The normal core body temperature of approximately 37°C is well conserved in vertebrates with minimal changes [2]. Core temperature typically exhibits diurnal rhythmicity, with a nadir of about 36.2°C in the morning and a peak of approximately 37.7°C in the afternoon [4]. Temperature elevates to 39°C to 40°C in febrile response to infection or other stress [2].

The febrile response 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 [5]. In contrast, simple heat illness or malignant hyperthermia is an unregulated rise in body temperature caused by inability to eliminate heat adequately [4]. Physiologically, fever begins with the production of one or more proinflammatory cytokines in response to exogenous pyrogenic substances (such as microorganisms, toxic agents) or immunologic mediators. Interleukin-1 (IL-1) was the first purified protein with demonstrated pyrogenic properties; subsequently, other cytokines such as tumor necrosis factor (TNF), lymphotoxin, interferons (IFNs), and interleukin (IL–6) were 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 raise 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 [5,6]. Fever induces the production of heat shock proteins (HSPs), a class of proteins critical for cellular survival during stress. HSPs that act as molecular chaperones may have an anti-inflammatory role and indirectly decrease the level of proinflammatory cytokines [2].

No single normal body temperature exists, and temperatures measured at different times of day and sites may vary. The Society of Critical Care Medicine and the Infectious Disease Society of America issued a consensus statement recommending that core temperature of higher than 38.3°C (101°F) be considered fever [7].

All ICU patients should be monitored with regular reliable temperature determinations. Rectal temperature is about 0.3° to 0.4°C higher than simultaneous oral temperature. Electronic thermometers operate in a predictive manner and complete a temperature reading before thermal equilibrium is reached, thereby providing rapid accurate reading. However, in a tachypneic patient, oral temperature, even obtained with an electronic thermometer, may be misleadingly low. Infrared detection tympanic thermometers appear equivalent to rectal probes when placed properly in the external auditory canal.

In general, axillary measurements and skin temperature recordings and chemical dot thermometers are unreliable and should not be used in the ICU [7]. Fever patterns are not helpful in suggesting or establishing specific diagnosis [8].

Although acute bacterial infections are among the most common and serious causes of fever in the ICU patients, fever may result from noninfectious illnesses as well (Table 76.1) [7,10]. Pseudosepsis is a clinical picture of noninfectious etiology characterized by fever, leukocytosis and hemodynamic parameters consistent with sepsis, that can occur in critically ill patients with large hematomas, acute vasculitis, subarachnoid hemorrhage, dissection of an aortic aneurysm, mesenteric ischemia, heat stroke, pancreatitis, or hyperthyroidism [11]. Fever may appear in the patient in whom the stress of surgery unmasks adrenal insufficiency or in the patient in whom malignant hyperpyrexia develops during surgery or in association with administration of nonanesthetic agents such as phenothiazines [12]. Bilateral adrenal hemorrhage, noted to occur in patients with a history of thromboembolic disease, recent surgery, and/or anticoagulant therapy, can present with fever,
hypotension, and abdominal or flank pain [13]. Fever is a cardinal manifestation of delirium tremens in patients with acute alcohol withdrawal, although it is necessary to exclude other complications of alcohol abuse such as pneumonia or spontaneous bacterial peritonitis [14]. Likewise, fever associated with seizures must be differentiated from possible underlying causes of seizure, such as meningitis, encephalitis, brain abscess, or stroke [4].

Fever and hyperthermia can be the sole manifestation of an adverse drug reaction in 3% to 5% of cases. Drug fever can occur several days after initiation of the drug and takes few days to subside after cessation of its administration [15].

Particular diagnostic and therapeutic difficulties arise with the appearance of fever in patients with malignancy, because it is important to differentiate between neoplastic fever (especially common with lymphoma, primary and metastatic liver tumors, hypernephroma, and colon carcinoma), fever due to mechanical complications caused by the malignancy (perforation, obstruction, or hemorrhage), and fever due to infection [8].

The patient infected with the human immunodeficiency virus (HIV) who develops fever poses a formidable diagnostic challenge because opportunistic infections may occur on occasion with more than one problem at a time. In addition, HIV-infected patients have a greater incidence of adverse reactions to drugs. Intermittent fevers without discernible etiology also occur in these patients [16].

Conspicuously absent from Table 76.1 is atelectasis. Although this process is widely regarded as a cause of fever, especially in the postoperative patient where atelectasis is common, there is no clear evidence of such [17].

Accurate and timely recognition of noninfectious causes of fever can avoid unnecessary use of antibiotics, reducing the risks of untoward reactions.

Nosocomial infections are an endemic problem in the ICU, in part because of the numerous invasive devices used to monitor and support critically ill patients, and also because of the acute illnesses that predispose critically ill patients to the development of infections. Although hospital-associated infections can arise in many sites, the most common sources of bacterial infection in the ICU are bacteremia, infections associated with intravenous lines, pneumonia, intra-abdominal infection, urinary tract infection, and sinusitis (Table 76.2) [18,19].

If able to communicate, the patient should be interviewed to identify localizing complaints. The patient and hospital chart should be reviewed thoroughly for a history of relevant antecedent problems (e.g., previous infections, cancer, allergic reactions to drugs). If the patient is unable to communicate, the medical record and medical personnel can provide insightful information concerning duration of intravascular accesses, amount and purulence of sputum or wound drainage, changes in skin condition, apparent abdominal or musculoskeletal pain or tenderness, difficulty in handling respiratory secretions and feeding, and changes in ventilator support parameters. Relatives and friends of the patient can provide epidemiologic information related to the patient’s exposures and risk factors for infections.

Physical examination of the febrile ICU patient may be difficult to conduct due to limitations imposed by catheters, ventilator tubes, and monitors but nonetheless should be thorough. Skin examination may demonstrate findings suggestive of drug reaction, vasculitis, endocarditis, or soft tissue necrosis. All intravenous and intra-arterial line sites should be inspected; a tender intravenous access site, with or without purulence, can indicate septic thrombophlebitis. Spreading erythema, warmth, and tenderness that appear to indicate cellulitis of an extremity also can be the hallmarks of deep venous thrombophlebitis, pyarthrosis, or gout. After the first 24 hours postoperatively, wounds should be examined; this may require fenestrating or changing a cast to allow examination of a fractured extremity if no other source of fever is found.

Head and neck examination can provide important signs of systemic and localized infection. Funduscopic examination, preferably by an ophthalmologist, can provide clues to systemic fungal or viral infections in the immune compromised [25]. Hospital-associated sinusitis often develops in patients who required extensive period of intensive care and it may have a paucity of associated symptoms. Oral lesions of recrudescent herpetic stomatitis are common in the ICU setting and often 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. More sensitive (although nonspecific) indicators of pneumonia include the chest roentgenogram and the occurrence of unexplained deterioration in arterial oxygenation and changes in the color and amount of respiratory secretions [26]. Unfortunately, pulmonary infiltrates and arterial hypoxemia also can be seen with congestive heart failure, atelectasis, aspiration pneumonitis, pulmonary embolism, acute respiratory distress syndrome, and, less commonly, reactions to medications and pulmonary hemorrhage. Cardiac examination may demonstrate a new or changing murmur possibly due to endocarditis.

Abdominal findings can be misleadingly unremarkable in the elderly, in the patient with obtunded sensorium, and in the patient receiving sedatives. Abdominal examination can be confounding in the patient with recent abdominal or thoracic surgery. Abdominal pain and tenderness may be localized (cholecystis, 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 [27].

Unexplained noninfectious fever is common in patients in the neurologic ICU such as in patients with subarachnoid hemorrhage and is associated with the development of symptomatic vasospasm [28].

Because the information provided by positive blood cultures has important prognostic and therapeutic implications, blood cultures should be obtained in patients with new fever when clinical evaluation suggests an infectious cause. It is recommended to draw three to four blood cultures from separate sites within the first 24 hours of the onset of fever [7]. When urinary tract may be the source of fever, a urine specimen (aspirated from the catheter sampling port) should be obtained and evaluated by microscopy, and quantitative culture [7].

In patients with clinical suspicion for pneumonia, a portable chest radiograph is mandatory, and efforts should be made to obtain secretions for stains and cultures. Sputum samples should be subjected to microscopic examination to document paucity of squamous cells and to assess the approximate number of polymorphonuclear leukocytes and numbers and types of bacteria as a guide for empiric antibiotic decision making and ultimate interpretation of the results of sputum culture. Techniques aimed at obtaining samples of secretions and tissue from the distal respiratory tract include protected and nonprotected bronchoalveolar lavage (BAL), transbronchial biopsy, protected specimen brush, telescoping plugged catheter, video-assisted lung biopsy, and open lung biopsy; respiratory secretions from these sampling methods may use quantitative culture thresholds to improve the diagnostic accuracy. BAL is the preferred diagnostic approach, with a low rate of complications (2%) and a diagnostic yield between 30% and 90% depending on the type of population studied, prior antibiotic treatment, and the definition of pneumonia used [26]. The triggering receptor expressed on myeloid cells (TREM-1) is upregulated by exposure to bacteria and fungi. Measurement soluble TREM-1 in BAL has been proposed in establishing or excluding the diagnosis of bacterial of fungal pneumonia [29].

In general, abnormal fluid collections (pleural effusion, joint effusion, ascites) should be sampled for microscopic, hematologic, and chemical analysis, as well as microbiologic culture. Microbiologic yield from ascites culture has been shown to be greater when ascitic fluid is placed into blood culture or fungal isolator media [30]. Infection, crystal-induced disease, trauma, and a variety of systemic diseases can create a painful, swollen peripheral joint; arthrocentesis is indicated to establish the nature of the effusion [31]. Meningitis is an uncommon nosocomial infection, except in cases of head trauma, CSF leakage, neurosurgery, or high-grade bacteremia with virulent invasive pathogens such as Staphylococcus aureus or Gram-negative bacilli. Thus, sampling of cerebrospinal fluid usually should not be considered in the initial workup for nosocomial fever. However, lumbar puncture should be considered in the febrile ICU patient with sudden, unexplained change in mental status and in the febrile patient who has undergone recent neurosurgery or head trauma and whose mental status is difficult to evaluate [32].

Symptomatic complaints or physical findings referable to the abdomen dictate the need for determination of liver chemistries and serum amylase, as well as CT abdominal diagnostic imaging [21].

Examination of fluid from an inflamed, effused joint necessarily includes analysis for crystals (as well as hematological analysis) smears, and cultures. Exacerbations of gout and pseudogout mimic the symptoms, physical examination, and leukocytosis of the septic joint, and coexistence of gout and joint infection, although uncommon, can occur [31,33].

Many patients in the ICU experience diarrhea, and by far the most common enteric cause of fever in the ICU is C. difficile, which should be suspected in any patient with fever or leukocytosis who received an antibacterial agent or chemotherapy within 60 days before the onset of diarrhea [7].

Serum procalcitonin levels can be employed as an adjunctive diagnostic tool for discriminating infection as the cause of fever [7].

Compelling evidence suggests that in infected critically ill patients, source control of the pathogen and early and appropriate antibiotic therapy remain the most important intervention that the clinician can implement for such patients [34]. Antimicrobial therapy should be evaluated daily to optimize efficacy, prevent resistance, and avoid toxicity [35]. Positive cultures may permit narrowing of the spectrum of antibiotic coverage or may dictate that additional organisms need to be covered by added antimicrobial therapy. Negative cultures in a patient who is unimproved yet stable on broad therapy indicate that antibiotics should be discontinued and the patient reevaluated. Negative cultures in a febrile patient who is unimproved or worsened may be a clue to disseminated fungal infection, and empiric antifungal therapy should be considered.