2000. Chest. Fiebre en UCI

DOI 10.1378/chest.117.3.855 2000;117;855-869Chest

*Fever in the ICU

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Fever in the ICU*

Paul E. Marik, MD, FCCP

Fever is a common problem in ICU patients. The presence of fever frequently results in theperformance of diagnostic tests and procedures that significantly increase medical costs andexpose the patient to unnecessary invasive diagnostic procedures and the inappropriate use ofantibiotics. ICU patients frequently have multiple infectious and noninfectious causes of fever,necessitating a systematic and comprehensive diagnostic approach. Pneumonia, sinusitis, andblood stream infection are the most common infectious causes of fever. The urinary tract isunimportant in most ICU patients as a primary source of infection. Fever is a basic evolutionaryresponse 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 noninfectiouscauses of fever in ICU patients and outlines a rational approach to the management of thisproblem. (CHEST 2000; 117:855–869)

Key words: cytokines; fever; ICU; sinusitis; urinary tract infection; ventilator-associated pneumonia

Abbreviations: CDC 5 Centers for Disease Control and Prevention; CFU 5 colony-forming units; ELISA 5 enzyme-linked immunosorbent assay; IL 5 interleukin; TNF 5 tumor necrosis factor; UTI 5 urinary tract infection;VAP 5 ventilator-associated pneumonia

F ever is a common problem in ICU patients. Thepresence of fever frequently results in the per-

formance of diagnostic tests and procedures thatsignificantly increase medical costs and expose thepatient to unnecessary invasive diagnostic proce-dures and the inappropriate use of antibiotics. Themain diagnostic dilemma is to exclude noninfectiouscauses of fever and then to determine the site and

For editorial comment see page 627

likely pathogens of those with infections. ICU pa-tients frequently have multiple infectious and non-infectious causes of fever,1 necessitating a systematicand comprehensive diagnostic approach. This articlereviews the common infectious and noninfectiouscauses of fever in ICU patients and outlines arational approach to the management of these pa-tients.

Pathogenesis of Fever

Cytokines released by monocytic cells play a cen-tral role in the genesis of fever. The cytokines

primarily involved in the development of fever in-clude interleukin (IL) 1, IL-6, and tumor necrosisfactor (TNF)-a.2–13 The interaction between thesecytokines is complex, with each being able to up-regulate and down-regulate their own expression aswell as that of the other cytokines. These cytokinesbind to their own specific receptors located in closeproximity to the preoptic region of the anteriorhypothalamus.2,3 Here, the cytokine receptor inter-action activates phospholipase A2, resulting in theliberation of plasma membrane arachidonic acid assubstrate for the cyclo-oxygenase pathway. Somecytokines appear to increase cyclo-oxygenase expres-sion directly, leading to liberation of prostaglandinE2. This small lipid mediator diffuses across theblood brain barrier, where it acts to decrease the rateof firing of preoptic warm-sensitive neurons, leadingto activation of responses designed to decrease heatloss and increase heat production.2,14 In a smallproportion of hospitalized patients, hyperthermiamay result from increased sympathetic activity withincreased heat production.

Significance of Fever

Fever appears to be a preserved evolutionaryresponse within the animal kingdom.15–20 With fewexceptions, reptiles, amphibians, and fish, as well asseveral invertebrate species, have been shown tomanifest fever in response to challenge with micro-organism.15–19 Increased body temperature has been

*From the Department of Internal Medicine, Section of CriticalCare, Washington Hospital Center, Washington, DC.Manuscript received May 11, 1999; revision accepted October25, 1999.Correspondence to: Paul E. Marik, MD, Department of InternalMedicine, Washington Hospital Center, 110 Irving St NW,Washington, DC 20010-2975; e-mail: [email protected]

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shown to enhance the resistance of animals to infec-tion.21,22 Although fever has some harmful effects,fever appears to be an adaptive response that hasevolved to help rid the host of invading pathogens.Temperature elevation has been shown to enhanceseveral parameters of immune function, includingantibody production, T-cell activation, production ofcytokines, and enhanced neutrophil and macrophagefunction.23–26 Furthermore, some pathogens such asStreptococcus pneumoniae are inhibited by febriletemperatures.27

It has long been known that increasing bodytemperature is associated with improved outcomefrom infectious diseases. The preantibiotic era pro-vides abundant, although uncontrolled data, on thedeliberate use of elevated body temperature to treatinfections. The beneficial effects of hot baths andmalarial fevers in syphilis were noted as early as the15th century.28 In mammalian models, increasingbody temperature results in enhanced resistance toinfection.29–32 In a retrospective analysis of 218patients with Gram-negative bacteremia, Bryant andcolleagues33 reported a positive correlation betweenmaximum temperature on the day of bacteremia andsurvival. Similarly, Weinstein and colleagues34 re-ported that a temperature . 38°C increased survivalin patients with spontaneous bacterial peritonitis.Dorn and colleagues35 reported that children withchickenpox who were treated with acetaminophenhad a longer time to crusting of lesions than whentreated with placebo.

An elevated body temperature may, however, alsobe associated with a number of deleterious effects,most notably an increase in cardiac output, oxygenconsumption, carbon dioxide production, and energyexpenditure.36 Oxygen consumption increases byapproximately 10% per degree Celsius.36 Thesechanges may be poorly tolerated in patients withlimited cardiorespiratory reserve. In patients whohave suffered a cerebrovascular accident or trau-matic head injury, moderate elevations of braintemperature may markedly worsen the resultinginjury.37 Maternal fever has been suggested to be acause of fetal malformations or spontaneous abor-tions.38,39 However, this association has not beenrigorously tested.

Definitions and Measurement of Fever

Accurate and reproducible measurement of bodytemperature is important in detecting disease and inmonitoring patients with an elevated temperature. Avariety of methods are used to measure body tem-perature, combining different sites, instruments, andtechniques. The mixed venous blood in the pulmo-

nary artery is considered the optimal site for coretemperature measurement; however, this methodrequires placement of a pulmonary artery cathe-ter.40–42 Infrared ear thermometry has been demon-strated to provide values that are a few tenths of adegree below temperatures in the pulmonary arteryand brain.43–46 Rectal temperatures obtained with amercury thermometer or electronic probe are oftena few tenths of a degree higher than core tempera-ture.40–42 Rectal temperatures are perceived by pa-tients as unpleasant and intrusive. Furthermore,access to the rectum may be limited by patientposition, with an associated risk of rectal trauma.Oral measurements are influenced by events such aseating and drinking and the presence of respiratorydevices delivering warmed gases.43 Axillary measure-ments substantially underestimate core temperatureand lack reproducibility.43 Body temperature istherefore most accurately measured by an intravas-cular thermistor, but measurement by infrared earthermometry or with an electronic probe in therectum is an acceptable alternative.47 Normal bodytemperature is generally considered to be 37.0°C(98.6°F) with a circadian variation of between 0.5 to1.0°C.2,14 The definition of fever is arbitrary anddepends on the purpose for which it is defined. TheSociety of Critical Care Medicine practice parame-ters define fever in the ICU as a temperature. 38.3°C ($ 101°F).47 Unless the patient has otherfeatures of an infectious process, only a temperature. 38.3°C ($ 101°F) warrants further investigation.

Fever Patterns

Attempts to derive reliable and consistent cluesfrom evaluation of a patient’s fever pattern is fraughtwith uncertainly and not likely to be helpful diagnos-tically.2,14,48 Most patients have remittent or inter-mittent fever that, when due to infection, usuallyfollow a diurnal variation.48 Sustained fevers havebeen reported in patients with Gram-negative pneu-monia or CNS damage.48 The appearance of fever atdifferent time points in the course of a patient’sillness may however provide some diagnostic clues.Fevers that arise . 48 h after institution of mechan-ical ventilation may be secondary to a developingpneumonia.49,50 Fevers that arise 5 to 7 days postop-eratively may be related to abscess formation.51

Fevers that arise 10 to 14 days postinstitution anti-biotics for intra-abdominal abscess may be due tofungal infections.52–54

Causes of Fever in the ICU

As outlined above, any disease process that resultsin the release of the proinflammatory cytokines IL-1,

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IL-6, and TNF-a will result in the development offever. While infections are the commonest cause offever in ICU patients, many noninfectious inflamma-tory conditions cause the release of the proinflam-matory cytokines with a febrile response.55–61 Simi-larly, it is important to appreciate that not all patientswith infections are febrile. Approximately 10% ofseptic patients are hypothermic and 35% are normo-thermic at presentation. Septic patients who fail todevelop a temperature have a significantly highermortality than febrile septic patients.62–64 The reasonthat patients with established infections fail to de-velop a febrile response is unclear; however, prelim-inary evidence suggests that this aberrant response isnot due to diminished cytokine production.65

The presence of fever in an ICU patient fre-quently triggers a battery of diagnostic tests that arecostly, expose the patient to unnecessary risks, andoften produce misleading or inconclusive results. Itis therefore important that fever in ICU patient beevaluated in a systematic, prudent, clinically appro-priate, and cost-effective manner.

Noninfectious Causes of Fever in the ICU

A large number of noninfectious disorders resultin tissue injury with inflammation and a febrilereaction. Those noninfectious disorders that should

be considered in ICU patients are listed in Table1.1,55,66–68 For reasons that are not entirely clear,most noninfectious disorders usually do not lead to afever . 38.9°C (102°F); therefore, if the tempera-ture increases above this threshold, the patientshould be considered to have an infectious etiologyas the cause of the fever.67 However, patients withdrug fever may have a temperature . 102°F.69–71

Similarly, fever secondary to blood transfusion maybe . 102°F.72,73

Most of those clinical conditions listed in Table 1are clinically obvious and do not require additionaldiagnostic tests to confirm their presence. However,a few of these disorders require special consider-ation. Although drug-induced fever is commonlycited as a cause of fever,74 , 300 cases of thiscondition have been reported in the literature.70

Furthermore, only a single case of drug fever hasbeen reported in an ICU patient population.1 How-ever, on the basis of the number of medicationsadministered to patients in the ICU, one wouldexpect drug fever to be a relatively common event.Although the true incidence of this disorder isunknown, drug fever should be considered in pa-tients with an otherwise unexplained fever, particu-larly if they are receiving b-lactam antibiotics, pro-cainamide, or diphenylhydantoin.70 Drug fever isusually characterized by high spiking temperaturesand shaking chills.70 It may be associated with a withleukocytosis and eosinophilia. Relative bradycardia,although commonly cited, is uncommon.67,70,74

Atelectasis is commonly implicated as a cause offever. Standard ICU texts list atelectasis as a cause offever, although they provide no primary source.51,75

Indeed a major surgery text states that “fever isalmost always present [in patients with atelecta-sis].”51 However, Engeron76 studied 100 postopera-tive cardiac surgery patients and was unable todemonstrate a relationship between atelectasis andfever. Furthermore, when atelectasis is induced inexperimental animals by ligation of a mainstembronchus, fever does not occur.77,78 However, Kisalaand coworkers79 demonstrated that IL-1 and TNF-alevels of macrophage cultures from atelectatic lungswere significantly increased compared with the con-trol lungs. The role of atelectasis as a cause of feveris unclear; however, atelectasis probably does notcause fever in the absence of pulmonary infection.

Febrile reactions complicate about 0.5% of bloodtransfusions, but may be more common followingplatelet transfusion.72,80,81 Antibodies against mem-brane antigens of transfused leukocytes and/or plate-lets are responsible for most febrile reactions tocellular blood components.72 Febrile reactions usu-ally begin within 30 min to 2 h after a blood-producttransfusion is begun. The fever generally lasts be-

Table 1—Noninfectious Causes of Fever in the ICU

Noninfectious Causes

Alcohol/drug withdrawalPostoperative fever (48 h postoperative)Posttransfusion feverDrug feverCerebral infarction/hemorrhageAdrenal insufficiencyMyocardial infarctionPancreatitisAcalculous cholecystitisIschemic bowelAspiration pneumonitisARDS (both acute and late fibroproliferative phase)Subarachnoid hemorrhageFat emboliTransplant rejectionDeep venous thrombosisPulmonary emboliGout/pseudogoutHematomaCirrhosis (without primary peritonitis)GI bleedPhlebitis/thrombophlebitisAdrenal insufficiencyIV contrast reactionNeoplastic feversDecubitus ulcers

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tween 2 h and 24 h and may be preceded by chills.73

An acute leucocytosis lasting up to 12 h commonlyoccurs following a blood transfusion.82

Patients with the ARDS may progress to a “chron-ic” stage characterized by pulmonary fibroprolifera-tion and fevers. Meduri and coworkers1,83 havedemonstrated that fever and leukocytosis may resultfrom the inflammatory-fibrotic process present inthe airspace of patients with late ARDS in theabsence of pulmonary infection. Corticosteroids ap-pear to be associated with an improvement in lunginjury and reduced mortality.83,84 Some authors rec-ommend an open lung biopsy prior to commencingcorticosteroid therapy, in order to obtain histologicevidence of the fibroproliferative phase of ARDSand to exclude infection.

Acalculous cholecystis occurs in approximately1.5% of critically ill patients.85,86 While relativelyuncommon, acalculous cholecystitis is an important“noninfectious” cause of fever in critically ill patients,as it is frequently unrecognized and therefore poten-tially life threatening.85,86 The pathophysiology ofacalculous cholecystitis is related to the complexinterplay of a number of pathogenetic mechanisms,including gallbladder ischemia, bile stasis with inpis-sation in the absence of stimuli for emptying of thegallbladder, positive-end expiratory pressure, andparenteral nutrition.87–92 Bacterial invasion of thegallbladder appears to be a secondary phenome-non.89

The diagnosis of acalculous cholecystitis is oftenexceedingly difficult and requires a high index ofsuspicion. Pain in the right upper quadrant is thefinding that most often leads the clinician to thecorrect diagnosis, but it may frequently be ab-sent.85,86,89 Nausea, vomiting, and fever are otherassociated clinical features. The clinical findings andlaboratory workup in patients with acalculous chole-cystitis are, however, often nonspecific. The mostdifficult patients are those recovering from abdomi-nal sepsis who deteriorate again, misleadingly sug-gesting a flare-up of the original infection. Rapiddiagnosis is essential because ischemia may progressrapidly to gangrene and perforation, with attendantincrease in the already high morbidity and mortali-ty.89 The diagnosis should therefore be considered inevery critically ill patient who has clinical findings ofsepsis with no obvious source.

Radiologic investigations are required for a pre-sumptive diagnosis of acalculous cholecystitis. Ultra-sound is the most common radiologic investigationused in the diagnosis of acalculous cholecystitis;features include increased wall thickness, intramurallucencies, gallbladder distension, pericholecysticfluid, and intramural sludge.93,94 Wall thickness $ 3mm is reported to be the most important diagnostic

feature on ultrasound examination, with a specificityof 90% and a sensitivity of 100%.93,94 In ICUpatients, hepatobiliary scintigraphy has a high false-positive rate (. 50%), limiting the value of thistest.95 However, a normal scan virtually excludedacalculous cholecystitis. CT scanning has been re-ported to have a high sensitivity and specificity;however, no prospective studies have been per-formed comparing ultrasonography with CT scan-ning in the diagnosis of acalculous cholecystitis.96

The management of acalculous cholecystitis issomewhat controversial.85,89,97 However, with thedevelopment of more advanced radiologic imagingtechniques, percutaneous cholecystostomy may bethe procedure of choice. Kiviniemi and coworker98

demonstrated diminution of pain in 94% of patients,with normalization of fever in 90% and leukocytecount in 84% of patients treated by percutaneouscholecystostomy. The procedure is associated withfew complications and is the definitive therapy inmost patients.99 Open cholecystectomy is, however,recommended should the abdominal signs, fever,and leucocytosis not improve within 48 h of percu-taneous cholecystostomy.85,89,97

While fever may occur in patients with deepvenous thrombosis, in patients suspected of deepvenous thrombosis, the predictive value of fever ispoor.100 Furthermore, in critically ill ICU patients,fever without other features of ileofemoral thrombo-sis is uncommon and does not warrant routinevenography as part of the initial diagnostic workup ofpyrexia in ICU patients.1,101

Infectious Causes of Fever

The prevalence of nosocomial infection in ICUshas been reported to vary from 3 to 31%.102–108 Datafrom the National Nosocomial Infection Surveillancesystem database from 1986 to 1990 documentednosocomial infection in 10% of the 164,034 patients,with a strong correlation between ICU length of stayand the development of infection.103 In a pointprevalence study conducted in 1992, The EPICStudy Investigators104 reported on the prevalence ofnosocomial infections in 10,038 patients hospitalizedin 1,417 European ICUs. In this study, 20.6% ofpatients had an ICU-acquired infection, with pneu-monia being the most common (46.9%), followed byurinary tract infection (17.6%) and blood streaminfection (12%). This data must, however, be inter-preted with some caution. The presence and type ofinfection in these studies was documented accordingto the “standard definitions” of the Centers forDisease Control and Prevention (CDC).109,110 Thedefinitions of nosocomial infection published by the

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CDC may, however, not be applicable to ICUpatients.109,110 For example, according to the mostrecent definitions published in 1988, the presence ofrales and purulent sputum or the presence of newchest radiographic findings and change in sputumcharacter were used to diagnose pneumonia.110 Inpatients receiving mechanical ventilation, less than athird of patients with these features would be con-sidered to have pneumonia using invasive diagnosticmethods.111–114 Similarly, fever and a urine cultureof $ 105 colony-forming units (CFU)/mL was con-sidered diagnostic of urinary tract infection. As isdiscussed below, the presence of these two finding incatheterized critically ill ICU patients does not rep-resent infection of the urinary tract.

The most common infections reported in ICU pa-tients are pneumonia, followed by sinusitis, bloodstream infection, and catheter-related infection.1,102–108

Table 2 lists the most important sites of infection inICU patients. As is discussed below, urinary tractinfection is probably unimportant in most ICU pa-tients.

Ventilator-Associated Pneumonia

Ventilator-associated pneumonia (VAP) occurs inapproximately 25% of patients undergoing mechan-ical ventilation.49,115–118 The impact of VAP on pa-tient outcome has been much debated117,119,120;however, Fagon and colleagues121 reported an attrib-utable mortality of 27%. The optimal management ofpatients with suspected VAP requires confirmationof the diagnosis and identification of the responsiblepathogen(s) in order to provide appropriate antimi-crobial therapy. The diagnosis of VAP remains one ofthe most difficult clinical dilemmas in critically illpatients receiving mechanical ventilation.49 Clinicalcriteria alone have been shown to be unreliable inthe diagnosis of this condition.113,115,122 A number ofinvasive and minimally invasive techniques havebeen reported to aid in the diagnosis of VAP. Thenumber of methods currently available attest to thefact that no single method is ideal.49,112,120,123–132

The optimal technique(s) for diagnosis of VAP re-mains unclear as a uniformly agreed on “gold stan-dard,” for the diagnosis is lacking.111,118,124,133–135

The impact that diagnostic tests for VAP have onpatient outcome is controversial. Using a decisionanalysis method, Sterling and coauthors136 demon-strated that invasive or semi-invasive microbiologicaldiagnostic techniques improved the outcome of pa-tients with suspected VAP. However, Luna andcolleagues137 and Rello and coworkers138 have dem-onstrated that the most important factor affectingoutcome in patients with VAP is the early initiationof appropriate antibiotic therapy. In the study byLuna et al,137 the mortality of patients who werechanged from inadequate antibiotic therapy to ap-propriate therapy based on the results of the BALwas comparable to the mortality of those patientswho continued to receive inadequate therapy. Kollefand Ward,139using noninvasive mini-BAL to diag-nose VAP, confirmed these findings. It should how-ever be noted that patients who have clinical featuresof VAP and in whom VAP is “excluded” based onquantitative culture of lower respiratory tract secre-tions and in whom antibiotics are stopped have asignificantly lower mortality than those patient whoare culture positive.121,139 Invasive or noninvasivesampling of lower respiratory tract sections withquantitative culture therefore allows for the safediscontinuation of antibiotics in the “culture nega-tive” patients.123,125,140–145 Furthermore, as the ini-tial empiric antibiotic regimen must be broad andcover both Gram-positive and negative organisms,these techniques allow for narrowing of the spec-trum once a pathogen has been isolated in thosepatients with confirmed pneumonia. This approachto suspected VAP will result in significant cost savingsand reduce the selection of resistant organisms.113

Sinusitis

Because paranasal sinusitis is usually clinicallysilent in intubated patients, it is not widely appreci-ated that nosocomial sinusitis is an important sourceof infection and fever in critically ill patients. Fur-thermore, many ear, nose, and throat surgeons are ofthe belief that paranasal sinusitis in intubated pa-tients receiving mechanical ventilation does notcause fever or systemic signs of infection. Nosoco-mial sinusitis is particularly common following nasalintubation, with an incidence of up to 85% after aweek of intubation.146–151 The incidence of nosoco-mial sinusitis appears to be lower in patients inwhom both the endotracheal and gastric tubes areplaced orally.146–151 The diagnosis of sinusitis re-quires a CT scan and cannot be accurately assessed

Table 2—Common Infectious Causes of Fever in theICU

Infectious Causes

VAPSinusitisCatheter-related sepsisPrimary Gram-negative septicemiaC difficile diarrheaAbdominal sepsisComplicated wound infections

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using standard radiography or echography.152 Sinus-itis is diagnosed by total opacification or the presenceof an air fluid level within any of the paranasalsinuses. The maxillary sinus is most commonly in-volved; however, most patients with radiologic max-illary sinusitis have abnormalities of the ethmoid andsphenoid sinuses.148 Since radiologic abnormalitiesof the paranasal sinuses do not necessarily implyinfection, diagnosis of infectious maxillary sinusitisrequires transnasal puncture following appropriatedisinfection of the nares.146,148,150,153 When the eth-moid or sphenoid sinuses only are involved, bacteri-ologic specimens can be obtained by an open eth-moidectomy/sphenoidotomy.146 Sinus infection isdiagnosed by the presence of pus associated withhigh quantitative cultures of implicated pathogens.Rouby and colleagues148 reported that only 38% ofpatients with radiologic maxillary sinusitis had trueinfectious sinusitis. In the series reported by Roubyet al,148 there was normalization of the core temper-ature and WBC count following removal of all nasaltubes, followed by transnasal puncture and drainagein the patients with infectious maxillary sinusitis.These authors did not use IV antibiotics. Similarly, inthe series reported by Grindlinger and colleagues146

and by Deutschman and coworkers,147 resolution ofsinusitis was associated with normalization of thetemperature and WBC count. Paranasal sinusitis isbest treated by removal of all nasal tubes togetherwith drainage of the maxillary sinuses. Broad-spec-trum antibiotics are generally recommended.146,147

Catheter-Associated Sepsis

Catheter-associated sepsis is defined as bloodstream infection due to an organism that has colo-nized a vascular catheter. Approximately 5% ofpatients with indwelling vascular catheters (uncoat-ed) will develop blood stream infection (' 10 infec-tions/1,000 catheter days).154–158 The incidence ofcatheter-associated sepsis increases with the lengthof time the catheter is in situ, the number of ports,and increases with the number of manipulations.Approximately 25% of central venous catheters be-come colonized (. 15 CFU), and approximately 20to 30% of colonized catheters will result in cathetersepsis.154–158 Staphylocuccus aureus and coagulase-negative staphylococci are the most common infect-ing (and colonizing) organisms, followed by entero-cocci, Gram-negative bacteria, and Candidaspecies.154–158

A number of methods of reducing catheter colo-nization and blood stream infection have been stud-ied, including topical antibiotics, antimicrobial flushsolutions, subcutaneous tunneling of catheters, and

silver-impregnated subcutaneous cuffs.156,159–162

These studies have generally shown poor or incon-sistent results. It has been suggested that antimicro-bial bonding of central venous catheters may be themost effective method of reducing the rate of cath-eter colonization and catheter-related sepsis.163,164

Several types of antiseptic or antimicrobial coatingshave been developed, including catheters coatedwith chlorhexidine gluconate and silver sulfadiazine,as well as with minocycline and rifampin. While anumber of studies have demonstrated the incidenceof catheter-related sepsis to be lower with chlorhexi-dine/sulfadiazine-coated catheters,165–167 not allstudies have duplicated these findings.168–170 Fur-thermore, Darouiche and colleagues154 have demon-strated that central venous catheters impregnatedwith minocycline and rifampin are associated with asignificantly lower rate of catheter colonization andblood stream infection than catheters coated withchlorhexidine and silver sulfadiazine.

Central venous catheterization via the femoral andinternal jugular veins are reported to have a similarinfection rates, which are higher than that for cath-eters inserted via the subclavian approach.154,163,165,171

Replacement of a colonized catheter over a guide-wire is associated with rapid recolonization of thereplacement catheter.172 If catheter sepsis is sus-pected, the catheter should be changed to a new site,with culture (quantitative or semiquantitative) of thecatheter tip.154,172–176 In patients with limited venousaccess or in patients in whom catheter sepsis is lesslikely, the catheter can be changed over a guidewire;however, withdrawal blood cultures and culture ofthe catheter tip should be performed and the cath-eter removed if the cultures are positive.

Urinary Tract Infection

Urinary tract infections (UTIs) have been reportedto be common in ICU patients, where they arereported to account for between 25 to 50% of allinfections.102–108 However, it is likely that most ofthese patients had “asymptomatic bacteriuria” ratherthan true infections of the urinary tract. The use ofantibiotics in patients with asymptomatic bacteriuriais based on a single study performed in the early1980s that may not be applicable today.177 Platt andcolleagues177 demonstrated that in hospitalized pa-tients bacteriuria with $ 105 CFUs of bacteria permilliliter of urine during bladder catheterization wasassociated with a 2.8-fold increase in mortality.Based on this study, thousands of ICU patients withurinary tract colonization have been treated withantibiotics.

Most ICU patients require an indwelling urinary

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catheter for monitoring fluid balance and renalfunction. The patients’ colonic flora rapidly colonizesthe urinary tract in these patients.178 Stark andMaki179 have demonstrated that in catheterized pa-tients, bacteria in the urinary system rapidly prolif-erate to exceed 105 CFU/mL over a short period oftime. Bacteriuria, defined as a quantitative culture of$ 105 CFU/mL, has been reported in up to 30%of catheterized hospitalized patients.180 The terms“bacteriuria” and “UTI” are generally although in-correctly used as synonyms. Indeed, most studies inICU patients have used bacteriuria to diagnose aUTI. Bacteriuria implies colonization of the urinarytract without bacterial invasion and an acute inflam-matory response.181 UTI implies an infection of theurinary tract.181 Criteria have not been developed fordifferentiating asymptomatic colonization of the uri-nary tract from symptomatic infection. Furthermore,the presence of white cells in the urine is not usefulfor differentiating colonization from infection, asmost catheter-associated bacteriurias have accompa-nying pyuria.182 It is therefore unclear how manycatheterized patients with . 105 CFU/mL actuallyhave UTI.

While catheter-associated bacteruria is common inICU patients, data for the early 1980s indicates that, 3% of catheter-associated bacteriuric patients willdevelop bacteremia caused by organisms in theurine.183 Therefore, the surveillance for and treat-ment of isolated bacteruria in most ICU patients iscurrently not recommended.184 Bacteriuria should,however, be treated following urinary tract manipu-lation or surgery, in patients with kidney stones, andin patients with urinary tract obstruction.

CLOSTRIDIA DIFFICILE Colitis

C difficile, the agent that causes pseudomembra-nous colitis and antibiotic-associated diarrhea, hasbecome a common nosocomial pathogen.185–187 Ap-proximately 20% of all hospitalized patients become“infected” with C difficile, of whom only about athird develop diarrhea.185–187 The majority of hospi-tal inpatients infected with C difficile are asymptom-atic.188,189 C difficile infection commonly presentswith mild to moderate diarrhea, sometimes accom-panied by lower abdominal cramping. Symptomsusually begin during or shortly after antibiotic ther-apy but are occasionally delayed for several weeks.Severe colitis without pseudomembrane formationmay occur with profuse, debilitating diarrhea, ab-dominal pain, and distension. Common systemicmanifestations include fever, nausea, anorexia, andmalaise. A neutrophilia and increased numbers offecal leukocytes are common.188,189 Pseudomembra-

nous colitis is the most dramatic manifestation of Cdifficile infection; these patients have marked ab-dominal and systemic signs and symptoms and maydevelop a fulminant and life-threatening colitis.

Stool assay for toxins A or B are the main clinicaltests used to diagnose C difficile infection.190–192 The“gold standard” test is the tissue culture cytotoxicityassay. This test has a high sensitivity (94 to 100%)and specificity (99%). The major disadvantages ofthis test are its high expense and the time needed tocomplete the assay (2 to 3 days). For these reasons,this test is no longer routinely performed. Toxinenzyme-linked immunosorbent assay (ELISA) testsare less sensitive (70 to 90%) than the cytotoxicitytest, but demonstrate excellent specificity (99%) andcan be rapidly processed, and have largely replacedthe cytotoxicity assay.190–192 It is suggested that twostool specimens be examined for leukocytes andtoxin ELISA test.190 Should the ELISA be negativeand a high index of suspicion for C difficile exist, thefollowing are recommended: (1) sigmoidoscopy,and/or (2) cytotoxicity assay, and/or (3) CT scan ofabdomen looking for thickened colonic wall.

Candida Infections

Candida species are important opportunisticpathogens in the ICU. The CDC National Nosoco-mial Infection Study reported that 7% of all nosoco-mial infections were due to candidal species.193 Inthe EPIC study,104 17% of nosocomial ICU infec-tions were due to fungi. Candida infections shouldbe considered in febrile ICU patients who have beenin the ICU for . 10 days and have received multiplecourses of antibiotics.53 Candida species are partic-ularly important pathogens in patients with ongoingperitonitis.52–54 It is important to realize that Can-dida species are constituents of the normal flora inabout 30% of all healthy people. Antibiotic therapyincreases the incidence of colonization by up to70%.53 It is probable that most ICU patients becomecolonized with Candida species soon after admission.Not all patients colonized with Candida will becomeinfected with Candida. Nonneutropenic patientswith isolation of Candida species from pulmonarysamples (tracheal aspirates, bronchoscopic or blindsampling methods), even in high concentrations, areunlikely to have invasive candidiasis.194,195 Indicationfor initiation of antifungal therapy in these patientsshould be based on histologic evidence or identifica-tion from sterile specimens. Similarly, isolation ofCandida species from the urine in ICU patients withindwelling catheters usually represents colonizationrather than infection. Although candiduria may be

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observed in up to 80% of patients with systemiccandidiasis, candidemia from a urinary tract source isextremely rare.54

Other Infections

Nosocomial meningitis is exceedingly uncommonin hospitalized patients who have not undergone aneurosurgical procedure.196,197 Lumbar puncture,therefore, need not be performed routinely in ICUpatients (nonneurosurgical) who develop a feverunless they have meningeal signs or contiguousinfection.196,197 In patients who have undergoneabdominal surgery and develop a fever, intra-abdom-inal infection must always be excluded. CT scanningof the abdomen is indicated in these patients. Simi-larly, in patients who have undergone other opera-tive procedures, wound infection must be excluded.

Diagnostic Evaluation

It is important that blood cultures as well as otherappropriate cultures be performed before the initi-ation of antibiotic therapy. The impact of antibiotictherapy on culture positivity is illustrated in patientswith suspected VAP, where a number of studies havedemonstrated that both prior and current antibiotictherapy reduces the predictive accuracy of invasivediagnostic testing. 198,199

Blood Cultures

Bacteremia and candidemia have been docu-mented in up to 10% of ICU patients and are animportant cause of morbidity and mortality in theICU.200–203 Blood cultures are therefore indicated inall febrile patients. Surveillance blood cultures, how-ever, are expensive and add very little to the man-agement of patients in the ICU.204

Bennett and Beeson205 reported that the presenceof microorganisms in the blood is the initiating eventleading to fever and chills 1 to 2 h later, and thatblood cultures are frequently negative at the time ofthe temperature spike. Thus blood cultures areideally drawn prior to the onset of a temperaturespike. In reality, this is not possible; therefore,spreading out the collection of blood cultures in-creases the likelihood of blood collection duringbacteremia. It is therefore recommended that atleast two and no more than three sets of bloodcultures should be obtained by separate needle sticksfrom different venipuncture sites.206 Colonization ofthe lumen of central venous catheters occurs withina short period of time after placement. Therefore,

blood cultures should not be obtained through intra-vascular catheters unless the catheter has been re-cently placed.207

The volume of blood drawn in adult patients is thesingle most important factor governing the sensitivityof blood cultures.180,206,208,209 Therefore, it is recom-mended that a minimum of 10 mL and preferably 20mL of blood be removed per draw divided amongthe minimum number of blood culture containersas recommended by the manufacturer.180,206,208,209

Resin-containing medium offers little clinical benefitto the majority of ICU patients.210 Once bloodstreaminfection is identified, repeated or follow-up culturesare not necessary in most cases. Subsequent bloodcultures may be justified in patients who deteriorateclinically or those who fail to improve despite ther-apy. However in some cases bacteremia may beprolonged, necessitating further blood cultures dur-ing treatment (eg, staphylococcal bacteremia).

Scintigraphy, CT Scanning, and UltrasoundExaminations

Scintigraphic scanning techniques have a low sen-sitivity and specificity in ICU patients and are there-fore not recommended.1,211,212 The advantages ofCT scanning and/or ultrasound over scintigraphy isthat the results of the test can be obtained immedi-ately with superior anatomic resolution, which canbe used to guide drainage procedures.

An Approach to the Critically Ill PatientWith Fever

From the forgoing information, the following ap-proach is suggested in ICU patients who develop afever (see Fig 1). Due to the frequency and excessmorbidity and mortality associated with bacteremia,blood cultures are recommenced in all ICU patientswho develop a fever. A comprehensive physicalexamination and review of the chest radiograph isessential. Noninfectious causes of fever should beexcluded. In patients with an obvious focus of infec-tions (eg, purulent nasal discharge, abdominal ten-derness, profuse green diarrhea), a focused diagnos-tic workup is required. If there is no clinicallyobvious source of infection and unless the patient isclinically deteriorating (falling BP, decreased urineoutput, increasing confusion, rising serum lactateconcentration, falling platelet count, or worseningcoagulopathy), or the temperature is . 39°C(102°F), it may be prudent to perform blood culturesand then observe the patient before embarking onfurther diagnostic tests and commencing empiric

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antibiotics. However, all neutropenic patients withfever and patients with severe (as outlined above) orprogressive signs of sepsis should be started onbroad-spectrum antimicrobial therapy immediatelyafter obtaining appropriate cultures.

In patients whose clinical picture is consistent withinfection and in whom no clinically obvious sourcehas been documented, removal of all central lines. 48 h old (with semiquantitative or quantitativeculture) is recommended as well as stool for WBCcount and C difficile toxin in those patients with

loose stools, and CT scan of the sinuses with removalof all nasal tubes. Urine culture is indicated only inpatients with abnormalities of the renal system orfollowing urinary tract manipulation. If the patient isat risk of abdominal sepsis or has any abdominalsigns (tenderness, distension, unable to tolerate en-teral feeds) CT scan of abdomen is indicated. Pa-tients with right upper quadrant tenderness requirean abdominal ultrasound.

Reevaluation of the patient’s status after 48 husing all available results and the evolution of the

Figure 1. Fever diagnostic algorithm. Dx 5 diagnostic; ABx 5 antibiotics; Rx 5 therapy.

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patients clinical condition is essential. If fever per-sists despite empiric antibiotics and no source ofinfection has been identified, empiric antifungaltherapy may be indicated if the patient has riskfactors for candidal infection. Additional diagnostictests may be appropriate at this time, includingvenography, a differential blood count for eosino-phils (diagnosis of drug fever), and abdominalimaging.

Treatment of Fever in the ICU

Almost all febrile ICU patients are treated withacetaminophen and external cooling methods torender the patients “afebrile.” However, fever is abasic evolutionary response to infection and may bean important host defense mechanism. The prepon-derance of evidence suggests that temperature in therange of the usual fever renders host defenses moreactive and many pathogens more susceptible to thesedefenses. Therefore, it seems illogical to treat feverper se. In addition, temperature is an importantphysical sign, allowing the physician to monitor theresponse to treatment. Furthermore, acute hepatitismay occur in ICU patients with reduced glutathionereserves (alcoholics, malnourished, etc.) who havereceived regular therapeutic doses of acetamino-phen. Based on this data, it is recommenced thatfebrile episodes not be routinely treated with anti-pyretic therapy; an evaluation of the relative benefitsand risks of antipyretic treatment should be evalu-ated in each individual case. Fever should, however,be treated in patients with acute brain insults, pa-tients with limited cardiorespiratory reserve (ie, isch-emic heart disease), and in patients in whom thetemperature increases above 40°C (104°F).2,14,37,213–217

Hypothermia blankets are frequently used in ICUpatients with febrile episodes.218 However, studieshave demonstrated that hypothermia blankets are nomore effective in cooling patients than are antipy-retic agents.218 Furthermore, the use of hypothermiablankets is associated with large temperature fluctu-ations and rebound hyperthermia.218 In addition,there is a fundamental illogic to the use of externalapplication of cold to lower temperature in a patientwith true fever. Because of the altered hypothalamicset point, the patient is already responding as if to acold environment. External cooling may result inaugmented hypermetabolism and a persistent fever.Indeed, Lenhardt and colleagues219 demonstratedthat active external cooling in volunteers with in-duced fever increased oxygen consumption by 35 to40% and was associated with a significant increase inepinephrine and norepinephrine levels.

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