Chapter 38: Fever in the ICU

Fever is a state of elevated core temperature that is often a sign of infection in patients admitted to the intensive care unit (ICU). It should prompt investigation into potential infectious as well as noninfectious etiologies. Treatment with empiric antibiotics may be indicated in particular in patients with other signs of sepsis such as tachycardia and hypotension. Fever may also be caused by potentially life-threatening noninfectious syndromes such as thromboembolic disease and it is important to investigate these possibilities as well.

The febrile response, of which temperature rise is a component, is a complex physiologic reaction to disease, involving cytokine-mediated rise in core temperature, generation of acute phase reactants, and activation of numerous physiologic, endocrinologic, and immunologic systems. In contrast, simple heat illness or malignant hyperthermia is an unregulated rise in body temperature caused by inability to eliminate heat adequately. Fever begins with the production of one or more proinflammatory cytokines in response to exogenous pyrogens (microorganisms, toxic agents) or immunologic mediators. Interleukin 1 (IL-1), tumor necrosis factor (TNF), lymphotoxin, interferons (IFNs), and interleukin 6 (IL-6) are known and documented to induce fever independently. Cytokines interact with receptors located at the organum vasculosum of the lamina terminalis causing synthesis and release of prostaglandins, chiefly prostaglandin E₂, which raises body temperature by initiating local cAMP production, which resets the thermoregulatory set point of the hypothalamus and by coordinating other adaptive responses such as shivering and peripheral vasoconstriction. Fever induces the production of heat shock proteins (HSPs), a class of proteins critical for cellular survival during stress. HSPs may have an anti-inflammatory role and indirectly decrease the level of proinflammatory cytokines. Core body temperature may be influenced by numerous external factors including cooling blankets or continuous venovenous hemofiltration. Patients who have suffered neurologic injury or central nervous system (CNS) hemorrhage may also have hypothalamic dysfunction that could lead to elevated body temperature.

The incidence of fever in the ICU ranges from 28% to 70%. Infectious as well as noninfectious etiologies contribute almost equally to the causation of febrile episodes. The finding of a new fever in an ICU patient has a significant impact on health care costs due to the blood cultures, radiologic imaging, and antibiotics that are often empirically initiated. It is therefore important to have a good understanding of the mechanisms and etiology of fever in ICU patients, how and when to initiate a diagnostic workup, and when initiation of antibiotics is indicated.

A new fever in a patient in the ICU should trigger a careful clinical assessment rather than automatic orders for laboratory and radiologic tests. A cost-conscious approach to obtaining cultures and imaging studies should be undertaken if indicated after a clinical evaluation.

History and Physical Examination

Many patients admitted to the ICU are not able to provide direct information about localizing complaints. In patients who are intubated or obtunded information should be obtained from medical records regarding relevant antecedent problems (eg, previous infections, cancer, allergic reactions to drugs, immunosuppression etc). Relatives and friends of the patient may also provide pertinent epidemiologic information related to the patient's exposures and risk factors for infections. Physical examination of the febrile ICU patient should include examination of devices including intravenous catheters, endotracheal and nasogastric tubes, and bladder catheters. Skin examination may demonstrate findings suggestive of drug reaction, vasculitis, infective endocarditis, or soft tissue infection. All intravenous and intra-arterial line sites should be inspected for signs of erythema, warmth, tenderness, and purulence. All surgical wounds should be examined 24 hours postoperatively. Head and neck examination may reveal important signs of localized and systemic infection. Funduscopic examination may provide clues to systemic viral or fungal infection, particularly in immunocompromised patients. Oral lesions of recrudescent herpetic stomatitis are common in the ICU setting and may be obscured by the presence of oral endotracheal tubes or orogastric feeding tubes. These lesions may be extensive, more ulcerated and necrotic, and less vesicular in appearance in a seriously ill patient. Examination of the lungs can be difficult in the intubated ICU patient and often is unrewardingly nonlocalizing and nonspecific. Abdominal findings can be misleadingly unremarkable in the elderly, in the patient with obtunded sensorium, and in the patient receiving sedatives and can be confounding in the patient with recent abdominal or thoracic surgery. Abdominal pain and tenderness may be localized (cholecystitis, intra-abdominal abscess, diverticulitis) or generalized (diffuse peritonitis, ischemic bowel, antibiotic-associated colitis). Examination of the genitalia and rectum may demonstrate unsuspected epididymitis, prostatitis, prostatic abscess, or perirectal abscess.

Catheter-Associated Bloodstream Infections

Catheter-associated bloodstream infections are one of the most common reasons for patients to have fever in the ICU. Central venous and arterial catheters are important tools for monitoring patients and delivering fluids, antibiotics, nutrition, and other therapies. Bacteria and yeast that colonize the skin of the patient or the hands of health care providers can easily gain access to the circulation via these devices. The risk of infection from these catheters is variable and depends on several factors such as length of the catheter, type of catheter such as arterial versus venous, tunneled versus nontunneled, technique of insertion, site of insertion, duration they have been in place, frequency of manipulation, patient population etc (Table 38–1). The highest risk is with short-term, noncuffed central venous catheters, in the range of 2 to 5 per 1000 catheter-days. There are several mechanisms, which may lead to the infection of an indwelling catheter. Skin pathogens can infect the catheter exit site or contaminate the catheter hub, leading to intraluminal catheter colonization and infection. Parenteral fluid, blood products, or intravenous medications can also be a source of infection. The catheter exit site should be inspected daily for evidence of erythema or pus; however these signs are absent in most cases with catheter-related bloodstream infection. Any expressible purulence or exudate should be sent for Gram stain and culture. Gram-positive organisms such as Staphylococcus aureus, coagulase-negative Staphylococcus, and Enterococcus species are commonly responsible for catheter-associated bloodstream infections. Increasingly these organisms have acquired resistance to beta-lactam antibiotics and even vancomycin. Many gram-positive organisms are also capable of forming biofilms which make them difficult to eradicate and removal of the central venous catheter is generally necessary for successful treatment of these infections.

Gram-negative organisms are also important cause of catheter-associated bloodstream infections. Enterobacteriaceae such Escherichia coli, Klebsiella pneumoniae, and Enterobacter species are considered normal flora of the gastrointestinal (GI) tract; however they may colonize the hubs and tubing of central catheters and they may eventually be a cause of bacteremia. Pseudomonas aeruginosa is another important gram-negative organism that is often associated with nosocomial infection, including catheter-associated bacteremia. Because of the production of endotoxin gram-negative organisms are likely to trigger the release of cytokines that clinically manifest with signs of sepsis. In the hospital environment many gram-negative organisms have acquired multiple antibiotic resistance mechanisms. In addition to production of extended-spectrum beta-lactamase, several gram-negative species have also acquired carbapenemases that have made them resistant to the carbapenem class of antibiotics. The spread of these organisms within ICUs and throughout health care institutions more generally has been a particular challenge for infection control programs.

Candida bloodstream infections are also a common source of fever in the ICU. The use of central venous catheters to deliver total parenteral nutrition and empiric broad-spectrum antibacterial agents are important risk factors for Candida bloodstream infections. Catheter removal is of particular importance in the setting of fungemia as these infections are typically very difficult to eradicate when the infected catheter has not been removed. Candida albicans is frequently recovered from blood cultures in these patients; however increasingly nonalbicans species are responsible for these types of infection. Empiric therapy for Candida bloodstream infections should be guided initially by the severity of the infection as well as the epidemiology of Candida species as several nonalbicans species are resistant to fluconazole.

Pulmonary Infection Including Ventilator-Associated Pneumonia

Pneumonia is the second most common cause of infection acquired in the ICU and ventilator-associated pneumonia (VAP) is a common source of fever in the intubated patient. Between 10% and 25% of patients on mechanical ventilation will develop VAP during their ICU stay. Several factors increase the risk of patients in the ICU for developing pneumonia including endotracheal intubation and altered levels of consciousness associated with primary processes or with sedation for mechanical ventilation. Cough responses normally important as a host defense may be impaired by these and other factors, including age over 60, male gender, chronic lung disease, aspiration, acute respiratory distress syndrome (ARDS), sinusitis, nasogastric tube use, delayed extubation, continuous sedation, use of paralytic agents, and endotracheal cuff pressures less than 20 cm of H₂O.

Nosocomial pathogens such as Pseudomonas and methicillin-resistant S aureus are more commonly associated with patients in the ICU. Precise microbiologic diagnosis is often challenging since obtaining an appropriate sputum sample or endotracheal aspirate is difficult in patients who are intubated. Organisms that colonize the airways may not reflect the true etiology of a lower respiratory tract infection in a patient with nosocomial pneumonia and sputum cultures should be interpreted with caution. High-quality sputum or bronchoalveolar lavage specimens with few squamous epithelial cells and many polymorphonuclear cells may be useful to guide antibiotic therapy. A higher-resolution study such as computerized tomography (CT) may be pursued if clinical suspicion is high enough and it may be helpful for detecting infiltrates in the posterior-inferior lung bases. Fiberoptic bronchoscopy with transbronchial biopsy may be especially useful for the detection of pathogens such as Pneumocystis jiroveci, Aspergillus species and other filamentous fungi, Nocardia, Legionella, cytomegalovirus (CMV), and Mycobacterium species. Thoracentesis can also be performed on patients with significant pleural effusions. Fluid should be sent for cell count, chemical analysis, and culture, especially if there is adjacent pulmonary infiltrate, suspicion of tuberculosis, or possible contamination of the pleural space due to surgery, trauma, or a fistula.

Urinary Tract Infection

Catheterization of the bladder is a common practice in ICUs for several reasons including close monitoring of fluid balance. Urinary tract infection can be a cause of fever for patients in the ICU, particularly if there is some obstruction to urinary flow such as nephrolithiasis or ureteral blockage by tumor. Colonization of urinary catheters by resistant organisms such as vancomycin-resistant Enterococcus (VRE) is also very common in patients in the ICU and interpretation of urine cultures must be made with caution with this caveat in mind. It is important to distinguish between asymptomatic bacteriuria from a genuine urinary tract infection.

Clostridium Difficile

The frequent use of empiric systemic antibiotics puts many patients in the ICU at risk for C difficile infection. In patients with C difficile infection watery diarrhea is generally accompanied by marked leukocytosis; however some patients with toxic megacolon may also present with abdominal distension and reduced bowel sounds. The diagnosis can be confirmed with stool polymerase chain reaction (PCR) testing for C difficile toxin. If sigmoidoscopy is performed, pseudomembranes may also be noted, but stool assays are generally adequate for diagnosis. In addition to therapy with oral vancomycin or metronidazole, systemic antibiotics should be discontinued if possible. Stool transplant has emerged as a potentially useful therapy in particular for patients with refractory C difficile infection.

Central Nervous System Infections

Nosocomial meningitis is most commonly seen in hospitalized patients who have undergone neurosurgical procedures. When an infection is suspected in a febrile patient with an intracranial device, cerebrospinal fluid (CSF) should be obtained for analysis from the CSF reservoir. In patients with ventriculostomies who develop stupor or signs of meningitis, the catheter tip should be removed and cultured. CSF should be analyzed with Gram stain, cell count, protein, and glucose measurements. The most common organisms are S aureus and coagulase-negative staphylococci; however, Gram-negative organisms such as Pseudomonas and Klebsiella may also be responsible for CNS infections in this setting. Additional testing for tuberculosis, viral and fungal disease should be performed if there is a clinical suspicion of these less common organisms.

Postoperative Infections

Surgical site infections can be important causes of fever in patients recovering from recent surgery. These infections will often present with erythema and purulence at a surgical site and eventually may lead to dehiscence of the wound. Prompt surgical debridement is generally required for patients with this etiology of fever. Deeper infections may also occur in particular in patients with recent bowel surgery where intraluminal organisms can leak into the peritoneum and cause abscesses. Evaluation with CT or direct examination in the operating room may be necessary for patients with abdominal or pelvic collections. Drainage of collections and correction of anastomotic leaks are generally required in addition to appropriate antibiotic therapy.

Sinusitis

Sinusitis is a less frequent infectious cause of fever in the ICU. Most ICU patients have nasogastric tubes and endotracheal tubes which predispose them to nosocomial sinusitis. Other risk factors include facial fractures or nasal packing. The most common organisms causing nosocomial sinusitis are those that colonize the naso-oropharynx. Gram-negative bacilli (especially P aeruginosa) constitute 60% of the bacteria isolated from nosocomial sinusitis. Gram-positive cocci such as S aureus are also common, and many infections are polymicrobial. Diagnosis may be made supported by imaging such as CT scan or confirmed with puncture and aspiration of the involved sinuses for culture and susceptibility if invasive testing is warranted.

A large number of noninfectious causes can cause tissue injury with inflammation and a febrile reaction (Table 38–2).

Postoperative Fever

Fever is common in the postoperative period during the first 48 hours and is due to release of endogenous pyrogens into the bloodstream. Usually fever this early in the postoperative period is noninfectious in origin; however fever more than 96 hours after surgery is more likely to represent an infection and needs full evaluation. Although atelectasis is considered to be the most common cause of postoperative fever, clinical evidence regarding this association is scarce.

Medication Allergy

Numerous medications may be associated with an allergic response that includes fever. Any medication can cause fever due to hypersensitivity, which may manifest as fever alone to life-threatening hypersensitivity. Most common drugs known to cause fever are beta-lactam antibiotics, phenytoin, quinidine, procainamide, and methyldopa. Reactions to antiepileptic medications such as phenytoin may also include elevated liver enzymes and skin eruptions but often fever is the only clinical manifestation of this problem. A high clinical suspicion is needed for diagnosing drug fever since there is nothing characteristic about these fever patterns and they do not invariably occur immediately after drug administration. They may occur days after commencing a new medication, but a temporal relationship of the fever to starting and stopping the medication is supportive of this diagnosis.

Acalculous Cholecystitis

Acute acalculous cholecystitis is a condition of inflammation of the gall bladder in the absence of calculi. It is a disease with significant morbidity and mortality as it can lead to complications such as empyema of the gallbladder, gangrene, or perforation. A high index of suspicion is necessary, as it may be a difficult diagnosis to make in the sedated and intubated patient. The pathophysiology of this disorder is complex and involves hypoperfusion and biliary stasis. Risk factors include trauma, surgery, positive-pressure ventilation, total parenteral nutrition, sedation, immunosuppression, transfusion of blood products, and hypotension. Ultrasound or CT scan can be supportive of the diagnosis. As soon as the diagnosis is suspected, blood cultures should be drawn and broad-spectrum antibiotics commenced. Surgical intervention may be necessary, but may not be feasible in unstable patients.

Thromboembolic Disease and Hematoma

Deep venous thrombosis may be another noninfectious cause of fever. Patients with immobility, vascular injury, and underlying malignancies are at particular risk for thromboembolism. Large hematomas may also produce fevers and may be difficult to detect when they occur in the retroperitoneal space. Thrombotic thrombocytopenic purpura (TTP) is another syndrome associated with fever that also includes microvascular injury, platelet destruction, altered mental status, and renal injury.

Malignancies and Central fever

Certain malignancies such as lymphoma are associated with “B symptoms” such as weight loss, fevers, and sweats that may mimic infection. Brain injury or hemorrhage in the CNS may lead to hypothalamic dysfunction. Central fever and tumor fever are generally established as an etiology when infectious etiologies and other noninfectious etiologies have been excluded.

Initial Empiric Therapy

Once an infectious cause is suspected source control and early initiation of appropriate antimicrobial therapy are often the most important interventions for management. Infected catheters should be removed and abscesses should be drained. Empiric therapy should be based on the site of infection as well as local hospital epidemiology. Antimicrobials should be evaluated daily to reassess their need and potential de-escalation to avoid toxicity and emergence of resistant organisms. Positive cultures may help to narrow antibiotic coverage (Table 38–3).

Gram-Positive Organisms

S aureus, Enterococcus, and coagulase-negative staphylococci are among the common gram-positive pathogens involved in nosocomial ICU infections. Vancomycin can be included in the initial empiric regimen if these organisms are suspected. Linezolid or daptomycin may be used if there is a history of vancomycin-resistant Enterococcus, or vancomycin allergy. If methicillin-susceptible S aureus is isolated therapy should be switched to nafcillin or cefazolin.

Streptococcus pneumoniae and alpha-hemolytic streptococci (Streptococcus viridans group) are more common in community-acquired infections such as pneumonia or infective endocarditis. Empiric therapy for nosocomial pneumonia often includes broad-spectrum antibiotics with good levels of penetration in the lung tissue. Gram-positive coverage with vancomycin or linezolid is favored over daptomycin due to surfactant binding of daptomycin. Broad-spectrum antibiotics with gram-negative activity may include cefepime or imipenem. In cases in which Legionella is suspected, fluoroquinolones or macrolides are appropriate.

Necrotizing fasciitis with group A Streptococcus may be seen in surgical site infections postoperatively and have a devastating outcome without surgical debridement and early appropriate antibiotic therapy. Penicillin G is usual drug of choice, as most streptococci are sensitive to penicillin. Clindamycin should be added for decreased toxin production effect for necrotizing fasciitis secondary to group A Streptococcus. Combination therapy may be necessary in certain infections such as enterococcal endocarditis which usually requires synergy with aminoglycoside in addition to vancomycin or penicillin.

Gram-Negative Organisms

Gram-negative organisms commonly encountered in an ICU-acquired infection include P aeruginosa, E coli, K pneumoniae, Acinetobacter species, and Stenotrophomonas. Abdominal infections usually have mixed bacteriology including anaerobes. The emergence of multidrug-resistant gram-negative organisms has been a challenging problem in the ICUs in recent times. These organisms may produce carbapenemase enzymes that confer resistance to broad-spectrum agents such as imipenem and meropenem. When gram-negative infections are suspected, empiric antimicrobial agents should be chosen with knowledge of the local ICU resistance pattern.

Extended-spectrum beta-lactam penicillins such as piperacillin combined with a beta-lactamase inhibitor such as tazobactam have good activity against Pseudomonas, E coli, Proteus, Serratia, Klebsiella, and most commonly encountered gram negatives. It also has excellent anaerobic activity comparable to metronidazole. Pharyngeal colonization with gram-negative bacilli rapidly develops in patients in the ICU, and initial therapy of nosocomial aspiration pneumonia requires the addition of an antipseudomonal penicillin, carbapenem, or cephalosporin. Higher doses of piperacillin/tazobactam should be considered for serious infections due to Pseudomonas. Although traditionally aminoglycosides have been added for synergy or double coverage for Pseudomonas, there is little data to support this approach routinely.

Fungal Infections

Invasive and disseminated fungal infections are becoming increasingly common in the ICU. Risk factors for invasive fungal infections include broad-spectrum antibiotic use, immunosuppression, and use of total parenteral nutrition. Patients with lymphoproliferative disease, transplant patients, and advanced HIV disease are also at risk. Bloodstream infections with C albicans remain the most commonly seen fungal infections and are usually susceptible to triazoles. Candida krusei and Candida glabrata may be resistant to fluconazole and voriconazole or caspofungin should be used when these organisms are suspected. Lipid preparations of amphotericin B are the initial drug of choice for empiric therapy of life-threatening, invasive, or systemic fungal infections including mucormycosis, cryptococcosis, histoplasmosis, and coccidioidomycosis.