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 ⫽ enzyme-
linked immunosorbent assay; IL ⫽ interleukin; TNF ⫽ tumor necrosis factor; UTI ⫽ urinary tract infection;
VAP ⫽ ventilator-associated pneumonia

F ever is a common problem in ICU patients. The

presence of fever frequently results in the per-
primarily involved in the development of fever in-
clude interleukin (IL) 1, IL-6, and tumor necrosis
formance of diagnostic tests and procedures that factor (TNF)-␣.2–13 The interaction between these
significantly increase medical costs and expose the cytokines is complex, with each being able to up-
patient to unnecessary invasive diagnostic proce- regulate and down-regulate their own expression as
dures and the inappropriate use of antibiotics. The well as that of the other cytokines. These cytokines
main diagnostic dilemma is to exclude noninfectious bind to their own specific receptors located in close
causes of fever and then to determine the site and proximity to the preoptic region of the anterior
hypothalamus.2,3 Here, the cytokine receptor inter-
For editorial comment see page 627 action activates phospholipase A2, resulting in the
liberation of plasma membrane arachidonic acid as
likely pathogens of those with infections. ICU pa- substrate for the cyclo-oxygenase pathway. Some
tients frequently have multiple infectious and non- cytokines appear to increase cyclo-oxygenase expres-
infectious causes of fever,1 necessitating a systematic sion directly, leading to liberation of prostaglandin
and comprehensive diagnostic approach. This article E2. This small lipid mediator diffuses across the
reviews the common infectious and noninfectious blood brain barrier, where it acts to decrease the rate
causes of fever in ICU patients and outlines a of firing of preoptic warm-sensitive neurons, leading
rational approach to the management of these pa- to activation of responses designed to decrease heat
tients. loss and increase heat production.2,14 In a small
proportion of hospitalized patients, hyperthermia
may result from increased sympathetic activity with
Pathogenesis of Fever increased heat production.

Cytokines released by monocytic cells play a cen-

tral role in the genesis of fever. The cytokines Significance of Fever
Fever appears to be a preserved evolutionary
*From the Department of Internal Medicine, Section of Critical
Care, Washington Hospital Center, Washington, DC. response within the animal kingdom.15–20 With few
Manuscript received May 11, 1999; revision accepted October exceptions, reptiles, amphibians, and fish, as well as
25, 1999. several invertebrate species, have been shown to
Correspondence to: Paul E. Marik, MD, Department of Internal
Medicine, Washington Hospital Center, 110 Irving St NW, manifest fever in response to challenge with micro-
Washington, DC 20010-2975; e-mail: pem4@mhg.edu organism.15–19 Increased body temperature has been

CHEST / 117 / 3 / MARCH, 2000 855

shown to enhance the resistance of animals to infec- nary artery is considered the optimal site for core
tion.21,22 Although fever has some harmful effects, temperature measurement; however, this method
fever appears to be an adaptive response that has requires placement of a pulmonary artery cathe-
evolved to help rid the host of invading pathogens. ter.40 – 42 Infrared ear thermometry has been demon-
Temperature elevation has been shown to enhance strated to provide values that are a few tenths of a
several parameters of immune function, including degree below temperatures in the pulmonary artery
antibody production, T-cell activation, production of and brain.43– 46 Rectal temperatures obtained with a
cytokines, and enhanced neutrophil and macrophage mercury thermometer or electronic probe are often
function.23–26 Furthermore, some pathogens such as a few tenths of a degree higher than core tempera-
Streptococcus pneumoniae are inhibited by febrile ture.40 – 42 Rectal temperatures are perceived by pa-
temperatures.27 tients as unpleasant and intrusive. Furthermore,
It has long been known that increasing body access to the rectum may be limited by patient
temperature is associated with improved outcome position, with an associated risk of rectal trauma.
from infectious diseases. The preantibiotic era pro- Oral measurements are influenced by events such as
vides abundant, although uncontrolled data, on the eating and drinking and the presence of respiratory
deliberate use of elevated body temperature to treat devices delivering warmed gases.43 Axillary measure-
infections. The beneficial effects of hot baths and ments substantially underestimate core temperature
malarial fevers in syphilis were noted as early as the and lack reproducibility.43 Body temperature is
15th century.28 In mammalian models, increasing therefore most accurately measured by an intravas-
body temperature results in enhanced resistance to cular thermistor, but measurement by infrared ear
infection.29 –32 In a retrospective analysis of 218 thermometry or with an electronic probe in the
patients with Gram-negative bacteremia, Bryant and rectum is an acceptable alternative.47 Normal body
colleagues33 reported a positive correlation between temperature is generally considered to be 37.0°C
maximum temperature on the day of bacteremia and (98.6°F) with a circadian variation of between 0.5 to
survival. Similarly, Weinstein and colleagues34 re- 1.0°C.2,14 The definition of fever is arbitrary and
ported that a temperature ⬎ 38°C increased survival depends on the purpose for which it is defined. The
in patients with spontaneous bacterial peritonitis. Society of Critical Care Medicine practice parame-
Dorn and colleagues35 reported that children with ters define fever in the ICU as a temperature
chickenpox who were treated with acetaminophen ⬎ 38.3°C (ⱖ 101°F).47 Unless the patient has other
had a longer time to crusting of lesions than when features of an infectious process, only a temperature
treated with placebo. ⬎ 38.3°C (ⱖ 101°F) warrants further investigation.
An elevated body temperature may, however, also
be associated with a number of deleterious effects, Fever Patterns
most notably an increase in cardiac output, oxygen
consumption, carbon dioxide production, and energy Attempts to derive reliable and consistent clues
expenditure.36 Oxygen consumption increases by from evaluation of a patient’s fever pattern is fraught
approximately 10% per degree Celsius.36 These with uncertainly and not likely to be helpful diagnos-
changes may be poorly tolerated in patients with tically.2,14,48 Most patients have remittent or inter-
limited cardiorespiratory reserve. In patients who mittent fever that, when due to infection, usually
have suffered a cerebrovascular accident or trau- follow a diurnal variation.48 Sustained fevers have
matic head injury, moderate elevations of brain been reported in patients with Gram-negative pneu-
temperature may markedly worsen the resulting monia or CNS damage.48 The appearance of fever at
injury.37 Maternal fever has been suggested to be a different time points in the course of a patient’s
cause of fetal malformations or spontaneous abor- illness may however provide some diagnostic clues.
tions.38,39 However, this association has not been Fevers that arise ⬎ 48 h after institution of mechan-
rigorously tested. ical ventilation may be secondary to a developing
pneumonia.49,50 Fevers that arise 5 to 7 days postop-
eratively may be related to abscess formation.51
Definitions and Measurement of Fever Fevers that arise 10 to 14 days postinstitution anti-
biotics for intra-abdominal abscess may be due to
Accurate and reproducible measurement of body fungal infections.52–54
temperature is important in detecting disease and in
monitoring patients with an elevated temperature. A Causes of Fever in the ICU
variety of methods are used to measure body tem-
perature, combining different sites, instruments, and As outlined above, any disease process that results
techniques. The mixed venous blood in the pulmo- in the release of the proinflammatory cytokines IL-1,

856 Reviews
IL-6, and TNF-␣ will result in the development of be considered in ICU patients are listed in Table
fever. While infections are the commonest cause of 1.1,55,66 – 68 For reasons that are not entirely clear,
fever in ICU patients, many noninfectious inflamma- most noninfectious disorders usually do not lead to a
tory conditions cause the release of the proinflam- fever ⬎ 38.9°C (102°F); therefore, if the tempera-
matory cytokines with a febrile response.55– 61 Simi- ture increases above this threshold, the patient
larly, it is important to appreciate that not all patients should be considered to have an infectious etiology
with infections are febrile. Approximately 10% of as the cause of the fever.67 However, patients with
septic patients are hypothermic and 35% are normo- drug fever may have a temperature ⬎ 102°F.69 –71
thermic at presentation. Septic patients who fail to Similarly, fever secondary to blood transfusion may
develop a temperature have a significantly higher be ⬎ 102°F.72,73
mortality than febrile septic patients.62– 64 The reason Most of those clinical conditions listed in Table 1
that patients with established infections fail to de- are clinically obvious and do not require additional
velop a febrile response is unclear; however, prelim- diagnostic tests to confirm their presence. However,
inary evidence suggests that this aberrant response is a few of these disorders require special consider-
not due to diminished cytokine production.65 ation. Although drug-induced fever is commonly
The presence of fever in an ICU patient fre- cited as a cause of fever,74 ⬍ 300 cases of this
quently triggers a battery of diagnostic tests that are condition have been reported in the literature.70
costly, expose the patient to unnecessary risks, and Furthermore, only a single case of drug fever has
often produce misleading or inconclusive results. It been reported in an ICU patient population.1 How-
is therefore important that fever in ICU patient be ever, on the basis of the number of medications
evaluated in a systematic, prudent, clinically appro- administered to patients in the ICU, one would
priate, and cost-effective manner. expect drug fever to be a relatively common event.
Although the true incidence of this disorder is
unknown, drug fever should be considered in pa-
Noninfectious Causes of Fever in the ICU tients with an otherwise unexplained fever, particu-
larly if they are receiving ␤-lactam antibiotics, pro-
A large number of noninfectious disorders result cainamide, or diphenylhydantoin.70 Drug fever is
in tissue injury with inflammation and a febrile usually characterized by high spiking temperatures
reaction. Those noninfectious disorders that should and shaking chills.70 It may be associated with a with
leukocytosis and eosinophilia. Relative bradycardia,
although commonly cited, is uncommon.67,70,74
Table 1—Noninfectious Causes of Fever in the ICU Atelectasis is commonly implicated as a cause of
Noninfectious Causes
fever. Standard ICU texts list atelectasis as a cause of
fever, although they provide no primary source.51,75
Alcohol/drug withdrawal Indeed a major surgery text states that “fever is
Postoperative fever (48 h postoperative)
Posttransfusion fever
almost always present [in patients with atelecta-
Drug fever sis].”51 However, Engeron76 studied 100 postopera-
Cerebral infarction/hemorrhage tive cardiac surgery patients and was unable to
Adrenal insufficiency demonstrate a relationship between atelectasis and
Myocardial infarction fever. Furthermore, when atelectasis is induced in
Pancreatitis
Acalculous cholecystitis
experimental animals by ligation of a mainstem
Ischemic bowel bronchus, fever does not occur.77,78 However, Kisala
Aspiration pneumonitis and coworkers79 demonstrated that IL-1 and TNF-␣
ARDS (both acute and late fibroproliferative phase) levels of macrophage cultures from atelectatic lungs
Subarachnoid hemorrhage were significantly increased compared with the con-
Fat emboli
Transplant rejection
trol lungs. The role of atelectasis as a cause of fever
Deep venous thrombosis is unclear; however, atelectasis probably does not
Pulmonary emboli cause fever in the absence of pulmonary infection.
Gout/pseudogout Febrile reactions complicate about 0.5% of blood
Hematoma transfusions, but may be more common following
Cirrhosis (without primary peritonitis)
GI bleed
platelet transfusion.72,80,81 Antibodies against mem-
Phlebitis/thrombophlebitis brane antigens of transfused leukocytes and/or plate-
Adrenal insufficiency lets are responsible for most febrile reactions to
IV contrast reaction cellular blood components.72 Febrile reactions usu-
Neoplastic fevers ally begin within 30 min to 2 h after a blood-product
Decubitus ulcers
transfusion is begun. The fever generally lasts be-

CHEST / 117 / 3 / MARCH, 2000 857

tween 2 h and 24 h and may be preceded by chills.73 feature on ultrasound examination, with a specificity
An acute leucocytosis lasting up to 12 h commonly of 90% and a sensitivity of 100%.93,94 In ICU
occurs following a blood transfusion.82 patients, hepatobiliary scintigraphy has a high false-
Patients with the ARDS may progress to a “chron- positive rate (⬎ 50%), limiting the value of this
ic” stage characterized by pulmonary fibroprolifera- test.95 However, a normal scan virtually excluded
tion and fevers. Meduri and coworkers1,83 have acalculous cholecystitis. CT scanning has been re-
demonstrated that fever and leukocytosis may result ported to have a high sensitivity and specificity;
from the inflammatory-fibrotic process present in however, no prospective studies have been per-
the airspace of patients with late ARDS in the formed comparing ultrasonography with CT scan-
absence of pulmonary infection. Corticosteroids ap- ning in the diagnosis of acalculous cholecystitis.96
pear to be associated with an improvement in lung The management of acalculous cholecystitis is
injury and reduced mortality.83,84 Some authors rec- somewhat controversial.85,89,97 However, with the
ommend an open lung biopsy prior to commencing development of more advanced radiologic imaging
corticosteroid therapy, in order to obtain histologic techniques, percutaneous cholecystostomy may be
evidence of the fibroproliferative phase of ARDS the procedure of choice. Kiviniemi and coworker98
and to exclude infection. demonstrated diminution of pain in 94% of patients,
Acalculous cholecystis occurs in approximately with normalization of fever in 90% and leukocyte
1.5% of critically ill patients.85,86 While relatively count in 84% of patients treated by percutaneous
uncommon, acalculous cholecystitis is an important cholecystostomy. The procedure is associated with
“noninfectious” cause of fever in critically ill patients, few complications and is the definitive therapy in
as it is frequently unrecognized and therefore poten- most patients.99 Open cholecystectomy is, however,
tially life threatening.85,86 The pathophysiology of recommended should the abdominal signs, fever,
acalculous cholecystitis is related to the complex and leucocytosis not improve within 48 h of percu-
interplay of a number of pathogenetic mechanisms, taneous cholecystostomy.85,89,97
including gallbladder ischemia, bile stasis with inpis- While fever may occur in patients with deep
sation in the absence of stimuli for emptying of the venous thrombosis, in patients suspected of deep
gallbladder, positive-end expiratory pressure, and venous thrombosis, the predictive value of fever is
parenteral nutrition.87–92 Bacterial invasion of the poor.100 Furthermore, in critically ill ICU patients,
gallbladder appears to be a secondary phenome- fever without other features of ileofemoral thrombo-
non.89 sis is uncommon and does not warrant routine
The diagnosis of acalculous cholecystitis is often venography as part of the initial diagnostic workup of
exceedingly difficult and requires a high index of pyrexia in ICU patients.1,101
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 ab- Infectious Causes of Fever
sent.85,86,89 Nausea, vomiting, and fever are other
associated clinical features. The clinical findings and The prevalence of nosocomial infection in ICUs
laboratory workup in patients with acalculous chole- has been reported to vary from 3 to 31%.102–108 Data
cystitis are, however, often nonspecific. The most from the National Nosocomial Infection Surveillance
difficult patients are those recovering from abdomi- system database from 1986 to 1990 documented
nal sepsis who deteriorate again, misleadingly sug- nosocomial infection in 10% of the 164,034 patients,
gesting a flare-up of the original infection. Rapid with a strong correlation between ICU length of stay
diagnosis is essential because ischemia may progress and the development of infection.103 In a point
rapidly to gangrene and perforation, with attendant prevalence study conducted in 1992, The EPIC
increase in the already high morbidity and mortali- Study Investigators104 reported on the prevalence of
ty.89 The diagnosis should therefore be considered in nosocomial infections in 10,038 patients hospitalized
every critically ill patient who has clinical findings of in 1,417 European ICUs. In this study, 20.6% of
sepsis with no obvious source. patients had an ICU-acquired infection, with pneu-
Radiologic investigations are required for a pre- monia being the most common (46.9%), followed by
sumptive diagnosis of acalculous cholecystitis. Ultra- urinary tract infection (17.6%) and blood stream
sound is the most common radiologic investigation infection (12%). This data must, however, be inter-
used in the diagnosis of acalculous cholecystitis; preted with some caution. The presence and type of
features include increased wall thickness, intramural infection in these studies was documented according
lucencies, gallbladder distension, pericholecystic to the “standard definitions” of the Centers for
fluid, and intramural sludge.93,94 Wall thickness ⱖ 3 Disease Control and Prevention (CDC).109,110 The
mm is reported to be the most important diagnostic definitions of nosocomial infection published by the

858 Reviews
CDC may, however, not be applicable to ICU The optimal technique(s) for diagnosis of VAP re-
patients.109,110 For example, according to the most mains unclear as a uniformly agreed on “gold stan-
recent definitions published in 1988, the presence of dard,” for the diagnosis is lacking.111,118,124,133–135
rales and purulent sputum or the presence of new The impact that diagnostic tests for VAP have on
chest radiographic findings and change in sputum patient outcome is controversial. Using a decision
character were used to diagnose pneumonia.110 In analysis method, Sterling and coauthors136 demon-
patients receiving mechanical ventilation, less than a strated that invasive or semi-invasive microbiological
third of patients with these features would be con- diagnostic techniques improved the outcome of pa-
sidered to have pneumonia using invasive diagnostic tients with suspected VAP. However, Luna and
methods.111–114 Similarly, fever and a urine culture colleagues137 and Rello and coworkers138 have dem-
of ⱖ 105 colony-forming units (CFU)/mL was con- onstrated that the most important factor affecting
sidered diagnostic of urinary tract infection. As is outcome in patients with VAP is the early initiation
discussed below, the presence of these two finding in of appropriate antibiotic therapy. In the study by
catheterized critically ill ICU patients does not rep- Luna et al,137 the mortality of patients who were
resent infection of the urinary tract. changed from inadequate antibiotic therapy to ap-
The most common infections reported in ICU pa- propriate therapy based on the results of the BAL
tients are pneumonia, followed by sinusitis, blood was comparable to the mortality of those patients
stream infection, and catheter-related infection.1,102–108 who continued to receive inadequate therapy. Kollef
Table 2 lists the most important sites of infection in and Ward,139using noninvasive mini-BAL to diag-
ICU patients. As is discussed below, urinary tract nose VAP, confirmed these findings. It should how-
infection is probably unimportant in most ICU pa- ever be noted that patients who have clinical features
tients. of VAP and in whom VAP is “excluded” based on
quantitative culture of lower respiratory tract secre-
tions and in whom antibiotics are stopped have a
Ventilator-Associated Pneumonia significantly lower mortality than those patient who
are culture positive.121,139 Invasive or noninvasive
Ventilator-associated pneumonia (VAP) occurs in sampling of lower respiratory tract sections with
approximately 25% of patients undergoing mechan- quantitative culture therefore allows for the safe
ical ventilation.49,115–118 The impact of VAP on pa- discontinuation of antibiotics in the “culture nega-
tient outcome has been much debated117,119,120; tive” patients.123,125,140 –145 Furthermore, as the ini-
however, Fagon and colleagues121 reported an attrib- tial empiric antibiotic regimen must be broad and
utable mortality of 27%. The optimal management of cover both Gram-positive and negative organisms,
patients with suspected VAP requires confirmation these techniques allow for narrowing of the spec-
of the diagnosis and identification of the responsible trum once a pathogen has been isolated in those
pathogen(s) in order to provide appropriate antimi- patients with confirmed pneumonia. This approach
crobial therapy. The diagnosis of VAP remains one of to suspected VAP will result in significant cost savings
the most difficult clinical dilemmas in critically ill and reduce the selection of resistant organisms.113
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 Sinusitis
been reported to aid in the diagnosis of VAP. The Because paranasal sinusitis is usually clinically
number of methods currently available attest to the silent in intubated patients, it is not widely appreci-
fact that no single method is ideal.49,112,120,123–132 ated that nosocomial sinusitis is an important source
of infection and fever in critically ill patients. Fur-
thermore, many ear, nose, and throat surgeons are of
Table 2—Common Infectious Causes of Fever in the the belief that paranasal sinusitis in intubated pa-
ICU tients receiving mechanical ventilation does not
Infectious Causes cause fever or systemic signs of infection. Nosoco-
mial sinusitis is particularly common following nasal
VAP
Sinusitis
intubation, with an incidence of up to 85% after a
Catheter-related sepsis week of intubation.146 –151 The incidence of nosoco-
Primary Gram-negative septicemia mial sinusitis appears to be lower in patients in
C difficile diarrhea whom both the endotracheal and gastric tubes are
Abdominal sepsis placed orally.146 –151 The diagnosis of sinusitis re-
Complicated wound infections
quires a CT scan and cannot be accurately assessed

CHEST / 117 / 3 / MARCH, 2000 859

using standard radiography or echography.152 Sinus- silver-impregnated subcutaneous cuffs.156,159 –162
itis is diagnosed by total opacification or the presence These studies have generally shown poor or incon-
of an air fluid level within any of the paranasal sistent results. It has been suggested that antimicro-
sinuses. The maxillary sinus is most commonly in- bial bonding of central venous catheters may be the
volved; however, most patients with radiologic max- most effective method of reducing the rate of cath-
illary sinusitis have abnormalities of the ethmoid and eter colonization and catheter-related sepsis.163,164
sphenoid sinuses.148 Since radiologic abnormalities Several types of antiseptic or antimicrobial coatings
of the paranasal sinuses do not necessarily imply have been developed, including catheters coated
infection, diagnosis of infectious maxillary sinusitis with chlorhexidine gluconate and silver sulfadiazine,
requires transnasal puncture following appropriate as well as with minocycline and rifampin. While a
disinfection of the nares.146,148,150,153 When the eth- number of studies have demonstrated the incidence
moid or sphenoid sinuses only are involved, bacteri- of catheter-related sepsis to be lower with chlorhexi-
ologic specimens can be obtained by an open eth- dine/sulfadiazine-coated catheters,165–167 not all
moidectomy/sphenoidotomy.146 Sinus infection is studies have duplicated these findings.168 –170 Fur-
diagnosed by the presence of pus associated with thermore, Darouiche and colleagues154 have demon-
high quantitative cultures of implicated pathogens. strated that central venous catheters impregnated
Rouby and colleagues148 reported that only 38% of with minocycline and rifampin are associated with a
patients with radiologic maxillary sinusitis had true significantly lower rate of catheter colonization and
infectious sinusitis. In the series reported by Rouby blood stream infection than catheters coated with
et al,148 there was normalization of the core temper- chlorhexidine and silver sulfadiazine.
ature and WBC count following removal of all nasal Central venous catheterization via the femoral and
tubes, followed by transnasal puncture and drainage internal jugular veins are reported to have a similar
in the patients with infectious maxillary sinusitis. infection rates, which are higher than that for cath-
These authors did not use IV antibiotics. Similarly, in eters inserted via the subclavian approach.154,163,165,171
the series reported by Grindlinger and colleagues146 Replacement of a colonized catheter over a guide-
and by Deutschman and coworkers,147 resolution of wire is associated with rapid recolonization of the
sinusitis was associated with normalization of the replacement catheter.172 If catheter sepsis is sus-
temperature and WBC count. Paranasal sinusitis is pected, the catheter should be changed to a new site,
best treated by removal of all nasal tubes together with culture (quantitative or semiquantitative) of the
with drainage of the maxillary sinuses. Broad-spec- catheter tip.154,172–176 In patients with limited venous
trum antibiotics are generally recommended.146,147 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
Catheter-Associated Sepsis the catheter tip should be performed and the cath-
eter removed if the cultures are positive.
Catheter-associated sepsis is defined as blood
stream infection due to an organism that has colo-
nized a vascular catheter. Approximately 5% of Urinary Tract Infection
patients with indwelling vascular catheters (uncoat-
ed) will develop blood stream infection (⬇ 10 infec- Urinary tract infections (UTIs) have been reported
tions/1,000 catheter days).154 –158 The incidence of to be common in ICU patients, where they are
catheter-associated sepsis increases with the length reported to account for between 25 to 50% of all
of time the catheter is in situ, the number of ports, infections.102–108 However, it is likely that most of
and increases with the number of manipulations. these patients had “asymptomatic bacteriuria” rather
Approximately 25% of central venous catheters be- than true infections of the urinary tract. The use of
come colonized (⬎ 15 CFU), and approximately 20 antibiotics in patients with asymptomatic bacteriuria
to 30% of colonized catheters will result in catheter is based on a single study performed in the early
sepsis.154 –158 Staphylocuccus aureus and coagulase- 1980s that may not be applicable today.177 Platt and
negative staphylococci are the most common infect- colleagues177 demonstrated that in hospitalized pa-
ing (and colonizing) organisms, followed by entero- tients bacteriuria with ⱖ 105 CFUs of bacteria per
cocci, Gram-negative bacteria, and Candida milliliter of urine during bladder catheterization was
species.154 –158 associated with a 2.8-fold increase in mortality.
A number of methods of reducing catheter colo- Based on this study, thousands of ICU patients with
nization and blood stream infection have been stud- urinary tract colonization have been treated with
ied, including topical antibiotics, antimicrobial flush antibiotics.
solutions, subcutaneous tunneling of catheters, and Most ICU patients require an indwelling urinary

860 Reviews
catheter for monitoring fluid balance and renal nous colitis is the most dramatic manifestation of C
function. The patients’ colonic flora rapidly colonizes difficile infection; these patients have marked ab-
the urinary tract in these patients.178 Stark and dominal and systemic signs and symptoms and may
Maki179 have demonstrated that in catheterized pa- develop a fulminant and life-threatening colitis.
tients, bacteria in the urinary system rapidly prolif- Stool assay for toxins A or B are the main clinical
erate to exceed 105 CFU/mL over a short period of tests used to diagnose C difficile infection.190 –192 The
time. Bacteriuria, defined as a quantitative culture of “gold standard” test is the tissue culture cytotoxicity
ⱖ 105 CFU/mL, has been reported in up to 30% assay. This test has a high sensitivity (94 to 100%)
of catheterized hospitalized patients.180 The terms and specificity (99%). The major disadvantages of
“bacteriuria” and “UTI” are generally although in- this test are its high expense and the time needed to
correctly used as synonyms. Indeed, most studies in complete the assay (2 to 3 days). For these reasons,
ICU patients have used bacteriuria to diagnose a
this test is no longer routinely performed. Toxin
UTI. Bacteriuria implies colonization of the urinary
enzyme-linked immunosorbent assay (ELISA) tests
tract without bacterial invasion and an acute inflam-
are less sensitive (70 to 90%) than the cytotoxicity
matory response.181 UTI implies an infection of the
urinary tract.181 Criteria have not been developed for test, but demonstrate excellent specificity (99%) and
differentiating asymptomatic colonization of the uri- can be rapidly processed, and have largely replaced
nary tract from symptomatic infection. Furthermore, the cytotoxicity assay.190 –192 It is suggested that two
the presence of white cells in the urine is not useful stool specimens be examined for leukocytes and
for differentiating colonization from infection, as toxin ELISA test.190 Should the ELISA be negative
most catheter-associated bacteriurias have accompa- and a high index of suspicion for C difficile exist, the
nying pyuria.182 It is therefore unclear how many following are recommended: (1) sigmoidoscopy,
catheterized patients with ⬎ 105 CFU/mL actually and/or (2) cytotoxicity assay, and/or (3) CT scan of
have UTI. abdomen looking for thickened colonic wall.
While catheter-associated bacteruria is common in
ICU patients, data for the early 1980s indicates that
⬍ 3% of catheter-associated bacteriuric patients will Candida Infections
develop bacteremia caused by organisms in the
urine.183 Therefore, the surveillance for and treat- Candida species are important opportunistic
ment of isolated bacteruria in most ICU patients is pathogens in the ICU. The CDC National Nosoco-
currently not recommended.184 Bacteriuria should, mial Infection Study reported that 7% of all nosoco-
however, be treated following urinary tract manipu- mial infections were due to candidal species.193 In
lation or surgery, in patients with kidney stones, and the EPIC study,104 17% of nosocomial ICU infec-
in patients with urinary tract obstruction. tions 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
CLOSTRIDIA DIFFICILE Colitis courses of antibiotics.53 Candida species are partic-
ularly important pathogens in patients with ongoing
C difficile, the agent that causes pseudomembra- peritonitis.52–54 It is important to realize that Can-
nous colitis and antibiotic-associated diarrhea, has dida species are constituents of the normal flora in
become a common nosocomial pathogen.185–187 Ap- about 30% of all healthy people. Antibiotic therapy
proximately 20% of all hospitalized patients become increases the incidence of colonization by up to
“infected” with C difficile, of whom only about a 70%.53 It is probable that most ICU patients become
third develop diarrhea.185–187 The majority of hospi- colonized with Candida species soon after admission.
tal inpatients infected with C difficile are asymptom- Not all patients colonized with Candida will become
atic.188,189 C difficile infection commonly presents infected with Candida. Nonneutropenic patients
with mild to moderate diarrhea, sometimes accom- with isolation of Candida species from pulmonary
panied by lower abdominal cramping. Symptoms samples (tracheal aspirates, bronchoscopic or blind
usually begin during or shortly after antibiotic ther- sampling methods), even in high concentrations, are
apy but are occasionally delayed for several weeks. unlikely to have invasive candidiasis.194,195 Indication
Severe colitis without pseudomembrane formation for initiation of antifungal therapy in these patients
may occur with profuse, debilitating diarrhea, ab- should be based on histologic evidence or identifica-
dominal pain, and distension. Common systemic tion from sterile specimens. Similarly, isolation of
manifestations include fever, nausea, anorexia, and Candida species from the urine in ICU patients with
malaise. A neutrophilia and increased numbers of indwelling catheters usually represents colonization
fecal leukocytes are common.188,189 Pseudomembra- rather than infection. Although candiduria may be

CHEST / 117 / 3 / MARCH, 2000 861

observed in up to 80% of patients with systemic blood cultures should not be obtained through intra-
candidiasis, candidemia from a urinary tract source is vascular catheters unless the catheter has been re-
extremely rare.54 cently placed.207
The volume of blood drawn in adult patients is the
single most important factor governing the sensitivity
Other Infections of blood cultures.180,206,208,209 Therefore, it is recom-
mended that a minimum of 10 mL and preferably 20
Nosocomial meningitis is exceedingly uncommon mL of blood be removed per draw divided among
in hospitalized patients who have not undergone a the minimum number of blood culture containers
neurosurgical procedure.196,197 Lumbar puncture, as recommended by the manufacturer.180,206,208,209
therefore, need not be performed routinely in ICU Resin-containing medium offers little clinical benefit
patients (nonneurosurgical) who develop a fever to the majority of ICU patients.210 Once bloodstream
unless they have meningeal signs or contiguous infection is identified, repeated or follow-up cultures
infection.196,197 In patients who have undergone are not necessary in most cases. Subsequent blood
abdominal surgery and develop a fever, intra-abdom- cultures may be justified in patients who deteriorate
inal infection must always be excluded. CT scanning clinically or those who fail to improve despite ther-
of the abdomen is indicated in these patients. Simi- apy. However in some cases bacteremia may be
larly, in patients who have undergone other opera- prolonged, necessitating further blood cultures dur-
tive procedures, wound infection must be excluded. ing treatment (eg, staphylococcal bacteremia).

Diagnostic Evaluation
Scintigraphy, CT Scanning, and Ultrasound
It is important that blood cultures as well as other Examinations
appropriate cultures be performed before the initi-
ation of antibiotic therapy. The impact of antibiotic Scintigraphic scanning techniques have a low sen-
therapy on culture positivity is illustrated in patients sitivity and specificity in ICU patients and are there-
with suspected VAP, where a number of studies have fore not recommended.1,211,212 The advantages of
demonstrated that both prior and current antibiotic CT scanning and/or ultrasound over scintigraphy is
therapy reduces the predictive accuracy of invasive that the results of the test can be obtained immedi-
diagnostic testing. 198,199 ately with superior anatomic resolution, which can
be used to guide drainage procedures.

Blood Cultures
An Approach to the Critically Ill Patient
Bacteremia and candidemia have been docu- With Fever
mented in up to 10% of ICU patients and are an
important cause of morbidity and mortality in the From the forgoing information, the following ap-
ICU.200 –203 Blood cultures are therefore indicated in proach is suggested in ICU patients who develop a
all febrile patients. Surveillance blood cultures, how- fever (see Fig 1). Due to the frequency and excess
ever, are expensive and add very little to the man- morbidity and mortality associated with bacteremia,
agement of patients in the ICU.204 blood cultures are recommenced in all ICU patients
Bennett and Beeson205 reported that the presence who develop a fever. A comprehensive physical
of microorganisms in the blood is the initiating event examination and review of the chest radiograph is
leading to fever and chills 1 to 2 h later, and that essential. Noninfectious causes of fever should be
blood cultures are frequently negative at the time of excluded. In patients with an obvious focus of infec-
the temperature spike. Thus blood cultures are tions (eg, purulent nasal discharge, abdominal ten-
ideally drawn prior to the onset of a temperature derness, profuse green diarrhea), a focused diagnos-
spike. In reality, this is not possible; therefore, tic workup is required. If there is no clinically
spreading out the collection of blood cultures in- obvious source of infection and unless the patient is
creases the likelihood of blood collection during clinically deteriorating (falling BP, decreased urine
bacteremia. It is therefore recommended that at output, increasing confusion, rising serum lactate
least two and no more than three sets of blood concentration, falling platelet count, or worsening
cultures should be obtained by separate needle sticks coagulopathy), or the temperature is ⬎ 39°C
from different venipuncture sites.206 Colonization of (102°F), it may be prudent to perform blood cultures
the lumen of central venous catheters occurs within and then observe the patient before embarking on
a short period of time after placement. Therefore, further diagnostic tests and commencing empiric

862 Reviews
 Figure 1. Fever diagnostic algorithm. Dx ⫽ diagnostic; ABx ⫽ antibiotics; Rx ⫽ therapy.

antibiotics. However, all neutropenic patients with loose stools, and CT scan of the sinuses with removal
fever and patients with severe (as outlined above) or of all nasal tubes. Urine culture is indicated only in
progressive signs of sepsis should be started on patients with abnormalities of the renal system or
broad-spectrum antimicrobial therapy immediately following urinary tract manipulation. If the patient is
after obtaining appropriate cultures. at risk of abdominal sepsis or has any abdominal
In patients whose clinical picture is consistent with signs (tenderness, distension, unable to tolerate en-
infection and in whom no clinically obvious source teral feeds) CT scan of abdomen is indicated. Pa-
has been documented, removal of all central lines tients with right upper quadrant tenderness require
⬎ 48 h old (with semiquantitative or quantitative an abdominal ultrasound.
culture) is recommended as well as stool for WBC Reevaluation of the patient’s status after 48 h
count and C difficile toxin in those patients with using all available results and the evolution of the

CHEST / 117 / 3 / MARCH, 2000 863

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