Fever in the Intensive Care Unit Patient
Authors: Sang-Oh Lee, M.D., Ph.D., Moritoki Egi, M.D. Ph.D., Younsuck Koh, M.D., Ph.D., FCCM
Introduction
The appearance of fever in an ICU patient is not a sign of impending doom, but it is a sign that requires attention. Fever is usually a physiological expression of the host’s response to infection (26) or inflammation pathology (11, 14). It is considered a host defense that promotes the synthesis of antibodies and cytokines, and activation of T cells, neutrophils and macrophages (15). At the same time, it may cause discomfort and increase minute ventilation and oxygen consumption (9, 21, 27). This section focuses on the definition, differential diagnostic evaluation, and management of fever in the ICU patient.
Measuring body temperature
One should use as reliable a method as possible to measure temperature. The device should be safe and conventional, and it must be calibrated properly and checked periodically according to the manufacturer’s specifications (26). The thermistor of a pulmonary artery catheter is considered to be the standard for measuring core temperature. However, its use may be accompanied by catheter-related infection and arrhythmia. The thermistors in bladder catheters are less invasive and provide continuous readings and stable measurements regardless of the urine flow rate. Esophageal/rectal probes also provide reliable and continuous readings but are uncomfortable in alert patients; there is also some risk of eroding or perforating the gastrointestinal tract. Readings from the rectum are often a few tenths of a degree higher than core temperature (32). Oral temperature measurement is convenient, but often not practical in critically ill patients. There are two types of device for monitoring tympanic membrane temperature. One is direct monitoring of the tympanic membrane, which is believed to reflect brain temperature and, thus, core body temperature. This type of probe is painful and its use risks damaging the tympanic membrane. The other is infrared ear thermometry, whose readings do not always agree with those obtained with pulmonary artery catheters. Thus, its use is not recommended (26). Axillary temperature is commonly used in the ICU (17), because of its convenience and safety. There are conflicting reports about its accuracy; hence its use is not recommended in critically ill patients (26). However, recent studies have shown it to be accurate in critically ill adult patients (31).
Defining the fever threshold for diagnostic purposes
There is no uniform definition of fever in the literature (4). Several guidelines define it as a core temperature of >38.0°C (100.4°F) (2) or 38.3°C (101.0°F). This variability depends on the purpose of the definition, what sensitivity is required and the nature of the patients evaluated. Normal body temperature is around 37.0°C (98.6°F), and varies by 0.5 to 1.0°C with the circadian rhythm. Various factors, such as specialized mattresses, air conditioning, cardiopulmonary bypass, dialysis, and continuous hemofiltration tend to affect it. Furthermore, thermoregulatory mechanisms can be disrupted by drugs or by damage to the central or autonomic nervous system. Thus, it is often difficult to determine whether an abnormal temperature is a reflection of a physiologic process, a drug, or an environmental factor (26). Nonetheless, it is reasonable to consider a temperature of >38.0°C to be febrile and to warrant assessing whether infection is present.
Differential diagnosis of febrile patients
Both infectious and non-infectious factors can cause fever. The fever itself cannot indicate the source of an infection, but does suggest that infection may be present. To identify the source, physicians should consider a systematic diagnostic approach. The common types of non-infective fever include postoperative fever and drug fever. Fever is common for the first 48 hours after surgery, and it is useful to remember that fever in this early postoperative period is usually noninfectious. However, if a patient develops fever >96 hours after surgery, this is likely to point to infection. Any drug can cause fever due to hypersensitivity, and a diagnosis of drug-induced fever is usually established by the temporal relationship of the fever to the starting and stopping of a drug. Unfortunately, severe rash especially urticaria and eosinophilia, classical hallmarks of drug fever, are uncommon. Other non-infectious causes of fever include acalculous cholecystitis, acute myocardial infarction, adrenal insufficiency, blood product transfusion, fat emboli, gout, heterotopic ossification, intracranial bleeding, malignant hyperthermia, neuroleptic malignant syndrome, pancreatitis, pulmonary infarction, stroke, thyroid storm, transplant rejection, tumor lysis syndrome and venous thrombosis (26).
Diagnostic approaches
History and Physical Examination
A comprehensive history should be taken and a physical examination performed whenever one encounters a patient in the ICU with an unexplained fever. Vascular access sites, drains, and hardware should be examined. Silent sources of infection, such as sinusitis, decubitus ulcers of the sacrum or head, and perineal or perianal abscesses, need to be carefully examined.
Imaging Studies
A chest radiograph is easily obtained in the ICU and worthwhile in many patients with respiratory symptoms or signs. It may detect a new or progressive pulmonary infiltrate, distinguish pneumonia from tracheobronchitis, and identify a respiratory source of fever other than pneumonia or tracheobronchitis. However, chest radiographs may be less helpful in patients with known pleural effusions, acute lung injury, or acute respiratory distress syndrome because such abnormalities may obscure other findings. In these situations, a computed tomography (CT) scan may be more useful for clarifying abnormal chest radiographic findings.
Abdominal imaging is indicated for patients with symptoms or signs of an intra-abdominal process, those who have undergone recent abdominal surgery, and those whose laboratory tests suggest a possible intra-abdominal process. For example, in a patient with fever, an elevated liver function test (LFT), abdominal CT scan or ultrasound may reveal acalculous cholecystitis, choledocholithiasis, or liver abscess.
Laboratory Studies
Transaminase, bilirubin, alkaline phosphatase, amylase, lipase, and lactate measurements are indicated for patients with abdominal pain or whose abdominal exam cannot be reliably assessed due to sedation or coma. Stool samples should be sent for testing for C. difficile colitis in any patient with fever and diarrhea who received an antibacterial agent or chemotherapy within 60 days prior to the onset of diarrhea (3, 5). Serum sodium, potassium, glucose, and cortisol levels should be examined if adrenal insufficiency is possible. Thyroid stimulating hormone (TSH), T3, and T4 levels should be drawn if thyroid storm is possible. Blood should be drawn for repeat blood typing and cross-matching if an acute hemolytic transfusion reaction is suspected.
Role of C-reactive protein and Procalcitonin
C-reactive protein (CRP) has been studied as a biomarker of infection, but it lacks specificity (23, 28), rises late, and doesn’t correlate well with the severity of disease (23). CRP tends to be lower among patients with liver disease (20). Procalcitonin (PCT) is more promising because of its higher specificity for infectious causes of fever, and it is an adjuvant tool for discriminating infection as the cause of fever (26, 35, 36). Both PCT and CRP predict mortality in ICU patients (13, 18).
Management of fever
Empiric antibiotic therapy in a febrile patient with a suspected infectious cause
If an infectious cause of fever is suspected, empirical antimicrobial therapy should be initiated as soon as possible after cultures are obtained, especially if the patient is seriously ill or deteriorating. Delay of effective antimicrobial therapy has been associated with increased mortality from infection and sepsis (7, 8, 10, 12, 16). Initial empirical antibiotic therapy should be directed against likely pathogens suggested by the suspected source of infection, the risk of infection by multidrug-resistant pathogens, and local knowledge of antimicrobial susceptibility patterns. In addition, empirical antifungal coverage should be considered in selected patients: e.g. for neutropenic cancer patients with persistent fever despite the use of broad spectrum antibiotics (6) and those with suspected femoral catheter infection (19).
Targeted antibiotics based on diagnostic results
There has been a rapid rise of resistance among bacterial pathogens in ICUs (24, 25). Multiple antibiotics and multiple courses of antibiotics in critically ill patients may predispose to colonization or infection by drug-resistant organisms. Thus, antibiotic therapy should be tailored to the microbiological and other diagnostic results. Particularly in ICU settings with a high prevalence of multidrug drug-resistant infections, infectious disease specialists should be consulted to determine the optimum antibiotics therapy (1).
Adjunctive therapy including surgery
Some infections in critically ill patients require surgical management. Foci of infection readily amenable to infection source control measures include intra-abdominal abscess, gastrointestinal perforation, cholangitis, and necrotizing soft tissue infection. If there is suspicion of surgical site infection, the incision should be opened and cultured (26). An infected central venous catheter (CVC) should generally be removed in patients with confirmed catheter-related bloodstream infections (CRB) unless there are major contraindications (e.g., there is no alternative venous access, the patient has significant bleeding diathesis, or quality of life issues take priority over the need to replace the catheter) (22). However, among patients with suspected but unconfirmed catheter infection, it remains unclear which strategy is preferred - immediate removal, or delaying removal until the blood culture results are available (30).
Use of antipyretics and physical cooling
Fever is an evolutionary host defense mechanism. Potential benefits of reducing fever include psychological relief on the part of the patient and the patient’s family, relief of discomfort, reduction of oxygen consumption and insensible water loss. It has been reported that fever control using external cooling in septic shock was safe and decreased vasopressor requirements and early mortality (33). However, antipyretics such as nonsteroidal anti-inflammatory drugs (NSAIDs) can cause negative hemodynamic effects in febrile septic patients. In our previous observational study, antipyretic use was associated with increased patient mortality (17) and this has been reported in other studies (9). Moreover, response to fever to with antibacterial agents can be measured if no antipyretics are given. Fever should be treated if a patient’s temperature exceeds 40 °C, because fever can cause nervous system damage (34). External cooling seems to be best for fever reduction in view of the potential harmful effects of antipyresis. Clinicians should distinguish fever from hyperthermia, which is a pathologic response with failure of normal homeostasis. In hyperthermia, immediate aggressive antipyretic management is crucial for a positive outcome.
Complications of fever
Fever can have detrimental effects, especially in severely ill patients. It increases sympathetic tone, resting energy expenditure, and oxygen consumption, all of which increase cardiac pulmonary workload. As mentioned, temperatures over 40 °C, can cause nervous system injury, and posttraumatic elevation of temperature is associated with increased inflammatory processes. Fever induces febrile seizures in 2−5 % of children six months to 5 years of age, and is also associated with morbidity and mortality due to brain injury. Moreover, fever within the first 24 h of hospitalization in patients with ischemic stroke was found in a meta-analysis to be associated with a doubling of the probability of death within one month of the onset of stroke (29).
Summary
Fever in invertebrates and vertebrates has evolved as an adaptive host defense response to various stresses. It is tightly regulated by immune responses, and can be a manifestation of combating infection or inflammation. There is no generally agreed response to fever. The risk-benefit ratio of fever in a septic host is uncertain. Which patients would be most likely to benefit from fever reduction, and by how much the temperature should be reduced, remain unanswered questions.
References
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Table 1 Differential Diagnosis of Fever on admission to the ICU
Disease or syndrome |
Symptoms |
Physical Findings |
Laboratory test |
Imaging study |
|---|---|---|---|---|
Infectious cause |
||||
Pneumonia |
• purulent tracheobronchial secretions |
• increased respiratory rate |
• quantitative and qualitative cultures from endotracheal secretion or expectorated sputum |
• a new or progressive pulmonary infiltrates on chest radiograph |
Urinary tract infection |
• suprapubic pain, flank pain, nausea, or vomiting |
• costovertebral angle tenderness |
• pyuria on urine microscope |
• usually not required |
Intravascular catheter-related infection |
• fever with or without chilling |
• inflammation or purulence at the insertion site |
• blood culture is essential for diagnosis of catheter-related bloodstream infection |
• usually not required |
Surgical site infection |
• pain on superficial incision site |
• redness and warmness on incision area |
• cultures of purulent discharge on the incision area or from the drainage tube should be done |
• CT scan or ultrasound should be considered to evaluate deep surgical site infection |
Non-infectious cause |
||||
Mesenteric ischemia |
• rapid onset of severe periumbilical abdominal pain |
• minimal signs initially |
• marked leukocytosis |
• mesenteric angiography remains the gold standard diagnostic study |
Adrenal crisis |
• anorexia, nausea, vomiting, abdominal pain, weakness, fatigue, or lethargy |
• shock |
• low serum cortisol concentration |
|
Thyroid storm |
• agitation, anxiety, delirium, psychosis, stupor, or coma |
• goiter, ophthalmopathy (in the presence of Graves’ disease) |
• nonspecific findings including hyperglycemia, mild hypercalcemia, abnormal liver function tests, leukocytosis, or leukopenia |
• cardiomegaly on chest radiography (due to congestive heart failure) |
Acute pancreatitis |
• abdominal pain, typically improved by leaning forward |
•abdominal tenderness, and distension |
• elevated amylase and/or lipase |
• abdominal CT scan shows peri-pancreatic inflammation or fluid collection |
Pulmonary emboli |
• dyspnea at rest or with exertion |
• tachypnea (m/c) |
• a negative D-dimer assay |
• spiral (helical) CT scan with intravenous contrast |
Table 2. Differential Diagnosis of Fever developing after ICU admission.
Disease or syndrome |
Symptoms |
Physical Findings |
Laboratory test |
Imaging study |
|---|---|---|---|---|
Infectious cause |
||||
Pneumonia |
• purulent tracheobronchial secretions |
• increased respiratory rate |
• quantitative and qualitative cultures from endotracheal secretion or expectorated sputum |
• a new or progressive pulmonary infiltrates on chest radiograph |
Urinary tract infection |
• suprapubic pain, flank pain, nausea, or vomiting |
• costovertebral angle tenderness |
• pyuria on urine microscope |
• usually not required |
C. difficile colitis |
• frequent loose stool |
• increased bowel sound |
• Stool EIA toxin A/B test |
• Colonoscopy or sigmoidoscopy may real pseudomembranous colitis |
Intravascular catheter-related infection |
• fever with or without chilling |
• inflammation or purulence at the insertion site |
• blood culture is essential for diagnosis of catheter-related bloodstream infection |
• usually not required |
Surgical site infection |
• pain on superficial incision site |
• redness and warmness on incision area |
• cultures of purulent discharge on the incision area or from the drainage tube should be done |
• CT scan or ultrasound should be considered to evaluate deep surgical site infection |
Sinusitis |
• headache or purulent nasal discharge |
• sinus tenderness |
• radiography of the paranasal sinus may shows an air fluid level |
|
Non-infectious cause |
||||
Acute hemolytic transfusion reaction |
• fever and chill |
• oozing of blood from puncture site |
• abnormal coagulation test from disseminated intravascular coagulation |
|
Non-hemolytic transfusion reaction |
• fever, chill or mild dyspnea |
• no specific findings |
• no specific findings |
|
Adrenal crisis |
• anorexia, nausea, vomiting, abdominal pain, weakness, fatigue, or lethargy |
• shock |
• low serum cortisol concentration |
|
Thyroid storm |
• agitation, anxiety, delirium, psychosis, stupor, or coma |
• goiter, ophthalmopathy (in the presence of Graves’ disease) |
• nonspecific findings including hyperglycemia, mild hypercalcemia, abnormal liver function tests, leukocytosis, or leukopenia |
• cardiomegaly on chest radiography (due to congestive heart failure) |
Acute pancreatitis |
• abdominal pain, typically improved by leaning forward |
•abdominal tenderness, and distension |
• elevated amylase and/or lipase |
• abdominal CT scan shows peri-pancreatic inflammation or fluid collection |
Adrenal crisis |
• anorexia, nausea, vomiting, abdominal pain, weakness, fatigue, or lethargy |
• shock |
• low serum cortisol concentration |
|
Thyroid storm |
• agitation, anxiety, delirium, psychosis, stupor, or coma |
• goiter, ophthalmopathy (in the presence of Graves’ disease) |
• nonspecific findings including hyperglycemia, mild hypercalcemia, abnormal liver function tests, leukocytosis, or leukopenia |
• cardiomegaly on chest radiography (due to congestive heart failure) |
Deep vein thrombosis (DVT) |
• calf or thigh pain |
• a palpable cord (reflecting a thrombosed vein) |
• a negative D-dimer assay |
• compression ultrasonography is useful test for diagnosing DVT |
Pulmonary emboli |
• dyspnea at rest or with exertion |
• tachypnea (m/c) |
• a negative D-dimer assay |
• spiral (helical) CT scan with intravenous contrast |
Drug fever |
• Pruritus |
• rash, urticarial |
Eosinophilia |
What's New?
Choi S-H, et al. Viral Infection in Patients with Severe Pneumonia Requiring Intensive Care Unit Admission. Am J Respir Crit Care Med 2012;186:325-32.
Rabinstein AA, et al. Non-infectious fever in the neurological intensive care unit: incidence, causes and predictors. J Neurol Neurosurg Psychiatry 2007;78:1278-1280.
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