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Postgraduate Education Corner: Contemporary Reviews in Critical Care Medicine |

Persistent Fever in the ICUPersistent Fever in the ICU FREE TO VIEW

Tayyab Rehman, MD; Bennett P. deBoisblanc, MD
Author and Funding Information

From the Section of Pulmonary & Critical Care Medicine (Drs Rehman and deBoisblanc), Department of Medicine, LSU Health Sciences Center, New Orleans, LA.

Correspondence to: Bennett P. deBoisblanc, MD, Section of Pulmonary & Critical Care Medicine, Department of Medicine, LSU Health Sciences Center, 1901 Perdido St, MEB, Ste 3205, New Orleans, LA 70112; e-mail: bdeboi@lsuhsc.edu


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(1):158-165. doi:10.1378/chest.12-2843
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Disorders of elevated body temperature may be classified as either fever or hyperthermia. Fever is caused by a pyrogen-mediated upward adjustment of the hypothalamic thermostat; hyperthermia results from a loss of physiologic control of temperature regulation. Fever in the ICU can be due to infectious or noninfectious causes. The initial approach to a febrile, critically ill patient should involve a thoughtful review of the clinical data to elicit the likely source of fever prior to the ordering of cultures, imaging studies, and broad-spectrum antibiotics. Both high fever and prolonged fever have been associated with increased mortality; however, a causal role for fever as a mediator of adverse outcomes during non-neurologic critical illness has not been established. Outside the realm of acute brain injury, the practice of treating fever remains controversial. To generate high-quality, evidence-based guidelines for the management of fever, large, prospective, multicenter trials are needed.

Fever is a ubiquitous finding among patients admitted to the ICU. The clinical significance of fever varies with its context. On one hand, fever may represent a response to a serious perturbation in the steady state, such as when an infection is present. On the other, fever may occur as a nonspecific physical sign accompanying critical illness, as is often the case in postoperative patients. Single temperature elevations that resolve without treatment are seldom of significance; however, persistently elevated temperature has major implications for the care of critically ill patients.1 Not infrequently, the finding of fever in the ICU triggers an unfocused, multimodal diagnostic workup and empirical dispensation of antimicrobial agents. Such an approach contributes to disruption of care, patient discomfort, antimicrobial resistance, and increased cost.2 This article recapitulates the salient aspects of febrile critical illness; discusses recent advances in its epidemiology, evaluation, and treatment; and advocates for a rational approach to its management.

As homeothermic organisms, humans must tightly regulate their core body temperature to maintain optimal conditions for fundamental biologic processes.3 The target temperature that the thermoregulatory system aims to achieve (ie, the set point) is determined in the preoptic region of the hypothalamus. To minimize variation from the set point, the hypothalamus integrates processes that generate, conserve, or dissipate heat to the environment.

Abnormally elevated body temperature can result from two pathophysiologically distinct disorders of thermoregulation:

  • 1. Fever results from an upward adjustment in the thermoregulatory set point. Pyrogens (eg, bacterial lipopolysaccharide, tumor necrosis factor-α, IL-1) induce the synthesis of prostaglandin E2, which raises the set point in the anterior hypothalamus. The hypothalamus, in turn, activates heat generation (through shivering and increased metabolism) and heat conservation (through peripheral vasoconstriction) to bring up the body temperature.4

  • 2. Hyperthermia is a pathophysiologic state of uncontrolled heat production (eg, malignant hyperthermia) and/or impaired heat dissipation (eg, heat stroke). There is no adjustment of the hypothalamic set point during hyperthermic syndromes.5

Normal oral temperature is approximately 36.8°C (98.2°F) with an amplitude of variability of 0.5°C between the morning and the evening.6 During critical illness, the variability can be even greater due to disruption of circadian rhythm, autonomic disturbances, drugs, the ICU environment, and artifacts. Selecting a single threshold to identify fever in the ICU involves a tradeoff between sensitivity and specificity, with significant implications for care. In the interest of standardization, a joint task force of the American College of Critical Care Medicine (ACCM) and the Infectious Diseases Society of America (IDSA) defined ICU fever as a core body temperature ≥ 38.3°C (101°F).7 Importantly, the task force emphasized that any threshold is arbitrary unless informed by the clinical context.

Historically, the pulmonary artery catheter thermistor has constituted the gold standard for the measurement of the core body temperature.8 Rectal probe, bladder thermistor, and infrared tympanic thermometer have been shown to closely approximate core temperature measurements.9 In contrast, the oral and the axillary sites are unreliable in critically ill patients and should be avoided. Serial temperature measurements should be performed using the same site, the same instrument, and the same technique, and these specifics should be clearly documented in the patient’s medical record.

The prevalence of ICU fever ranges from 26% to 70% depending on the population studied and the definition of fever used.10-13 Infectious and noninfectious causes are equally represented.10,11 Young age, male sex, septic shock, trauma, emergent surgery, and neurocritical illness are associated with the development of fever.11-13 Prolonged fever (lasting > 5 days) and high fever (≥ 39.3°C) are more likely to be infectious.10,13 In surgical ICUs, fever occurs most commonly on postoperative day 1.11

Both fever and admission hypothermia are associated with an increased ICU length of stay.12 Prolonged fever10 and high fever13,14 are also associated with a significantly increased risk of death. Whether fever plays a causal role in mediating adverse outcomes in nonneurologic critical illness remains to be elucidated.

The approach to fever in the ICU is at times reflexive, equating fever with infection. The finding of elevated body temperature triggers an order set that includes culturing of several body sites (eg, blood, urine, sputum), imaging of the chest and/or abdomen and the initiation of broad-spectrum antibiotics. To promote a more rational approach, a joint American College of Critical Care Medicine and Infectious Diseases Society of America guideline was issued in 2008.7 Recognizing that the sources of fever may be either infectious or noninfectious, the guideline panel recommended that “any unexplained temperature elevation merits a clinical assessment by a healthcare professional that includes a review of the patient’s history and a focused physical examination before any laboratory tests or imaging procedures are ordered.”7 The goal is to promote individualized management based on consideration of factors unique to each patient. A head-to-toe approach, such as the one suggested in Table 1, can provide a framework for the formulation of a probable differential diagnosis and cost-effective workup.

Table Graphic Jump Location
Table 1 —Common Causes of Persistent Fever in the ICU: A Head-to-Toe Approach to Differential Diagnosis

CVC = central venous catheter; PICC = peripherally inserted central catheter; SBP = spontaneous bacterial peritonitis; SLE = systemic lupus erythematosus; UTI = urinary tract infection.

Approximately 50% of fevers in the ICU are due to infections.10 Nearly all patients in the ICU undergo placement of devices (eg, central venous catheters [CVCs], arterial lines, urinary catheters, endotracheal tubes, and nasogastric tubes) that bypass natural host defenses and provide easy portals of entry to microorganisms. The use of a “daily goals” checklist to assess ongoing need of these devices is an effective strategy to reduce the rates of ICU-acquired infections.

When clinical evidence makes infection the likely source of fever, culturing of the blood should be performed, preferably prior to initiating antibiotics.15 Three blood cultures achieve a 99% detection rate of true bacteremia.16,17 All blood cultures can be drawn simultaneously, as the yield is not increased by serial draws.18 However, a separate venipuncture site should be used for each blood culture.17 A blood volume of ≥ 20 mL per culture is required for optimal yield.17

Central Line-Associated Blood Stream Infection

For surveillance purposes, a blood stream infection in a patient with a CVC of ≥ 48 h duration is considered as a central line-associated blood stream infection (CLABSI) provided that it is not related to an infection at another site (eg, pneumonia, pyelonephritis).19 Using this definition, the rate of CLABSI in the ICU is estimated to vary from 1.4 to 5.5 per 1,000 catheter-days.20

In evaluating a patient in the ICU with fever, a detailed examination of the CVC insertion site should be performed, looking for signs of local inflammation or purulence. Any exudate should be swabbed and sent for Gram staining and culture. In hemodynamically stable patients, a CVC without local signs of infection can be left in place awaiting culture results. However, in unstable patients, it is best to remove the suspicious catheter without waiting for microbiologic confirmation.21 Vascular access in these cases should be secured using a fresh catheter insertion site prior to the removal of the old line.

Paired blood cultures, from the catheter and from a peripheral venipuncture, should be drawn simultaneously. If the blood culture from the catheter becomes positive ≥ 2 h before the one obtained from the peripheral site and both cultures show growth of the same organism (differential time to positivity method), the diagnosis of CLABSI is established.22 Alternatively, a quantitative blood culture showing a greater than fivefold higher colony count from the catheter also suggests CLABSI.21 Finally, semiquantitative culturing of 5 cm of the catheter tip (roll-plate method) should be performed on all CVCs removed from patients with suspected CLABSI. Isolation of < 15 colony-forming units (CFU) is consistent with contamination, while ≥ 15 CFU per catheter tip represents catheter colonization.23 A diagnosis of CLABSI is confirmed only if catheter colonization is accompanied by a positive peripheral blood culture with an identical organism.24 Though not widely available, quantitative culturing of catheter segments (sonication method) provides more accurate results, especially for catheters that have been in place for a longer time.24,25

Ventilator-Associated Respiratory Infection

Mechanical ventilation with an endotracheal tube increases the risk of pneumonia sixfold to 20-fold.26,27 The attributable mortality from ventilator-associated pneumonia (VAP) is estimated around 10%.28 Importantly, VAP is preventable, and appropriate and timely therapy can improve outcomes.27

More recent data suggest that on-demand chest radiography is as safe as routine daily chest radiography for patients undergoing mechanical ventilation.29,30 In the presence of fever, leukocytosis, purulent secretions, and declining Pao2/Fio2, a chest radiograph (CXR) is indicated. There is no radiographic pattern diagnostic of VAP, but the finding of a new or progressive pulmonary infiltrate is supportive. When symptoms and signs of lower respiratory tract infection are present but the CXR does not demonstrate an infiltrate, the preferred diagnostic label is ventilator-associated tracheobronchitis. Ventilator-associated tracheobronchitis is increasingly viewed as a precursor to VAP.31

Evaluation of lower respiratory secretions is central to the diagnostic workup of VAP. The precise sampling approach (noninvasive vs invasive) remains controversial. Noninvasive approaches include tracheobronchial aspiration and blind mini-BAL. Invasive approaches use bronchoscopy to perform sampling via BAL or protected specimen brushing. A large multicenter trial demonstrated the equivalency of endotracheal aspiration to bronchoscopic BAL sampling.32 However, the study excluded patients infected or colonized with Pseudomonas species and methicillin-resistant Staphylococcus aureus, somewhat limiting its external validity.33 A 2012 meta-analysis concluded that invasive strategies do not result in reduced mortality, reduced time in the ICU or on mechanical ventilation, or higher rates of antibiotic change when compared with noninvasive strategies.34

Urinary Tract Infection

An overwhelming majority of urinary tract infections (UTIs) in the ICU are catheter related, with an estimated incidence of nine to 11 per 1,000 catheter-days. Secondary bacteremia occurs in only 1% to 5% of these cases.35 Although ICU-acquired UTI is associated with increased length of stay, cost, and crude mortality, it is not an independent risk factor for death.36

Typical symptoms of UTI (ie, dysuria, urgency, pelvic discomfort, or flank pain) are infrequently reported by patients with catheters in the ICU and have little predictive value.37 Moreover, neither fever nor leukocytosis is associated with a positive urine culture during the first 14 days of ICU stay.38 Results of routine urinalysis are insensitive but relatively specific for UTI in critically ill patients who are catheterized.39,40

In the evaluation of ICU fever, it is recommended to restrict urine cultures to patients with catheters and no other obvious source of fever. The urine sample should be obtained from the catheter port, not from the urine bag.41 Any growth ≥ 102 CFU/mL of urine in a patient with a catheter is abnormal and indicates at least colonization of the urinary tract.41 The traditionally used criterion of ≥ 105 CFU/mL is too insensitive for patients with catheters. As a general guideline, we recommend empirical antibiotics for presumed UTI in febrile patients with catheters when the results of urinalysis are positive and no other source of fever or infection is obvious. The results of the urine culture should be used to guide rapid antibiotic de-escalation.

Clostridium difficile Infection

By definition, patients with well-formed stools do not have Clostridium difficile infection (CDI). However, a patient in the ICU who has fever, leukocytosis, and diarrhea should be assessed for CDI. Fever is noted in 30% and leukocytosis in 50% of documented CDI cases.42 Severe CDI may also present with abdominal pain, ileus, and a systemic inflammatory response.42

Laboratory assessment of suspected CDI includes enzyme immunoassay for toxin A and toxin B (rapid and widely available but insensitive), cell cytotoxicity assay (highly specific, but of limited availability with a turnaround time of ≥ 48 h), and stool culture (costly and time consuming, with frequent false-positive results).43,44 Real-time polymerase chain reaction testing for toxin A or toxin B genes is both rapid and accurate and has become the preferred option in the ICU setting.45 In severe cases, endoscopic finding of pseudomembranes and CT scan evidence of colonic wall thickening, pericolonic stranding, and megacolon are also supportive of the diagnosis.46

Oral vancomycin, either alone or in combination with metronidazole, is recommended for critically ill patients with severe CDI. When ileus is present, vancomycin retention enemas should be added. Colectomy should be considered for patients with fulminant CDI characterized by one or more of the following: septic shock, toxic megacolon, acute abdomen, serum lactate > 5 mM, and peripheral blood WBC > 50,000/μL.43

Nosocomial Sinusitis

The paranasal sinuses can become colonized and infected if there is anatomic obstruction of ostial drainage. Nasogastric tubes, nasotracheal tubes, and nasal packs are major risk factors for nosocomial sinusitis.47 While oral placement of gastric and endotracheal tubes can reduce the incidence of nosocomial sinusitis, the risk remains elevated compared with patients without such devices.47 In a prospective study of orotracheally intubated patients with a new-onset fever > 48 h after ICU admission, sinusitis was found to be the sole cause of fever in 16% of patients and a contributory cause in 30% of patients.48

In the presence of risk factors for nosocomial sinusitis, purulent nasal drainage, and no other explanation of fever, a CT scan of the sinuses should be performed. The finding of an air-fluid level or complete opacification of a sinus constitutes radiographic sinusitis. The diagnostic accuracy of CT scan is > 90% when accompanied by the finding of purulence in the middle meatus.49 Ultrasonography is not as accurate as CT scanning but has the advantage of point-of-care testing with real-time interpretation of results and is the preferred imaging modality in patients who cannot be safely transported outside the ICU. However, ultrasonography is highly operator dependent and does not provide adequate assessment of the frontal, ethmoid, and sphenoidal sinuses.50,51

Febrile, critically ill patients with radiographic sinusitis should undergo diagnostic sampling of the sinus fluid prior to the initiation of antibiotics. Endoscopic-guided middle meatus aspiration is the modality of choice for this purpose and is recommended in preference to the conventional sinus puncture and aspiration.52

About one-half of all fevers in the ICU are due to noninfectious etiologies.2,10 A major goal of the evaluation of persistent fever is to search for clinical clues of noninfectious sources of fever. Infectious and noninfectious fever may occur together in the same patient.

Hyperthermic Syndromes

While pathophysiologically distinct, hyperthermic syndromes can clinically mimic fever. Commonly encountered examples include environmental heat-related illness, malignant hyperthermia, serotonin syndrome and neuroleptic malignant syndrome (NMS). In addition, recreational drug use (eg, cocaine, methamphetamines, mephedrone [bath salts]), and agitated withdrawal from alcohol, opiates, or benzodiazepines can also cause significant elevations of the core body temperature.2

Environmental heat-related illness results from a failure of heat dissipation. The spectrum of illness ranges from minor heat cramps, heat syncope, or heat exhaustion to the potentially life-threatening heat stroke (core body temperature > 40°C with significant CNS dysfunction).5 During climatic heat waves, the elderly with limited mobility and chronic medical conditions constitute a cohort at particularly high risk.

Malignant hyperthermia is a pharmacogenetic syndrome associated with the administration of succinylcholine or inhalational anesthetics.53 In susceptible individuals, these drugs induce dysregulation of calcium homeostasis in the skeletal muscles, resulting in intense tonic contraction and uncontrolled thermogenesis. The syndrome is clinically obvious within 30 min of drug administration, although presentations delayed up to 24 h have been reported. Treatment includes prompt discontinuation of the offending agent, external cooling, IV fluids, and dantrolene.

Serotonin syndrome is caused by the overactivation of 5-HT1a and 5-HT2a receptors. It commonly occurs in patients taking selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) who then receive either another drug that possesses serotonergic activity or that interferes with the cytochrome P450 metabolism of SSRIs or TCAs.54 Clinically, the syndrome manifests as a triad of altered mental status, autonomic hyperactivity, and neuromuscular abnormalities. Discontinuation of the offending agent can lead to rapid resolution of symptoms. Benzodiazepines and the serotonin antagonist, cyproheptadine, are used to treat severe cases.

NMS is precipitated by the antidopaminergic activity of neuroleptic agents.54 The clinical presentation of NMS resembles that of serotonin syndrome (Table 2). NMS can develop at any time during treatment, while serotonin syndrome usually develops within minutes to hours after exposure to the offending drug. In addition to stopping neuroleptic medications, bromocriptine, a central dopamine agonist, is used for treatment.

Table Graphic Jump Location
Table 2 —Neuroleptic Malignant Syndrome vs Serotonin Syndrome

ADR = adverse drug reaction; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.

Drug Fever

Almost any drug can cause fever, but the ones most commonly implicated in the ICU include antibiotics (especially β-lactams), anticonvulsants (diphenylhydantoins), and antiarrhythmics (quinidine and procainamide).55 No fever pattern is characteristic of drug fever. Relative bradycardia, rash, and eosinophilia are seen in a minority of cases.56 The temporal association between the initiation of a drug and the onset of fever or discontinuation of a suspected drug and resolution of fever provides helpful clues. Drug fever remains a diagnosis of exclusion.

Postoperative Fever

Fever is common in the first 72 h after surgery and is predominantly noninfectious. A rational approach to postoperative fever is to clinically assess for infectious sources, but initiate a workup only if clues other than fever or leukocytosis point toward an infection. The yield of a nonfocused approach is low and adds significantly to cost of care. Routine chest radiography and sputum analysis in the early postoperative period are not indicated, as they fail to prompt a change in management.57 In a retrospective review of 537 patients undergoing major gynecologic surgery, the prevalence of early postoperative fever was 39%.58 Of the 77 patients evaluated with blood cultures, none had a positive result. In a separate cohort of 1,100 patients who had undergone orthopedic surgery, the diagnostic yield of CXRs, blood cultures, and urine cultures was 2%, 6%, and 22%, respectively; however, the yield increased substantially for fever occurring after postoperative day 3 (OR, 23.3), for high fever ≥ 39°C (OR, 2.4), and for persistent or recurrent fever (OR, 8.6).59 The average cost of a fever evaluation was $960, while the cost associated with a change in treatment was $8,208.59 More recent studies have found no association between fever and postoperative atelectasis.60

VTE

In the PIOPED (Prospective Investigation of Pulmonary Embolism Diagnosis) study, fever ≥ 37.8°C without an alternative cause was noted in 14% of patients with pulmonary embolism.61 VTE-related fever is usually low grade, short-lived, and resolves with anticoagulation therapy.62 VTE-related fever is associated with an increased 30-day mortality.63

Acalculous Cholecystitis

Spontaneous ischemic or inflammatory injury of the gall bladder may develop during critical illness. Occlusion of the cystic duct, bile stasis, distension, and secondary infection can lead to gangrene and perforation of the gall bladder.64 The diagnosis should be suspected in any patient with fever, leukocytosis, and a right upper quadrant pain. Bedside ultrasonography has a sensitivity and specificity of > 80%.65 CT scanning performs slightly better but is limited by the need to transport critically ill patients to the radiology suite.65 In patients at high surgical risk, percutaneous cholecystostomy can prove a life-saving intervention.66

To lower the core body temperature, two approaches can be used: pharmacologic agents, such as acetaminophen and nonsteroidal antiinflammatory drugs; and physical measures, such as ice packs, cooling blankets, and endovascular cooling devices.

The choice of antipyretic agent should be informed by the presence or absence of hepatic and renal injury, and the risk of GI bleeding.67 Acetaminophen should be avoided in patients with liver failure, but may be preferred over ibuprofen in the setting of coagulopathy, GI bleeding, and kidney injury. Physical measures offer more reliable temperature control68 and can successfully lower temperature even when pharmacologic antipyretic therapy has failed.69 External cooling can provoke shivering, which may necessitate the use of sedatives, and even paralytics.

While a standard practice in patients with acute brain injury,70 the value of treatment of fever in patients with nonneurologic critical illness remains obscure. In a randomized, controlled trial, 82 trauma patients with fever (≥ 38.5°C) but without brain injury were treated with either an “aggressive” or a “permissive” fever control strategy.71 Patients in the “aggressive” arm received acetaminophen 650 mg q6h for temperature ≥ 38.5°C, with the addition of a cooling blanket for temperature ≥ 39.5°C. Patients in the “permissive” arm were not treated unless the core temperature was ≥ 40°C, at which point they received acetaminophen and cooling blankets to lower their temperature below 40°C. The study was stopped after an interim analysis revealed a trend toward higher mortality and higher rates of infection in the “aggressive” arm (seven deaths vs one death; P = .06).

In a multicenter trial, 200 febrile (≥ 38.3°C) patients with respiratory failure and vasopressor-dependent septic shock were randomized to either external cooling targeting normothermia (36.5°C-37°C) or to usual care without cooling.72 The primary end point, a 50% reduction in the baseline vasopressor dose at 48 h, was not significantly different between the two groups. However, a few secondary end points favored the external cooling strategy, including a lower vasopressor dose at 12 h and greater shock reversal. Importantly, the mortality was not significantly different either at ICU or at hospital discharge. Similarly, a 2013 meta-analysis including 399 patients from five randomized trials found no survival benefit for antipyretic therapy in febrile critical illness (acute neurologic injury excluded).73

Fever in the ICU is a common clinical entity. High fever and prolonged fever are associated with an increased risk of death, although a causal relationship has not been established. The reflexive practice of equating fever with infection should be replaced with one that begins with a thoughtful clinical assessment and takes into account both infectious and noninfectious etiologies of elevated body temperature. With the exception of acute brain injury and hyperthermic syndromes, the practice of temperature control in the ICU remains controversial. To develop an evidence-based approach to the management of ICU fever, multicenter, randomized controlled trials are needed.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

CDI

Clostridium difficile infection

CFU

colony-forming units

CLABSI

central line-associated blood stream infection

CVC

central venous catheter

CXR

chest radiograph

NMS

neuroleptic malignant syndrome

SSRI

selective serotonin reuptake inhibitor

TCA

tricyclic antidepressant

UTI

urinary tract infection

VAP

ventilator-associated pneumonia

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Bagshaw SM, Laupland KB. Epidemiology of intensive care unit-acquired urinary tract infections. Curr Opin Infect Dis. 2006;19(1):67-71. [CrossRef] [PubMed]
 
Tambyah PA, Maki DG. Catheter-associated urinary tract infection is rarely symptomatic: a prospective study of 1,497 catheterized patients. Arch Intern Med. 2000;160(5):678-682. [PubMed]
 
Golob JF Jr, Claridge JA, Sando MJ, et al. Fever and leukocytosis in critically ill trauma patients: it’s not the urine. Surg Infect (Larchmt). 2008;9(1):49-56. [CrossRef] [PubMed]
 
Tambyah PA, Maki DG. The relationship between pyuria and infection in patients with indwelling urinary catheters: a prospective study of 761 patients. Arch Intern Med. 2000;160(5):673-677. [PubMed]
 
Schwartz DS, Barone JE. Correlation of urinalysis and dipstick results with catheter-associated urinary tract infections in surgical ICU patients. Intensive Care Med. 2006;32(11):1797-1801. [CrossRef] [PubMed]
 
Wilson ML, Gaido L. Laboratory diagnosis of urinary tract infections in adult patients. Clin Infect Dis. 2004;38(8):1150-1158. [CrossRef] [PubMed]
 
Bobo LD, Dubberke ER, Kollef M. Clostridium difficile in the ICU: the struggle continues. Chest. 2011;140(6):1643-1653. [CrossRef] [PubMed]
 
Cohen SH, Gerding DN, Johnson S, et al; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America. Clinical practice guidelines forClostridium difficileinfection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-455. [CrossRef] [PubMed]
 
Leclair MA, Allard C, Lesur O, Pépin J. Clostridium difficileinfection in the intensive care unit. J Intensive Care Med. 2010;25(1):23-30. [CrossRef] [PubMed]
 
Stamper PD, Alcabasa R, Aird D, et al. Comparison of a commercial real-time PCR assay for tcdB detection to a cell culture cytotoxicity assay and toxigenic culture for direct detection of toxin-producingClostridium difficilein clinical samples. J Clin Microbiol. 2009;47(2):373-378. [CrossRef] [PubMed]
 
Riddle DJ, Dubberke ER. Clostridium difficileinfection in the intensive care unit. Infect Dis Clin North Am. 2009;23(3):727-743. [CrossRef] [PubMed]
 
Rouby JJ, Laurent P, Gosnach M, et al. Risk factors and clinical relevance of nosocomial maxillary sinusitis in the critically ill. Am J Respir Crit Care Med. 1994;150(3):776-783. [CrossRef] [PubMed]
 
van Zanten AR, Dixon JM, Nipshagen MD, de Bree R, Girbes AR, Polderman KH. Hospital-acquired sinusitis is a common cause of fever of unknown origin in orotracheally intubated critically ill patients. Crit Care. 2005;9(5):R583-R590. [CrossRef] [PubMed]
 
Kountakis SE, Burke L, Rafie JJ, Bassichis B, Maillard AA, Stiernberg CM. Sinusitis in the intensive care unit patient. Otolaryngol Head Neck Surg. 1997;117(4):362-366. [CrossRef] [PubMed]
 
Tiedjen KU, Becker E, Heimann KD, Knorz S, Hildmann H. Value of B-image ultrasound in diagnosis of paranasal sinus diseases in comparison with computerized tomography [in German]. Laryngorhinootologie. 1998;77(10):541-546. [CrossRef] [PubMed]
 
Zagólski O, Strek P. Ultrasonography of the nose and paranasal sinuses [in Polish]. Pol Merkur Lekarski. 2007;22(127):32-35. [PubMed]
 
Talmor M, Li P, Barie PS. Acute paranasal sinusitis in critically ill patients: guidelines for prevention, diagnosis, and treatment. Clin Infect Dis. 1997;25(6):1441-1446. [CrossRef] [PubMed]
 
Denborough M. Malignant hyperthermia. Lancet. 1998;352(9134):1131-1136. [CrossRef] [PubMed]
 
McAllen KJ, Schwartz DR. Adverse drug reactions resulting in hyperthermia in the intensive care unit. Crit Care Med. 2010;38(6)(Suppl):S244-S252. [CrossRef] [PubMed]
 
Mackowiak PA. Drug fever: mechanisms, maxims and misconceptions. Am J Med Sci. 1987;294(4):275-286. [CrossRef] [PubMed]
 
Mackowiak PA, LeMaistre CF. Drug fever: a critical appraisal of conventional concepts. An analysis of 51 episodes in two Dallas hospitals and 97 episodes reported in the English literature. Ann Intern Med. 1987;106(5):728-733. [CrossRef] [PubMed]
 
Simon SD, Castle EP, Ferrigni RG, Andrews PE. Routine postoperative chest x-ray following laparoscopic nephrectomy. JSLS. 2005;9(2):205-207. [PubMed]
 
Fanning J, Neuhoff RA, Brewer JE, Castaneda T, Marcotte MP, Jacobson RL. Yield of postoperative fever evaluation. Prim Care Update Ob Gyns. 1998;5(4):146. [CrossRef] [PubMed]
 
Ward DT, Hansen EN, Takemoto SK, Bozic KJ. Cost and effectiveness of postoperative fever diagnostic evaluation in total joint arthroplasty patients. J Arthroplasty. 2010;25(6)(suppl):43-48. [CrossRef] [PubMed]
 
Mavros MN, Velmahos GC, Falagas ME. Atelectasis as a cause of postoperative fever: where is the clinical evidence? Chest. 2011;140(2):418-424. [CrossRef] [PubMed]
 
Stein PD, Afzal A, Henry JW, Villareal CG. Fever in acute pulmonary embolism. Chest. 2000;117(1):39-42. [CrossRef] [PubMed]
 
Nucifora G, Badano L, Hysko F, Allocca G, Gianfagna P, Fioretti P. Pulmonary embolism and fever: when should right-sided infective endocarditis be considered? Circulation. 2007;115(6):e173-e176. [CrossRef] [PubMed]
 
Barba R, Di Micco P, Blanco-Molina A, et al. Fever and deep venous thrombosis. Findings from the RIETE registry. J Thromb Thrombolysis. 2011;32(3):288-292. [CrossRef] [PubMed]
 
Huffman JL, Schenker S. Acute acalculous cholecystitis: a review. Clin Gastroenterol Hepatol. 2010;8(1):15-22. [CrossRef] [PubMed]
 
Kiewiet JJ, Leeuwenburgh MM, Bipat S, Bossuyt PM, Stoker J, Boermeester MA. A systematic review and meta-analysis of diagnostic performance of imaging in acute cholecystitis. Radiology. 2012;264(3):708-720. [CrossRef] [PubMed]
 
Chung YH, Choi ER, Kim KM, et al. Can percutaneous cholecystostomy be a definitive management for acute acalculous cholecystitis? J Clin Gastroenterol. 2012;46(3):216-219. [CrossRef] [PubMed]
 
Plaisance KI. Toxicities of drugs used in the management of fever. Clin Infect Dis. 2000;31(suppl 5):S219-S223. [CrossRef] [PubMed]
 
Hoedemaekers CW, Ezzahti M, Gerritsen A, van der Hoeven JG. Comparison of cooling methods to induce and maintain normo- and hypothermia in intensive care unit patients: a prospective intervention study. Crit Care. 2007;11(4):R91. [CrossRef] [PubMed]
 
Carhuapoma JR, Gupta K, Coplin WM, Muddassir SM, Meratee MM. Treatment of refractory fever in the neurosciences critical care unit using a novel, water-circulating cooling device. A single-center pilot experience. J Neurosurg Anesthesiol. 2003;15(4):313-318. [CrossRef] [PubMed]
 
Diringer MN, Reaven NL, Funk SE, Uman GC. Elevated body temperature independently contributes to increased length of stay in neurologic intensive care unit patients. Crit Care Med. 2004;32(7):1489-1495. [CrossRef] [PubMed]
 
Schulman CI, Namias N, Doherty J, et al. The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surg Infect (Larchmt). 2005;6(4):369-375. [CrossRef] [PubMed]
 
Schortgen F, Clabault K, Katsahian S, et al. Fever control using external cooling in septic shock: a randomized controlled trial. Am J Respir Crit Care Med. 2012;185(10):1088-1095. [CrossRef] [PubMed]
 
Niven DJ, Stelfox HT, Laupland KB. Antipyretic therapy in febrile critically ill adults: A systematic review and meta-analysis. J Crit Care. 2013;28(3):303-310. [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1 —Common Causes of Persistent Fever in the ICU: A Head-to-Toe Approach to Differential Diagnosis

CVC = central venous catheter; PICC = peripherally inserted central catheter; SBP = spontaneous bacterial peritonitis; SLE = systemic lupus erythematosus; UTI = urinary tract infection.

Table Graphic Jump Location
Table 2 —Neuroleptic Malignant Syndrome vs Serotonin Syndrome

ADR = adverse drug reaction; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.

References

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Raad I, Hanna H, Maki D. Intravascular catheter-related infections: advances in diagnosis, prevention, and management. Lancet Infect Dis. 2007;7(10):645-657. [CrossRef] [PubMed]
 
Safdar N, Fine JP, Maki DG. Meta-analysis: methods for diagnosing intravascular device-related bloodstream infection. Ann Intern Med. 2005;142(6):451-466. [CrossRef] [PubMed]
 
Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J Respir Crit Care Med. 2002;165(7):867-903. [CrossRef] [PubMed]
 
American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171(4):388-416. [CrossRef] [PubMed]
 
Melsen WG, Rovers MM, Koeman M, Bonten MJ. Estimating the attributable mortality of ventilator-associated pneumonia from randomized prevention studies. Crit Care Med. 2011;39(12):2736-2742. [PubMed]
 
Hejblum G, Chalumeau-Lemoine L, Ioos V, et al. Comparison of routine and on-demand prescription of chest radiographs in mechanically ventilated adults: a multicentre, cluster-randomised, two-period crossover study. Lancet. 2009;374(9702):1687-1693. [CrossRef] [PubMed]
 
Oba Y, Zaza T. Abandoning daily routine chest radiography in the intensive care unit: meta-analysis. Radiology. 2010;255(2):386-395. [CrossRef] [PubMed]
 
Craven DE, Hjalmarson KI. Ventilator-associated tracheobronchitis and pneumonia: thinking outside the box. Clin Infect Dis. 2010;51(Suppl 1):S59-S66. [CrossRef] [PubMed]
 
Canadian Critical Care Trials Group. A randomized trial of diagnostic techniques for ventilator-associated pneumonia. N Engl J Med. 2006;355(25):2619-2630. [CrossRef] [PubMed]
 
Kollef MH. Diagnosis of ventilator-associated pneumonia. N Engl J Med. 2006;355(25):2691-2693. [CrossRef] [PubMed]
 
Berton DC, Kalil AC, Teixeira PJ. Quantitative versus qualitative cultures of respiratory secretions for clinical outcomes in patients with ventilator-associated pneumonia. Cochrane Database Syst Rev. 2012;1:CD006482. [PubMed]
 
Laupland KB, Bagshaw SM, Gregson DB, Kirkpatrick AW, Ross T, Church DL. Intensive care unit-acquired urinary tract infections in a regional critical care system. Crit Care. 2005;9(2):R60-R65. [CrossRef] [PubMed]
 
Bagshaw SM, Laupland KB. Epidemiology of intensive care unit-acquired urinary tract infections. Curr Opin Infect Dis. 2006;19(1):67-71. [CrossRef] [PubMed]
 
Tambyah PA, Maki DG. Catheter-associated urinary tract infection is rarely symptomatic: a prospective study of 1,497 catheterized patients. Arch Intern Med. 2000;160(5):678-682. [PubMed]
 
Golob JF Jr, Claridge JA, Sando MJ, et al. Fever and leukocytosis in critically ill trauma patients: it’s not the urine. Surg Infect (Larchmt). 2008;9(1):49-56. [CrossRef] [PubMed]
 
Tambyah PA, Maki DG. The relationship between pyuria and infection in patients with indwelling urinary catheters: a prospective study of 761 patients. Arch Intern Med. 2000;160(5):673-677. [PubMed]
 
Schwartz DS, Barone JE. Correlation of urinalysis and dipstick results with catheter-associated urinary tract infections in surgical ICU patients. Intensive Care Med. 2006;32(11):1797-1801. [CrossRef] [PubMed]
 
Wilson ML, Gaido L. Laboratory diagnosis of urinary tract infections in adult patients. Clin Infect Dis. 2004;38(8):1150-1158. [CrossRef] [PubMed]
 
Bobo LD, Dubberke ER, Kollef M. Clostridium difficile in the ICU: the struggle continues. Chest. 2011;140(6):1643-1653. [CrossRef] [PubMed]
 
Cohen SH, Gerding DN, Johnson S, et al; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America. Clinical practice guidelines forClostridium difficileinfection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-455. [CrossRef] [PubMed]
 
Leclair MA, Allard C, Lesur O, Pépin J. Clostridium difficileinfection in the intensive care unit. J Intensive Care Med. 2010;25(1):23-30. [CrossRef] [PubMed]
 
Stamper PD, Alcabasa R, Aird D, et al. Comparison of a commercial real-time PCR assay for tcdB detection to a cell culture cytotoxicity assay and toxigenic culture for direct detection of toxin-producingClostridium difficilein clinical samples. J Clin Microbiol. 2009;47(2):373-378. [CrossRef] [PubMed]
 
Riddle DJ, Dubberke ER. Clostridium difficileinfection in the intensive care unit. Infect Dis Clin North Am. 2009;23(3):727-743. [CrossRef] [PubMed]
 
Rouby JJ, Laurent P, Gosnach M, et al. Risk factors and clinical relevance of nosocomial maxillary sinusitis in the critically ill. Am J Respir Crit Care Med. 1994;150(3):776-783. [CrossRef] [PubMed]
 
van Zanten AR, Dixon JM, Nipshagen MD, de Bree R, Girbes AR, Polderman KH. Hospital-acquired sinusitis is a common cause of fever of unknown origin in orotracheally intubated critically ill patients. Crit Care. 2005;9(5):R583-R590. [CrossRef] [PubMed]
 
Kountakis SE, Burke L, Rafie JJ, Bassichis B, Maillard AA, Stiernberg CM. Sinusitis in the intensive care unit patient. Otolaryngol Head Neck Surg. 1997;117(4):362-366. [CrossRef] [PubMed]
 
Tiedjen KU, Becker E, Heimann KD, Knorz S, Hildmann H. Value of B-image ultrasound in diagnosis of paranasal sinus diseases in comparison with computerized tomography [in German]. Laryngorhinootologie. 1998;77(10):541-546. [CrossRef] [PubMed]
 
Zagólski O, Strek P. Ultrasonography of the nose and paranasal sinuses [in Polish]. Pol Merkur Lekarski. 2007;22(127):32-35. [PubMed]
 
Talmor M, Li P, Barie PS. Acute paranasal sinusitis in critically ill patients: guidelines for prevention, diagnosis, and treatment. Clin Infect Dis. 1997;25(6):1441-1446. [CrossRef] [PubMed]
 
Denborough M. Malignant hyperthermia. Lancet. 1998;352(9134):1131-1136. [CrossRef] [PubMed]
 
McAllen KJ, Schwartz DR. Adverse drug reactions resulting in hyperthermia in the intensive care unit. Crit Care Med. 2010;38(6)(Suppl):S244-S252. [CrossRef] [PubMed]
 
Mackowiak PA. Drug fever: mechanisms, maxims and misconceptions. Am J Med Sci. 1987;294(4):275-286. [CrossRef] [PubMed]
 
Mackowiak PA, LeMaistre CF. Drug fever: a critical appraisal of conventional concepts. An analysis of 51 episodes in two Dallas hospitals and 97 episodes reported in the English literature. Ann Intern Med. 1987;106(5):728-733. [CrossRef] [PubMed]
 
Simon SD, Castle EP, Ferrigni RG, Andrews PE. Routine postoperative chest x-ray following laparoscopic nephrectomy. JSLS. 2005;9(2):205-207. [PubMed]
 
Fanning J, Neuhoff RA, Brewer JE, Castaneda T, Marcotte MP, Jacobson RL. Yield of postoperative fever evaluation. Prim Care Update Ob Gyns. 1998;5(4):146. [CrossRef] [PubMed]
 
Ward DT, Hansen EN, Takemoto SK, Bozic KJ. Cost and effectiveness of postoperative fever diagnostic evaluation in total joint arthroplasty patients. J Arthroplasty. 2010;25(6)(suppl):43-48. [CrossRef] [PubMed]
 
Mavros MN, Velmahos GC, Falagas ME. Atelectasis as a cause of postoperative fever: where is the clinical evidence? Chest. 2011;140(2):418-424. [CrossRef] [PubMed]
 
Stein PD, Afzal A, Henry JW, Villareal CG. Fever in acute pulmonary embolism. Chest. 2000;117(1):39-42. [CrossRef] [PubMed]
 
Nucifora G, Badano L, Hysko F, Allocca G, Gianfagna P, Fioretti P. Pulmonary embolism and fever: when should right-sided infective endocarditis be considered? Circulation. 2007;115(6):e173-e176. [CrossRef] [PubMed]
 
Barba R, Di Micco P, Blanco-Molina A, et al. Fever and deep venous thrombosis. Findings from the RIETE registry. J Thromb Thrombolysis. 2011;32(3):288-292. [CrossRef] [PubMed]
 
Huffman JL, Schenker S. Acute acalculous cholecystitis: a review. Clin Gastroenterol Hepatol. 2010;8(1):15-22. [CrossRef] [PubMed]
 
Kiewiet JJ, Leeuwenburgh MM, Bipat S, Bossuyt PM, Stoker J, Boermeester MA. A systematic review and meta-analysis of diagnostic performance of imaging in acute cholecystitis. Radiology. 2012;264(3):708-720. [CrossRef] [PubMed]
 
Chung YH, Choi ER, Kim KM, et al. Can percutaneous cholecystostomy be a definitive management for acute acalculous cholecystitis? J Clin Gastroenterol. 2012;46(3):216-219. [CrossRef] [PubMed]
 
Plaisance KI. Toxicities of drugs used in the management of fever. Clin Infect Dis. 2000;31(suppl 5):S219-S223. [CrossRef] [PubMed]
 
Hoedemaekers CW, Ezzahti M, Gerritsen A, van der Hoeven JG. Comparison of cooling methods to induce and maintain normo- and hypothermia in intensive care unit patients: a prospective intervention study. Crit Care. 2007;11(4):R91. [CrossRef] [PubMed]
 
Carhuapoma JR, Gupta K, Coplin WM, Muddassir SM, Meratee MM. Treatment of refractory fever in the neurosciences critical care unit using a novel, water-circulating cooling device. A single-center pilot experience. J Neurosurg Anesthesiol. 2003;15(4):313-318. [CrossRef] [PubMed]
 
Diringer MN, Reaven NL, Funk SE, Uman GC. Elevated body temperature independently contributes to increased length of stay in neurologic intensive care unit patients. Crit Care Med. 2004;32(7):1489-1495. [CrossRef] [PubMed]
 
Schulman CI, Namias N, Doherty J, et al. The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surg Infect (Larchmt). 2005;6(4):369-375. [CrossRef] [PubMed]
 
Schortgen F, Clabault K, Katsahian S, et al. Fever control using external cooling in septic shock: a randomized controlled trial. Am J Respir Crit Care Med. 2012;185(10):1088-1095. [CrossRef] [PubMed]
 
Niven DJ, Stelfox HT, Laupland KB. Antipyretic therapy in febrile critically ill adults: A systematic review and meta-analysis. J Crit Care. 2013;28(3):303-310. [CrossRef] [PubMed]
 
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