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1. 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 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 formance of diagnostic tests and procedures that significantly increase medical costs and expose the patient to unnecessary invasive diagnostic proce- dures and the inappropriate use of antibiotics. The main diagnostic dilemma is to exclude noninfectious causes of fever and then to determine the site and 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 factor (TNF)-a.2–13The interaction between these cytokines is complex, with each being able to up- regulate 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.2,3Here, the cytokine receptor inter- action 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 expres- sion 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.2,14In a small proportion of hospitalized patients, hyperthermia may result from increased sympathetic activity with increased heat production. 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,1necessitating 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 pa- tients. Pathogenesis of Fever 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 response within the animal kingdom.15–20With few exceptions, reptiles, amphibians, and fish, as well as several invertebrate species, have been shown to manifest fever in response to challenge with micro- organism.15–19Increased body temperature has been *From the Department of Internal Medicine, Section of Critical Care, Washington Hospital Center, Washington, DC. Manuscript received May 11, 1999; revision accepted October 25, 1999. Correspondence to: Paul E. Marik, MD, Department of Internal Medicine, Washington Hospital Center, 110 Irving St NW, Washington, DC 20010-2975; e-mail: pem4@mhg.edu 855 CHEST / 117 / 3 / MARCH, 2000

2. shown to enhance the resistance of animals to infec- tion.21,22Although 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.23–26Furthermore, 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 pro- vides 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.28In mammalian models, increasing body temperature results in enhanced resistance to infection.29–32In a retrospective analysis of 218 patients with Gram-negative bacteremia, Bryant and colleagues33reported a positive correlation between maximum temperature on the day of bacteremia and survival. Similarly, Weinstein and colleagues34re- ported that a temperature . 38°C increased survival in patients with spontaneous bacterial peritonitis. Dorn and colleagues35reported 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.36Oxygen consumption increases by approximately 10% per degree Celsius.36These changes may be poorly tolerated in patients with limited cardiorespiratory reserve. In patients who have suffered a cerebrovascular accident or trau- matic head injury, moderate elevations of brain temperature may markedly worsen the resulting injury.37Maternal fever has been suggested to be a cause of fetal malformations or spontaneous abor- tions.38,39However, this association has not been rigorously tested. nary artery is considered the optimal site for core temperature measurement; however, this method requires placement of a pulmonary artery cathe- ter.40–42Infrared ear thermometry has been demon- strated to provide values that are a few tenths of a degree below temperatures in the pulmonary artery and brain.43–46Rectal temperatures obtained with a mercury thermometer or electronic probe are often a few tenths of a degree higher than core tempera- ture.40–42Rectal temperatures are perceived by pa- tients 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.43Axillary measure- ments substantially underestimate core temperature and lack reproducibility.43Body temperature is therefore most accurately measured by an intravas- cular thermistor, but measurement by infrared ear thermometry or with an electronic probe in the rectum is an acceptable alternative.47Normal 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.2,14The definition of fever is arbitrary and depends on the purpose for which it is defined. The Society of Critical Care Medicine practice parame- ters define fever in the ICU as a temperature . 38.3°C ($ 101°F).47Unless the patient has other features of an infectious process, only a temperature . 38.3°C ($ 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 diagnos- tically.2,14,48Most patients have remittent or inter- mittent fever that, when due to infection, usually follow a diurnal variation.48Sustained fevers have been reported in patients with Gram-negative pneu- monia or CNS damage.48The 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 mechan- ical ventilation may be secondary to a developing pneumonia.49,50Fevers 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 to fungal infections.52–54 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 tem- perature, combining different sites, instruments, and techniques. The mixed venous blood in the pulmo- Causes of Fever in the ICU As outlined above, any disease process that results in the release of the proinflammatory cytokines IL-1, 856 Reviews

3. IL-6, and TNF-a will result in the development of fever. While infections are the commonest cause of fever in ICU patients, many noninfectious inflamma- tory conditions cause the release of the proinflam- matory cytokines with a febrile response.55–61Simi- larly, it is important to appreciate that not all patients with infections are febrile. Approximately 10% of septic patients are hypothermic and 35% are normo- thermic at presentation. Septic patients who fail to develop a temperature have a significantly higher mortality than febrile septic patients.62–64The reason that patients with established infections fail to de- velop a febrile response is unclear; however, prelim- inary evidence suggests that this aberrant response is not due to diminished cytokine production.65 The presence of fever in an ICU patient fre- quently 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 appro- priate, and cost-effective manner. be considered in ICU patients are listed in Table 1.1,55,66–68For reasons that are not entirely clear, most noninfectious disorders usually do not lead to a fever . 38.9°C (102°F); therefore, if the tempera- ture increases above this threshold, the patient should be considered to have an infectious etiology as the cause of the fever.67However, 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 consider- ation. 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.1How- ever, 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 pa- tients with an otherwise unexplained fever, particu- larly if they are receiving b-lactam antibiotics, pro- cainamide, or diphenylhydantoin.70Drug fever is usually characterized by high spiking temperatures and shaking chills.70It 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 atelecta- sis].”51However, Engeron76studied 100 postopera- tive 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.77,78However, Kisala and coworkers79demonstrated that IL-1 and TNF-a levels of macrophage cultures from atelectatic lungs were significantly increased compared with the con- trol 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.72,80,81Antibodies against mem- brane antigens of transfused leukocytes and/or plate- lets are responsible for most febrile reactions to cellular blood components.72Febrile reactions usu- ally begin within 30 min to 2 h after a blood-product transfusion is begun. The fever generally lasts be- 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 857 CHEST / 117 / 3 / MARCH, 2000

4. 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 “chron- ic” stage characterized by pulmonary fibroprolifera- tion and fevers. Meduri and coworkers1,83have 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 ap- pear to be associated with an improvement in lung injury and reduced mortality.83,84Some authors rec- ommend 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.85,86While relatively uncommon, acalculous cholecystitis is an important “noninfectious” cause of fever in critically ill patients, as it is frequently unrecognized and therefore poten- tially life threatening.85,86The pathophysiology of acalculous cholecystitis is related to the complex interplay of a number of pathogenetic mechanisms, including gallbladder ischemia, bile stasis with inpis- sation in the absence of stimuli for emptying of the gallbladder, positive-end expiratory pressure, and parenteral nutrition.87–92Bacterial invasion of the gallbladder appears to be a secondary phenome- non.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 ab- sent.85,86,89Nausea, vomiting, and fever are other associated clinical features. The clinical findings and laboratory workup in patients with acalculous chole- cystitis are, however, often nonspecific. The most difficult patients are those recovering from abdomi- nal sepsis who deteriorate again, misleadingly sug- gesting 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 mortali- ty.89The 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 pre- sumptive diagnosis of acalculous cholecystitis. Ultra- sound 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.93,94Wall thickness $ 3 mm is reported to be the most important diagnostic feature on ultrasound examination, with a specificity of 90% and a sensitivity of 100%.93,94In ICU patients, hepatobiliary scintigraphy has a high false- positive rate (. 50%), limiting the value of this test.95However, a normal scan virtually excluded acalculous 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 is somewhat controversial.85,89,97However, 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.99Open 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 deep venous thrombosis, in patients suspected of deep venous thrombosis, the predictive value of fever is poor.100Furthermore, in critically ill ICU patients, fever without other features of ileofemoral thrombo- sis 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%.102–108Data 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.103In a point prevalence study conducted in 1992, The EPIC Study Investigators104reported 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 pneu- monia being the most common (46.9%), followed by urinary tract infection (17.6%) and blood stream infection (12%). This data must, however, be inter- preted 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).109,110The definitions of nosocomial infection published by the 858 Reviews

5. CDC may, however, not be applicable to ICU patients.109,110For 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.110In patients receiving mechanical ventilation, less than a third of patients with these features would be con- sidered to have pneumonia using invasive diagnostic methods.111–114Similarly, fever and a urine culture of $ 105colony-forming units (CFU)/mL was con- sidered diagnostic of urinary tract infection. As is discussed below, the presence of these two finding in catheterized 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, 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 pa- tients. 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 on patient outcome is controversial. Using a decision analysis method, Sterling and coauthors136demon- strated that invasive or semi-invasive microbiological diagnostic techniques improved the outcome of pa- tients with suspected VAP. However, Luna and colleagues137and Rello and coworkers138have dem- onstrated 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,137the mortality of patients who were changed from inadequate antibiotic therapy to ap- propriate 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 diag- nose VAP, confirmed these findings. It should how- ever be noted that patients who have clinical features 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 significantly lower mortality than those patient who are culture positive.121,139Invasive or noninvasive sampling of lower respiratory tract sections with quantitative culture therefore allows for the safe discontinuation of antibiotics in the “culture nega- tive” patients.123,125,140–145Furthermore, as the ini- tial empiric antibiotic regimen must be broad and cover both Gram-positive and negative organisms, these techniques allow for narrowing of the spec- trum 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 Ventilator-Associated Pneumonia Ventilator-associated pneumonia (VAP) occurs in approximately 25% of patients undergoing mechan- ical ventilation.49,115–118The impact of VAP on pa- tient outcome has been much debated117,119,120; however, Fagon and colleagues121reported an attrib- utable 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 antimi- crobial therapy. The diagnosis of VAP remains one of the most difficult clinical dilemmas in critically ill patients receiving mechanical ventilation.49Clinical criteria alone have been shown to be unreliable in the diagnosis of this condition.113,115,122A 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 Sinusitis Because paranasal sinusitis is usually clinically silent in intubated patients, it is not widely appreci- 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 the belief that paranasal sinusitis in intubated pa- tients receiving mechanical ventilation does not cause fever or systemic signs of infection. Nosoco- mial sinusitis is particularly common following nasal intubation, with an incidence of up to 85% after a week of intubation.146–151The incidence of nosoco- mial sinusitis appears to be lower in patients in whom both the endotracheal and gastric tubes are placed orally.146–151The diagnosis of sinusitis re- quires a CT scan and cannot be accurately assessed 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 859 CHEST / 117 / 3 / MARCH, 2000

6. using standard radiography or echography.152Sinus- itis 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 in- volved; however, most patients with radiologic max- illary sinusitis have abnormalities of the ethmoid and sphenoid sinuses.148Since 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.146,148,150,153When the eth- moid or sphenoid sinuses only are involved, bacteri- ologic specimens can be obtained by an open eth- moidectomy/sphenoidotomy.146Sinus infection is diagnosed by the presence of pus associated with high quantitative cultures of implicated pathogens. Rouby and colleagues148reported that only 38% of patients with radiologic maxillary sinusitis had true infectious sinusitis. In the series reported by Rouby et al,148there was normalization of the core temper- ature 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,147resolution 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-spec- trum antibiotics are generally recommended.146,147 silver-impregnated These studies have generally shown poor or incon- sistent results. It has been suggested that antimicro- bial bonding of central venous catheters may be the most effective method of reducing the rate of cath- eter 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 chlorhexi- dine/sulfadiazine-coated studies have duplicated these findings.168–170Fur- thermore, Darouiche and colleagues154have demon- strated 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 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 the replacement catheter.172If catheter sepsis is sus- pected, the catheter should be changed to a new site, with culture (quantitative or semiquantitative) of the catheter tip.154,172–176In 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 cath- eter removed if the cultures are positive. subcutaneous cuffs.156,159–162 not all catheters,165–167 Catheter-Associated Sepsis Catheter-associated sepsis is defined as blood stream infection due to an organism that has colo- nized a vascular catheter. Approximately 5% of patients with indwelling vascular catheters (uncoat- ed) will develop blood stream infection (’ 10 infec- tions/1,000 catheter days).154–158The 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 be- come colonized (. 15 CFU), and approximately 20 to 30% of colonized catheters will result in catheter sepsis.154–158Staphylocuccus aureus and coagulase- negative staphylococci are the most common infect- ing (and colonizing) organisms, followed by entero- cocci, Gram-negative bacteria, species.154–158 A number of methods of reducing catheter colo- nization and blood stream infection have been stud- ied, including topical antibiotics, antimicrobial flush solutions, subcutaneous tunneling of catheters, and 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.102–108However, 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.177Platt and colleagues177demonstrated that in hospitalized pa- tients bacteriuria with $ 105CFUs 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 and Candida 860 Reviews

7. catheter for monitoring fluid balance and renal function. The patients’ colonic flora rapidly colonizes the urinary tract in these patients.178Stark and Maki179have demonstrated that in catheterized pa- tients, bacteria in the urinary system rapidly prolif- erate to exceed 105CFU/mL over a short period of time. Bacteriuria, defined as a quantitative culture of $ 105CFU/mL, has been reported in up to 30% of catheterized hospitalized patients.180The terms “bacteriuria” and “UTI” are generally although in- correctly 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 inflam- matory response.181UTI implies an infection of the urinary tract.181Criteria have not been developed for differentiating asymptomatic colonization of the uri- nary 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 accompa- nying pyuria.182It is therefore unclear how many catheterized patients with . 105CFU/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.183Therefore, the surveillance for and treat- ment of isolated bacteruria in most ICU patients is currently not recommended.184Bacteriuria should, however, be treated following urinary tract manipu- lation or surgery, in patients with kidney stones, and in patients with urinary tract obstruction. nous colitis is the most dramatic manifestation of C difficile infection; these patients have marked ab- dominal 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.190–192The “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.190–192It is suggested that two stool specimens be examined for leukocytes and toxin ELISA test.190Should 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 Nosoco- mial Infection Study reported that 7% of all nosoco- mial infections were due to candidal species.193In the EPIC study,10417% of nosocomial ICU infec- 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 courses of antibiotics.53Candida species are partic- ularly important pathogens in patients with ongoing peritonitis.52–54It is important to realize that Can- dida 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%.53It 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.194,195Indication for initiation of antifungal therapy in these patients should be based on histologic evidence or identifica- tion 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 CLOSTRIDIA DIFFICILE Colitis C difficile, the agent that causes pseudomembra- nous colitis and antibiotic-associated diarrhea, has become a common nosocomial pathogen.185–187Ap- proximately 20% of all hospitalized patients become “infected” with C difficile, of whom only about a third develop diarrhea.185–187The majority of hospi- tal inpatients infected with C difficile are asymptom- atic.188,189C difficile infection commonly presents with mild to moderate diarrhea, sometimes accom- panied by lower abdominal cramping. Symptoms usually begin during or shortly after antibiotic ther- apy but are occasionally delayed for several weeks. Severe colitis without pseudomembrane formation may occur with profuse, debilitating diarrhea, ab- dominal pain, and distension. Common systemic manifestations include fever, nausea, anorexia, and malaise. A neutrophilia and increased numbers of fecal leukocytes are common.188,189Pseudomembra- 861 CHEST / 117 / 3 / MARCH, 2000

8. observed in up to 80% of patients with systemic candidiasis, candidemia from a urinary tract source is extremely rare.54 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 the single most important factor governing the sensitivity of blood cultures.180,206,208,209Therefore, it is recom- mended 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.210Once 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 ther- apy. However in some cases bacteremia may be prolonged, necessitating further blood cultures dur- ing treatment (eg, staphylococcal bacteremia). Other Infections Nosocomial meningitis is exceedingly uncommon in hospitalized patients who have not undergone a neurosurgical procedure.196,197Lumbar puncture, therefore, need not be performed routinely in ICU patients (nonneurosurgical) who develop a fever unless they have meningeal signs or contiguous infection.196,197In patients who have undergone abdominal surgery and develop a fever, intra-abdom- inal infection must always be excluded. CT scanning of 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 Scintigraphy, CT Scanning, and Ultrasound Examinations It is important that blood cultures as well as other appropriate cultures be performed before the initi- ation 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 Scintigraphic scanning techniques have a low sen- sitivity and specificity in ICU patients and are there- fore not recommended.1,211,212The advantages of CT scanning and/or ultrasound over scintigraphy is that the results of the test can be obtained immedi- ately with superior anatomic resolution, which can be used to guide drainage procedures. Blood Cultures An Approach to the Critically Ill Patient With Fever Bacteremia and candidemia have been docu- mented in up to 10% of ICU patients and are an important cause of morbidity and mortality in the ICU.200–203Blood cultures are therefore indicated in all 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 Beeson205reported 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 in- creases 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.206Colonization of the lumen of central venous catheters occurs within a short period of time after placement. Therefore, From the forgoing information, the following ap- proach 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 infec- tions (eg, purulent nasal discharge, abdominal ten- derness, profuse green diarrhea), a focused diagnos- tic 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 (102°F), it may be prudent to perform blood cultures and then observe the patient before embarking on further diagnostic tests and commencing empiric temperature is . 39°C 862 Reviews

9. Figure 1. Fever diagnostic algorithm. Dx 5 diagnostic; ABx 5 antibiotics; Rx 5 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 en- teral feeds) CT scan of abdomen is indicated. Pa- tients 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 863 CHEST / 117 / 3 / MARCH, 2000

10. patients clinical condition is essential. If fever per- sists 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 eosino- phils (diagnosis of drug fever), and abdominal imaging. References 1 Meduri GU, Mauldin GL, Wunderink RG, et al. Causes of fever and pulmonary densities in patients with clinical manifestations of ventilator-associated pneumonia. Chest 1994; 106:221–235 2 Mackowiak PA. Concepts of fever. Arch Intern Med 1998; 158:1870–1881 3 Saper CB, Breder CD. The neurologic basis of fever. N Engl J Med 1994; 330:1880–1886 4 Dinarello CA, Cannon JG, Mancilla J. Interleukin-6 as an endogenous pyrogen: induction of prostaglandin E2 in brain but not peripheral blood mononuclear cells. Brain Res 1991; 562:199–206 5 Dinarello CA, Wolff SM. The role of interleukin-1 in disease. N Engl J Med 1993; 328:106–113 6 Dinarello CA, Cannon JG, Mier JW, et al. Multiple biolog- ical activities of human recombinant interleukin 1. J Clin Invest 1986; 77:1734–1739 7 Dinarello CA. Interleukin-1 and the pathogenesis of the acute-phase response. N Engl J Med 1984; 311:1413–1418 8 Fontana A, Weber E, Dayer JM. Synthesis of interleukin 1/endogenous pyrogen in the brain of endotoxin-treated mice: a step in fever induction? J Immunol 1984; 133:1696– 1698 9 Gourine AV, Rudolph K, Tesfaigzi J, et al. Role of hypotha- lamic interleukin-1 beta in fever induced by cecal ligation and puncture in rats. Am J Physiol 1998; 275(3 Pt 2):R754– R761 10 Leon LR, White AA, Kluger MJ. Role of IL-6 and TNF in thermoregulation and survival during sepsis in mice. Am J Physiol 1998; 275(1 Pt 2):R269–R277 11 Kluger MJ, Kozak W, Leon LR, et al. The use of knockout mice to understand the role of cytokines in fever. Clin Exp Pharmacol Physiol 1998; 25:141–144 12 Klir JJ, McClellan JL, Kluger MJ. Interleukin-1 beta causes the increase in anterior hypothalamic interleukin-6 during LPS-induced fever in rats. Am J Physiol 1994; 266(6 Pt 2):R1845–R1848 13 Klir JJ, Roth J, Szelenyi Z, et al. Role of hypothalamic interleukin-6 and tumor necrosis factor-alpha in LPS fever in rat. Am J Physiol 1993; 265(3 Pt 2):R512–R517 14 Mackowiak PA, Bartlett JG, Borden EC, et al. Concepts of fever: recent advances and lingering dogma. Clin Infect Dis 1997; 25:119–138 15 Kluger MJ, Kozak W, Conn CA, et al. The adaptive value of fever. Infect Dis Clin N Am 1996; 10:1–20 16 Kluger MJ, Vaughn LK. Fever and survival in rabbits infected with Pasteurella multocida. J Physiol 1978; 282: 243–251 17 Bernheim HA, Kluger MJ. Fever and antipyresis in the lizard Dipsosaurus dorsalis. Am J Physiol 1976; 231:198–203 18 D’Alecy LG, Kluger MJ. Avian febrile response. J Physiol 1975; 253:223–232 19 Vaughn LK, Bernheim HA, Kluger MJ. Fever in the lizard Dipsosaurus dorsalis. Nature 1974; 252:473–474 20 Covert JB, Reynolds WW. Survival value of fever in fish. Nature 1977; 267:43–45 21 Bernheim HA, Kluger MJ. Fever: effect of drug-induced antipyresis on survival. Science 1976; 193:237–239 22 Kluger MJ, Ringler DH, Anver MR. Fever and survival. Science 1975; 188:166–168 23 Jampel HD, Duff GW, Gershon RK, et al. Fever and immunoregulation: III. Hyperthermia augments the pri- mary in vitro humoral immune response. J Exp Med 1983; 157:1229–1238 24 van Oss CJ, Absolom DR, Moore LL, et al. Effect of 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 prepon- derance 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 acetamino- phen. Based on this data, it is recommenced that febrile episodes not be routinely treated with anti- pyretic therapy; an evaluation of the relative benefits and 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 the temperature increases above 40°C (104°F).2,14,37,213–217 Hypothermia blankets are frequently used in ICU patients with febrile episodes.218However, studies have demonstrated that hypothermia blankets are no more effective in cooling patients than are antipy- retic agents.218Furthermore, the use of hypothermia blankets is associated with large temperature fluctu- ations and rebound hyperthermia.218In 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 colleagues219demonstrated that active external cooling in volunteers with in- duced fever increased oxygen consumption by 35 to 40% and was associated with a significant increase in epinephrine and norepinephrine levels. 864 Reviews

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