care 1995; 4:286 –292
Milewski A, Ferguson KL, Terndrup TE. Comparison of
pulmonary artery, rectal, and tympanic membrane temperatures in adult intensive care unit patients. Clin Pediatr
1991; 30(4 Suppl):13–16
Nierman DM. Core temperature measurement in the intensive care unit. Crit Care Med 1991; 19:818 – 823
Erickson RS, Kirklin SK. Comparison of ear-based, bladder,
oral, and axillary methods for core temperature measurement. Crit Care Med 1993; 21:1528 –1534
Hayward JS, Eckerson JD, Kemna D. Thermal and cardiovascular changes during three methods of resuscitation from
mild hypothermia. Resuscitation 1984; 11:21–33
Shiraki K, Konda N, Sagawa S. Esophageal and tympanic
temperature responses to core blood temperature changes
during hyperthermia. J Appl Physiol 1986; 61:98 –102
Shiraki K, Sagawa S, Tajima F, et al. Independence of brain
and tympanic temperatures in an unanesthetized human.
J Appl Physiol 1988; 65:482– 486
47 O’Grady NP, Barie PS, Bartlett J, et al. Practice parameters
for evaluating new fever in critically ill adult patients. Crit
Care Med 1998; 26:392– 408
48 Musher DM, Fainstein V, Young EJ, et al. Fever patterns:
their lack of clinical significance. Arch Intern Med 1979;
139:1225–1228
49 Chastre J, Fagon JY, Trouillet JL. Diagnosis and treatment
of nosocomial pneumonia in patients in intensive care units.
Clin Infect Dis 1995; 21(Suppl 3):S226 –S237
50 Kollef MH. Ventilator-associated pneumonia: a multivariate
analysis. JAMA 1993; 270:1965–1970
51 Hiyama DT, Zinner MJ. Surgical complications. In:
Schwartz SI, Shires GT, Spencer FC et al, eds. Principles of
surgery. New York, NY: McGraw-Hill, 1994; 455– 487
52 Calandra T, Bille J, Schneider R, et al. Clinical significance
of Candida isolated from peritoneum in surgical patients.
Lancet 1989; 2:1437–1440
53 Petri MG, Konig J, Moecke HP, et al. Epidemiology of
invasive mycosis in ICU patients: a prospective multicenter
study in 435 non-neutropenic patients. Paul-Ehrlich Society
for Chemotherapy, Divisions of Mycology and Pneumonia
Research. Intensive Care Med 1997; 23:317–325
54 Nolla-Salas J, Sitges-Serra A, Leon-Gil C, et al. Candidemia
in non-neutropenic critically ill patients: analysis of prognostic factors and assessment of systemic antifungal therapy.
Study Group of Fungal Infection in the ICU. Intensive Care
Med 1997; 23:23–30
55 Ferrara JL. The febrile platelet transfusion reaction: a
cytokine shower. Transfusion 1995; 35:89 –90
56 Chen CC, Wang SS, Lee FY, et al. Proinflammatory cytokines in early assessment of the prognosis of acute pancreatitis. Am J Gastroenterol 1999; 94:213–218
57 Osman MO, El-Sefi T, Lausten SB, et al. Sodium fusidate
and the cytokine response in an experimental model of acute
pancreatitis. Br J Surg 1998; 85:1487–1492
58 Feuerstein GZ, Wang X, Barone FC. The role of cytokines
in the neuropathology of stroke and neurotrauma. Neuroimmunomodulation 1998; 5:143–159
59 DeGraba TJ. The role of inflammation after acute stroke:
utility of pursuing anti-adhesion molecule therapy. Neurology 1998; 51(3 Suppl 3):S62–S68
60 Carlstedt F, Lind L, Lindahl B. Proinflammatory cytokines,
measured in a mixed population on arrival in the emergency
department, are related to mortality and severity of disease.
J Intern Med 1997; 242:361–365
61 Marx N, Neumann FJ, Ott I, et al. Induction of cytokine
expression in leukocytes in acute myocardial infarction. J Am
Coll Cardiol 1997; 30:165–170
62 Clemmer TP, Fisher CJ, Jr, Bone RC, et al. Hypothermia in
the sepsis syndrome and clinical outcome. The Methylprednisolone Severe Sepsis Study Group. Crit Care Med 1992;
20:1395–1401
63 Sprung CL, Peduzzi PN, Shatney CH, et al. Impact of
encephalopathy on mortality in the sepsis syndrome. The
Veterans Administration Systemic Sepsis Cooperative Study
Group. Crit Care Med 1990; 18:801– 806
64 Arons MM, Wheeler AP, Bernard GR, et al. Effects of
ibuprofen on the physiology and survival of hypothermic
sepsis. Crit Care Med 1999; 27:699 –707
65 Marik PE, Zaloga GP. Hypothermia and cytokines in septic
shock [abstract]. Crit Care Med 1999; 27(Suppl):A136
66 Clarke DE, Kimelman J, Raffin TA. The evaluation of fever
in the intensive care unit. Chest 1991; 100:213–220
67 Cunha BA. Fever in the critical care unit. Crit Care Clin
1998; 14:1–14
68 Chambers LA, Kruskall MS, Pacini DG, et al. Febrile
reactions after platelet transfusion: the effect of single versus
CHEST / 117 / 3 / MARCH, 2000
865
multiple donors. Transfusion 1990; 30:219 –221
69 Hanson MA. Drug fever: remember to consider it in
diagnosis. Postgrad Med 1991; 89:167–170
70 Mackowiak PA, LeMaistre CF. Drug fever: a critical appraisal of conventional concepts; an analysis of 51 episodes
in two Dallas hospitals and 97 episodes reported in the
English literature. Ann Intern Med 1987; 106:728 –733
71 Mackowiak PA. Drug fever: mechanisms, maxims and misconceptions. Am J Med Sci 1987; 294:275–286
72 Barton JC. Nonhemolytic, noninfectious transfusion reactions. Semin Hematol 1981; 18:95–121
73 Rutledge R, Sheldon GF, Collins ML. Massive transfusion.
Crit Care Clin 1986; 2:791– 805
74 Wood AJJ. Adverse drug reactions. In: Fauci AS, Braunwald
E, Isselbacher KJ et al, eds. Harrison’s principles of internal
medicine. New York, NY: McGraw-Hill, 1998; 422– 430
75 Fry DE. Postoperative fever. In: Mackowiak PA, ed. Fever:
basic mechanisms and management. New York, NY: Raven
Press, 1991; 243–254
76 Engoren M. Lack of association between atelectasis and
fever. Chest 1995; 107:81– 84
77 Shields RT. Pathogenesis of postoperative pulmonary atelectasis an experimental study. Arch Surg 1949; 48:489 –503
78 Lansing AM. Mechanism of fever in pulmonary atelectasis.
Arch Surg 1963; 87:168 –174
79 Kisala JM, Ayala A, Stephan RN, et al. A model of pulmonary atelectasis in rats: activation of alveolar macrophage and
cytokine release. Am J Physiol 1993; 264(3 Pt 2):R610 –R614
80 Menitove JE, McElligott MC, Aster RH. Febrile transfusion
reaction: what blood component should be given next? Vox
Sanguinis 1982; 42:318 –321
81 Snyder EL, Stack G. Febrile and nonimmune transfusions
reactions. In: Rossi EC, Simon TL, Moss GS, eds. Principles
of transfusion medicine. Baltimore, MD: Williams and
Wilkins, 1991
82 Fenwick JC, Cameron M, Naiman SC, et al. Blood transfusion as a cause of leucocytosis in critically ill patients. Lancet
1994; 344:855– 856
83 Meduri GU, Belenchia JM, Estes RJ, et al. Fibroproliferative phase of ARDS: clinical findings and effects of corticosteroids. Chest 1991; 100:943–952
84 Meduri GU, Headley S, Golden E, et al. Effect of prolonged
methylprednisolone therapy in unresolving acute respiratory
distress syndrome: a randomized controlled trial. JAMA
1999; 280:159 –165
85 Orlando R, Gleason E, Drezner AD. Acute acalculous
cholecystitis in the critically ill patient. Am J Surg 1983;
145:472– 476
86 Long TN, Heimbach DM, Carrico CJ. Acalculous cholecystitis in critically ill patients. Am J Surg 1978; 136:31–36
87 Johnson EE, Hedley-White J. Continuous positive-pressure
ventilation and portal flow in dogs with pulmonary edema.
J Appl Physiol 1972; 33:385–389
88 Johnson EE, Hedley-White J. Continuous positive pressure
ventilation and choledochoduodenal flow resistance. J Appl
Physiol 1975; 39:937–942
89 Barie PS, Fischer E. Acute acalculous cholecystitis. J Am
Coll Surg 1995; 180:232–244
90 Malet PF. Acalculous cholecystitis: a new perspective. Gastroenterology 1990; 99:1529 –1530
91 Roslyn JJ, Pitt HA, Mann L, et al. Parenteral nutritioninduced gallbladder disease: a reason for early cholecystectomy. Am J Surg 1984; 148:58 – 63
92 Petersen SR, Sheldon GF. Acute acalculous cholecystitis: a
complication of hyperalimentation. Am J Surg 1979; 138:
814 – 817
93 Deitch EA, Engel JM. Acute acalculous cholecystitis: ultra866
sonic diagnosis. Am J Surg 1981; 142:290 –292
94 Deitch EA. Utility and accuracy of ultrasonically measured
gallbladder wall as a diagnostic criteria in biliary tract
disease. Dig Dis Sci 1981; 26:686 – 693
95 Kalff V, Froelich JW, Lloyd R, et al. Predictive value of an
abnormal hepatobiliary scan in patients with severe intercurrent illness. Radiology 1983; 146:191–194
96 Blankenberg F, Wirth R, Jeffrey RBJ, et al. Computed
tomography as an adjunct to ultrasound in the diagnosis of
acute acalculous cholecystitis. Gastrointest Radiol 1991;
16:149 –153
97 Roslyn JJ, Zinner MJ. Gallbladder and extrahepatic biliary
system. In: Schwartz SI, Shires GT, Spencer FC et al, ed.
Principles of surgery. New York, NY: McGraw-Hill, 1994;
1367–1399
98 Kiviniemi H, Makela JT, Autio R, et al. Percutaneous
cholecystostomy in acute cholecystitis in high-risk patients:
an analysis of 69 patients. Int Surg 1998; 83:299 –302
99 van Overhagen H, Meyers H, Tilanus HW, et al. Percutaneous cholecystectomy for patients with acute cholecystitis
and an increased surgical risk. Cardiovasc Intervent Radiol
1996; 19:72–76
100 Diamond PT, Macciocchi SN. Predictive power of clinical
symptoms in patients with presumptive deep venous thrombosis. Am J Phys Med Rehabil 1997; 76:49 –51
101 Marik PE, Andrews L, Maini B. The incidence of deep
venous thrombosis in ICU patients. Chest 1997; 111:661–
664
102 Brown RB, Hosmer D, Chen HC, et al. A comparison of
infections in different ICU’s within the same hospital. Crit
Care Med 1985; 13:472– 476
103 Jarvis WR, Edwards JR, Culver DH, et al. Nosocomial
infection rates in adult and pediatric intensive care units in
the United States. National Nosocomial Infections Surveillance System. Am J Med 1991; 91(3B):185S–191S
104 Vincent JL, Bihari DJ, Suter PM, et al. The prevalence of
nosocomial infection in intensive care units in Europe:
results of the European Prevalence of Infection in Intensive
Care (EPIC) Study. EPIC International Advisory Committee. JAMA 1995; 274:639 – 644
105 Daschner FD, Frey P, Wolff G, et al. Nosocomial infections
in intensive care wards: a multicenter prospective study.
Intensive Care Med 1982; 8:5–9
106 Bueno-Cavanillas A, Delgado-Rodriguez M, Lopez-Luque
A, et al. Influence of nosocomial infection on mortality rate
in an intensive care unit. Crit Care Med 1994; 22:55– 60
107 Bjerke HS, Leyerle B, Shabot MM. Impact of ICU nosocomial infections on outcome from surgical care. Am Surg
1991; 57:798 – 802
108 Potgieter PD, Linton DM, Oliver S, et al. Nosocomial
infections in a respiratory intensive care unit. Crit Care Med
1987; 15:495– 498
109 Haley RW, Quade D, Freeman HE, et al. Study on the
efficacy of nosocomial infection control (SENIC Project):
summary of study design. Am J Epidemiol 1980; 111:472–
485
110 Garner JS, Jarvis WR, Emorl TG, et al. CDC definitions for
nosocomial infections. Am J Infect Control 1988; 16:128 –
140
111 Baker AM, Bowton DL, Haponik EF. Decision making in
nosocomial pneumonia: an analytic approach to the interpretation of quantitative bronchoscopic cultures. Chest
1995; 107:85–95
112 Chastre J, Trouillet JL, Fagon JY. Diagnosis of pulmonary
infections in mechanically ventilated patients. Semin Respir
Infect 1996; 11:65–76
113 Fagon JY, Chastre J, Domart Y, et al. Nosocomial pneumoReviews
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
nia in patients receiving continuous mechanical ventilation:
prospective analysis of 52 episodes with use of a protected
specimen brush and quantitative culture techniques. Am
Rev Respir Dis 1989; 139:877– 884
Meduri GU. Diagnosis and differential diagnosis of ventilator-associated pneumonia. Clin Chest Med 1995; 16:61–93
Fagon JY, Chastre J, Hance AJ, et al. Detection of nosocomial lung infection in ventilated patients: use of a protected
specimen brush and quantitative culture in 147 patients. Am
Rev Respir Dis 1988; 138:110 –116
Torres A, Aznar R, Gatell JM, et al. Incidence, risk, and
prognosis factors of nosocomial pneumonia in mechanically
ventilated patients. Am Rev Respir Dis 1990; 142:523–528
Timsit JF, Chevret S, Valcke J, et al. Mortality of nosocomial
pneumonia in ventilated patients: influence of diagnostic
tools. Am J Respir Crit Care Med 1996; 154:116 –123
Timsit JF, Misset B, Goldstein FW, et al. Reappraisal of
distal diagnostic testing in the diagnosis of ICU-acquired
pneumonia. Chest 1995; 108:1632–1639
Craig CP, Connelley S. Effect of intensive care unit nosocomial pneumonia on duration and mortality. Am J Infect
Control 1984; 12:233–238
Bregeon F, Papazian L, Visconti A, et al. Relationship of
microbiologic diagnostic criteria to morbidity and mortality
in patients with ventilator-associated pneumonia. JAMA
1997; 277:655– 662
Fagon JY, Chastre J, Hance AJ, et al. Nosocomial pneumonia in ventilated patients: a cohort study evaluating attributable mortality and hospital stay. Am J Med 1993; 94:281–288
Fagon JY, Chastre J, Hance AJ, et al. Evaluation of clinical
judgment in the identification and treatment of nosocomial
pneumonia in ventilated patients. Chest 1993; 103:547–553
Marik PE, Brown WJ. A comparison of bronchoscopic vs
blind protected specimen brush sampling in patients with
suspected ventilator-associated pneumonia. Chest 1995;
108:203–207
Chastre J, Fagon JY, Bornet-Lecso M, et al. Evaluation of
bronchoscopic techniques for the diagnosis of nosocomial
pneumonia. Am J Respir Crit Care Med 1995; 152:231–240
Kollef MH, Bock KR, Richards RD, et al. The safety and
diagnostic accuracy of minibronchoalveolar lavage in patients with suspected ventilator-associated pneumonia. Ann
Intern Med 1995; 122:743–748
Allaouchiche B, Jaumain H, Dumontet C, et al. Early
diagnosis of ventilator-associated pneumonia: is it possible to
define a cutoff value of infected cells in BAL fluid? Chest
1996; 110:1558 –1565
Speich R, Wust J, Hess T, et al. Prospective evaluation of a
semiquantitative dip slide method compared with quantitative bacterial cultures of BAL fluid. Chest 1996; 109:1423–
1429
Kollef MH, Eisenberg PR, Ohlendorf MF, et al. The
accuracy of elevated concentrations of endotoxin in bronchoalveolar lavage fluid for the rapid diagnosis of gramnegative pneumonia. Am J Respir Crit Care Med 1996;
154:1020 –1028
Timset JF, Misset B, Azoulay E, et al. Usefulness of airway
visualization in the diagnosis of nosocomial pneumonia in
ventilated patients. Chest 1996; 110:172–179
Jourdain B, Joly-Guillou ML, Dombret MC, et al. Usefulness of quantitative cultures of BAL fluid for diagnosing
nosocomial pneumonia in ventilated patients. Chest 1997;
111:411– 418
Torres A, el-Ebiary M, Fabregas N, et al. Value of intracellular bacteria detection in the diagnosis of ventilator associated pneumonia. Thorax 1996; 51:378 –384
el-Ebiary M, Torres A, Gonzalez J, et al. Quantitative
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
cultures of endotracheal aspirates for the diagnosis of ventilator-associated pneumonia. Am Rev Respir Dis 1993;
148:1552–1557
Marquette CH, Copin MC, Wallet F, et al. Diagnostic tests
for pneumonia in ventilated patients: prospective evaluation
of diagnostic accuracy using histology as a diagnostic gold
standard. Am J Respir Crit Care Med 1995; 151:1878 –1888
Kirtland SH, Corely DE, Winterbauer RH, et al. The
diagnosis of ventilator-associated pneumonia: a comparison
of histologic, microbiologic, and clinical criteria. Chest 1997;
112:445– 457
Corely DE, Kirtland SH, Winterbauer RH, et al. Reproducibility of the histologic diagnosis of pneumonia among a
panel of four pathologists: analysis of a gold standard. Chest
1997; 112:458 – 465
Sterling TR, Ho EJ, Brehm WT, et al. Diagnosis and
treatment of ventilator-associated pneumonia: impact on
survival; a decision analysis. Chest 1996; 110:1025–1034
Luna CM, Vujacich P, Niederman MS, et al. Impact of BAL
data on the therapy and outcome of ventilator-associated
pneumonia. Chest 1997; 111:676 – 685
Rello J, Gallego M, Mariscal D, et al. The value of routine
microbial investigation in ventilator-associated pneumonia.
Am J Respir Crit Care Med 1997; 156:196 –200
Kollef MH, Ward S. The influence of mini-BAL cultures on
patients outcomes: implications for the antibiotic management of ventilator-associated pneumonia. Chest 1998; 113:
412– 420
Wearden PD, Chendrasekhar A, Timberlake GA. Comparison of nonbronchoscopic techniques with bronchoscopic
brushing in the diagnosis of ventilator-associated pneumonia. J Trauma 1996; 41:703–707
Bello S, Tajada A, Chacon E, et al. “Blind” protected
specimen brushing versus bronchoscopic techniques in the
aetiolological diagnosis of ventilator- associated pneumonia.
Eur Respir J 1996; 9:1494 –1499
Papazian L, Thomas P, Garbe L, et al. Bronchoscopic or
blind sampling techniques for the diagnosis of ventilatorassociated pneumonia. Am J Respir Crit Care Med 1995;
152:1982–1991
Leal-Noval SR, Alfaro-Rodriguez E, Murillo-Cabeza F, et al.
Diagnostic value of the blind brush in mechanically-ventilated patients with nosocomial pneumonia. Intensive Care
Med 1992; 18:410 – 414
Rouby JJ, De Lassale EM, Poete P, et al. Nosocomial
bronchopneumonia in the critically ill: histologic and bacteriologic aspects. Am Rev Respir Dis 1992; 146:1059 –1066
Marik PE, Careau P. A comparison of mini-bronchoalveolar
lavage and blind-protected specimen brush sampling in
ventilated patients with suspected pneumonia. J Crit Care
1998; 13:67–72
Grindlinger GA, Niehoff J, Hughes L, et al. Acute paranasal
sinusitis related to nasotracheal intubation of head-injured
patients. Crit Care Med 1987; 15:214 –217
Deutschman CS, Wilton P, Sinow J, et al. Paranasal sinusitis
associated with nasotracheal intubation: a frequently unrecognized and treatable source of sepsis. Crit Care Med 1986;
14:111–114
Rouby JJ, Laurent P, Gosnach M, et al. Risk factors and
clinical relevance of nosocomial maxillary sinusitis in the
critically ill. Am J Respir Crit Care Med 1994; 150:776 –783
Fassoulaki A, Pamouktsoglou P. Prolonged nasotracheal
intubation and its association with inflammation of paranasal
sinuses. Anesth Analg 1989; 69:50 –52
Holzapfel L, Chastang C, Demingeon G, et al. Randomized
study assessing the systematic search for maxillary sinusitis
in nasotracheally mechanically ventilated patients. Am J
CHEST / 117 / 3 / MARCH, 2000
867
Respir Crit Care Med 1999; 159:695–701
151 Hansen M, Poulsen MR, Bendixen DK, et al. Incidence of
sinusitis in patients with nasotracheal intubation. Br J Anaesth 1988; 61:231–232
152 Zinreich SJ. Paranasal sinus imaging. Otolaryngol Head
Neck Surg 1990; 103:863– 869
153 Holzapfel L, Chevret S, Madinier G, et al. Influence of
long-term oro- or nasotracheal intubation on nosocomial
maxillary sinusitis and pneumonia: results of a prospective,
randomized, clinical trial. Crit Care Med 1993; 21:1132–
1138
154 Darouiche R, Raad I, Heard SO, et al. A comparison of two
antimicrobial-impregnated central venous catheters. N Engl
J Med 1999; 340:1– 8
155 Maki DG. Pathogenesis, prevention, and management of
infections due to intravascular devices used for infusion
therapy. In: Bisno A, Waldvogel F, eds. Infections associated
with indwelling medical devices. Washington, DC: American Society for Microbiology, 1989; 161–177
156 Mimoz O, Pieroni L, Lawrence C, et al. Prospective,
randomized trial of two antiseptic solutions for prevention of
central venous or arterial catheter colonization and infection
in intensive care unit patients. Crit Care Med 1996; 24:
1818 –1823
157 Tacconelli E, Tumbarello M, Pittiruti M, et al. Central
venous catheter-related sepsis in a cohort of 366 hospitalized
patients. Eur J Clin Microbiol Infect Dis 1997; 16:203–209
158 Wenzel RP, Edmond MB. The evolving technology of
venous access. N Engl J Med 1991; 340:48 – 49
159 Maki DG, Brand JD. A comparative study of polyantibiotic
and iodophor ointments in prevention of vascular catheterrelated infection. Am J Med 1981; 70:739 –744
160 Timsit JF, Sebille V, Farkas JC, et al. Effect of subcutaneous
tunneling on internal jugular catheter-related sepsis in critically ill patients: a prospective randomized multicenter
study. JAMA 1996; 276:1416 –1420
161 Flowers RI, Schwenzer J, Kopel RF. Efficacy of an attachable subcutaneous cuff for the prevention of intravascular
catheter-related infection: a randomized controlled trial.
JAMA 1989; 261:878 – 883
162 Hasaniya NWMA, Angelis M, Brown MR, et al. Efficacy of
subcutaneous silver-impregnated cuffs in preventing central
venous catheter infections. Chest 1996; 109:1030 –1032
163 Raad I, Darouiche R. Prevention of infections associated
with intravascular devices. Curr Opin Crit Care 1996;
2:361–365
164 Raad I, Darouiche RO, Hachem R, et al. Antimicrobial
durability and rare ultrastructural colonization of indwelling
central catheters coated with minocycline and rifampin. Crit
Care Med 1998; 26:219 –224
165 Raad I, Darouiche R, Dupuis J, et al. Central venous
catheters coated with minocycline and rifampin for the
prevention of catheter-related colonization and blood
stream infections: a randomized, double-blind trial. Ann
Intern Med 1997; 127:267–274
166 Maki DG, Stolz SM, Wheeler S, et al. Prevention of central
venous catheter-related bloodstream infection by use of an
antiseptic-impregnated catheter: a randomized, controlled
trial. Ann Intern Med 1997; 127:257–266
167 Civatta JM, Hudson-Civatta J, Ball S. Decreasing catheterrelated infection and hospital costs by continuous quality
improvement. Crit Care Med 1996; 24:1660 –1665
168 Sherertz RJ, Hard SO, Raad II, et al. Gamma radiationsterilized, triple-lumen catheters coated with a low concentration of chlorhexidine were not efficacious at preventing
catheter infections in intensive care unit patients. Antimicrob Agents Chemother 1996; 40:1995–1997
868
169 Pemberton LB, Ross V, Cuddy P, et al. No difference in
catheter sepsis between standard and antiseptic central
venous catheters: a prospective randomized trial. Arch Surg
1996; 131:986 –989
170 Ciresi DL, Albrecht RM, Volkers PA, et al. Failure of
antiseptic bonding to prevent central venous catheter-related infection and sepsis. Am Surg 1996; 62:641– 646
171 Williams JF, Seneff MG, Friedman BC, et al. Use of femoral
venous catheters in critically ill adults: prospective study.
Crit Care Med 1991; 19:550 –553
172 Cook D, Randolph A, Kernerman P, et al. Central venous
catheter replacement strategies: a systemic review of the
literature. Crit Care Med 1997; 25:1417–1424
173 Cobb DK, High KP, Sawyer WT, et al. A controlled trial of
scheduled replacement of central venous and pulmonary
artery catheters. N Engl J Med 1992; 327:1062–1068
174 Maki DG, Weise CE, Sarafin HW. A semiquantitative
culture method for identifying intravenous-catheter related
infection. N Engl J Med 1977; 296:1305–1309
175 Raad I, Sabbagh MF, Rand KH, et al. Quantitative tip
culture methods and the diagnosis of central venous catheter-related infections. Diagn Microbiol Infect Dis 1991;
15:13–20
176 Sherertz RJ, Raad I, Belani A, et al. Three-year experience
with sonicated vascular catheter cultures in a clinical microbiology laboratory. J Clin Microbiol 1990; 28:76 – 82
177 Platt R, Polk BF, Murdock B, et al. Mortality associated with
nosocomial urinary tract infection. N Engl J Med 1982;
307:637– 642
178 Daifuku R, Stamm W. Association of rectal and urethral
colonization with urinary tract infection in patients with
indwelling catheters. JAMA 1984; 252:2028 –2030
179 Stark RP, Maki DG. Bacteriuria in the catheterized patient:
what quantitative level of bacteriuria is relevant? N Engl
J Med 1984; 311:560 –564
180 Brown DF, Warren RE. effect of sample volume on yield of
positive blood cultures from adult patients with hematological malignancy. J Clin Pathol 1990; 43:777–779
181 Paradisi F, Corti G, Mangani V. Urosepsis in the critical care
unit. Crit Care Clin 1998; 114:165–180
182 Warren JW. Catheter-associated urinary tract infections.
Infect Dis Clin North Am 1997; 11:609 – 619
183 Krieger JN, Kaiser DL, Wenzel RP. Urinary tract etiology of
bloodstream infections in hospitalized patients. J Infect Dis
1983; 148:57– 62
184 Garibaldi RA, Mooney BR, Epstein BJ, et al. An evaluation
of daily bacteriologic monitoring to identify preventable
episodes of catheter-associated urinary tract infection. Infect
Control 1982; 3:466 – 470
185 Wilcox MH, Smyth ET. Incidence and impact of Clostridium difficile infection in the UK, 1993–1996. J Hosp Infect
1998; 39:181–187
186 Brazier JS. The epidemiology and typing of Clostridium
difficile. J Antimicrob Chemother 1998; 41(Suppl C):47–57
187 Lai KK, Melvin ZS, Menard MJ, et al. Clostridium difficileassociated diarrhea: epidemiology, risk factors, and infection
control. Infect Control Hosp Epidemiol 1997; 18:628 – 632
188 Adams HP, Brott TG, Crowell RM, et al. Guidelines for the
management of patients with acute ischemic stroke: a
statement for the healthcare professionals from a special
writing group of the stroke council, American Heart Association. Circulation 1994; 90:1588 –1601
189 Borriello SP. Pathogenesis of Clostridium difficile infection.
J Antimicrob Chemother 1998; 41(Suppl C):13–19
190 Manabe YC, Vinetz JM, Moore RD, et al. Clostridium
difficile colitis: an efficient clinical approach to diagnosis.
Ann Intern Med 1995; 123:835– 840
Reviews
191 Brazier JS. The diagnosis of Clostridium difficile-associated
disease. J Antimicrob Chemother 1998; 41(Suppl C):29 – 40
192 Kelly CP, Pouthoulakis C, LaMont JT Clostridia Difficile
Colitis. N Engl J Med 1994; 330:257–262
193 Beck-Sague C, Jarvis WR. Secular trends in the epidemiology of nosocomial fungal infections in the United States,
1980 –1990. National Nosocomial Infections Surveillance
System. J Infect Dis 1993; 167:1247–1251
194 Rello J, Esandi ME, Diaz E, et al. The role of Candida sp
isolated from bronchoscopic samples in nonneutropenic
patients. Chest 1998; 114:146 –149
195 el Ebiary M, Torres A, Fabregas N, et al. Significance of the
isolation of Candida species from respiratory samples in
critically ill, non-neutropenic patients: an immediate postmortem histologic study. Am J Respir Crit Care Med 1997;
156(2 Pt 1):583–590
196 Adelson-Mitty J, Fink MP, Lisbon A. The value of lumbar
puncture in the evaluation of critically ill, non-immunosuppressed, surgical patients: a retrospective analysis of 70
cases. Intensive Care Med 1997; 23:749 –752
197 Metersky ML, Williams A, Rafanan AL. Retrospective analysis: are fever and mental status indications for lumbar
puncture in a hospitalized patient who has not undergone
neurosurgery. Clin Infect Dis 1997; 25:285–288
198 Dotson RG, Pingleton SK. The effect of antibiotic therapy
on recovery of intracellular bacteria from bronchoalveolar
lavage in suspected ventilator- associated nosocomial pneumonia. Chest 1993; 103:541–546
199 Souweine B, Veber B, Bedos JP, et al. Diagnostic accuracy
of protected specimen brush and bronchoalveolar lavage in
nosocomial pneumonia: impact of previous antimicrobial
treatments. Crit Care Med 1998; 26:236 –244
200 Crowe M, Ispahani P, Humphreys H, et al. Bacteraemia in
the adult intensive care unit of a teaching hospital in
Nottingham, UK, 1985–1996. Eur J Clin Microbiol Infect
Dis 1998; 17:377–384
201 Valles J, Leon C, Alvarez-Lerma F. Nosocomial bacteremia
in critically ill patients: a multicenter study evaluating
epidemiology and prognosis. Spanish Collaborative Group
for Infections in Intensive Care Units of Sociedad Espanola
de Medicina Intensiva y Unidades Coronarias (SEMIUC).
Clin Infect Dis 1997; 24:387–395
202 Brun-Buisson C, Doyon F, Carlet J. Bacteremia and severe
sepsis in adults: a multicenter prospective survey in ICUs
and wards of 24 hospitals. French Bacteremia-Sepsis Study
Group. Am J Respir Crit Care Med 1996; 154(3 Pt 1):617–
624
203 Brun-Buisson C, Doyon F, Carlet J, et al. Incidence, risk
factors, and outcome of severe sepsis and septic shock in
adults: a multicenter prospective study in intensive care
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
units. French ICU Group for Severe Sepsis. JAMA 1995;
274:968 –974
Levin PD, Hersch M, Rudensky B, et al. Routine surveillance blood cultures: their place in the management of
critically ill patients. J Infect 1997; 35:125–128
Bennett IL, Beeson RB. Bacteremia: a consideration of
some experimental and clinical aspects. Yale J Biol Med
1954; 262:241–262
Chandrasekar PH, Brown WJ. Clinical issues of blood
cultures. Arch Intern Med 1994; 154:841– 849
Wormser GP, Onorato IM, Preminger TJ, et al. Sensitivity
and specificity of blood cultures obtained through intravascular catheters. Crit Care Med 1990; 18:152–156
Ilstrup DM, Washington JA. The importance of volume of
blood culture in the detection of bacteremia and fungemia.
Diagn Microbiol Infect Dis 1983; 1:107–110
Mermel LA, Maki DG. Detection of bacteremia in adults:
consequences of culturing an inadequate volume of blood.
Ann Intern Med 1993; 119:270 –272
Levin PD, Yinnon AM, Hersch M, et al. Impact of the resin
blood culture medium on the treatment of critically ill
patients. Crit Care Med 1996; 24:797– 801
Davis LP, Fink-Bennett D. Nuclear medicine in the acutely
ill patient: II. Crit Care Clin 1994; 10:383– 400
Meduri GU, Belenchia JM, Massie JD, et al. The role of
gallium-67 scintigraphy in diagnosing sources of fever in
ventilated patients. Intensive Care Med 1996; 22:395– 403
Berrouschot J, Sterker M, Bettin S, et al. Mortality of
space-occupying (’malignant’) middle cerebral artery infarction under conservative intensive care. Intensive Care Med
1998; 24:620 – 623
Clifton GL, Allen S, Barrodale P, et al. A phase II study of
moderate hypothermia in severe brain injury. J Neurotrauma 1993; 10:263–271
Marion DW, Obrist WD, Carlier PM, et al. The use of
moderate therapeutic hypothermia for patients with severe
head injuries: a preliminary report. J Neurosurg 1993;
79:354 –362
Marion DW, Penrod LE, Kelsey SF, et al. Treatment of
traumatic brain injury with moderate hypothermia. N Engl
J Med 1997; 336:540 –546
Mackowiak PA. Fever: blessing or curse? A unifying hypothesis. Ann Intern Med 1994; 120:1037–1040
O’Donnel J, Axelrod P, Fisher C, et al. Use of and effectiveness of hypothermia blankets for febrile patients in the
intensive care unit. Clin Infect Dis 1997; 24:1208 –1213
Lenhardt R, Negishi C, Sessler DI, et al. The effects of
physical treatment on induced fever in humans. Am J Med
1999; 106:550 –555
CHEST / 117 / 3 / MARCH, 2000
869