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: [email protected]
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
Reviews
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
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