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Fever in the intensive care unit

Fever in the intensive care unit
Literature review current through: Jan 2024.
This topic last updated: Nov 22, 2023.

INTRODUCTION — Fever is common in the intensive care unit (ICU) patient and may be associated with increased morbidity and mortality [1]. This review will focus on patients who have not been admitted with fever but rather those who develop new fever during their ICU admission.

In the ICU, fever should prompt important diagnostic and treatment decisions. The definition, epidemiology, etiologies, diagnostic evaluation, and management of fever in the ICU are reviewed here. The pathophysiology of fever as well as approach to fever of unknown etiology, neutropenic fever, and fever in immunocompromised hosts are discussed separately. (See "Pathophysiology and treatment of fever in adults" and "Fever of unknown origin in adults: Evaluation and management" and "Fever of unknown origin in adults: Etiologies" and "Overview of neutropenic fever syndromes" and "Diagnostic approach to the adult cancer patient with neutropenic fever" and "Approach to the immunocompromised patient with fever and pulmonary infiltrates" and "Drug fever".)

DEFINITION — Normal body temperature is approximately 37°C (98.6°F) and ranges from 36.0 to 37.5°C (96.8 to 99.5°F), although this varies with the time of day (low in early morning and peaks late evening) and the method of measurement used.

The definition of fever (also known as pyrexia) is arbitrary and defined differently by several institutions. However, a joint task force from the American College of Critical Care Medicine and the Infectious Diseases Society of America defined fever as a body temperature of 38.3°C (101°F) or higher [2]. We adhere to this definition in this review because it is widely accepted and most studies have used this definition. However, it is reasonable to use a lower temperature to define fever in immunocompromised patients. (See "Pathophysiology and treatment of fever in adults".)

Hyperthermia/hyperpyrexia refers to syndromes associated with a high fever that often exceeds 41°C (105.8°F). Hyperthermia/hyperpyrexia syndromes are frequently noninfectious in etiology (eg, environmental, pharmacologic, endocrine), can be rapidly fatal, and their treatment differs from that of regular fever in the ICU (table 1). Expanded definitions of fever are discussed separately. (See "Pathophysiology and treatment of fever in adults".)

TEMPERATURE MEASUREMENT — Temperature can be measured at peripheral or core sites in the ICU patient. Importantly, regardless of which method is chosen, the same method and site of measurement should be used repeatedly to facilitate the trending of serial measurements. While central sites are more accurate and preferred when in place, peripheral sites are more commonly used since most ICU patients do not have a core device in place [2]. Guidelines also suggest that when central devices are not feasible, oral or rectal temperatures are preferred [2].

Core measurements – Core measurements include intravascular (eg, pulmonary artery catheter), intravesicular (ie, bladder), esophageal (via balloon thermistor), and rectal measurements [2-8]. Core methods are preferred when these devices are in place or accurate temperature measurements are critical to diagnosis and management. However, intravascular thermistors may give unreliable temperature readings if the catheter itself (eg, a pulmonary artery catheter) is used to rapidly administer volume [2].

Peripheral measurements – Peripheral measurements are typically oral, but others that are less accurate include temporal artery and tympanic sites, axillary, and chemical dot monitors [2,7,9-14]. Among these, oral is preferred.

EPIDEMIOLOGY

Incidence — Fever complicates up to 70 percent of all ICU admissions and is often due to an infection or another serious condition [1,15]. However, rates range from 26 to 88 percent and vary depending on the ICU patient population and the definition of fever [16].

Outcomes — In one observational study of 24,204 adult ICU admissions, fever ≥39.5°C (103°F) was associated with an increase in mortality (20 versus 12 percent), compared with fever below 39.5°C (103°F) [1]. Fever has also been associated with an increased length of stay, increased cost of care, and, when compared with patients who do not have fever, it may result in poor outcomes in patients with traumatic head injury, subarachnoid hemorrhage, or pancreatitis [15,17-23]. Fever may prompt unnecessary investigations and lead to inappropriate antimicrobial use.

The importance of fever as a pathophysiological process is poorly understood. While on one hand, fever may be an appropriate adaptation to an underlying infective process, in other situations fever may be harmful. For example, one study reported that patients with high peak temperatures between 39 and 39.4°C had significantly lower hospital mortality compared with those who had peak temperatures between 36.5 and 36.9°C (odds ratio 0.56, 95% CI 0.48-0.66); in contrast, mortality increased with rising temperature in those noninfectious cases of fever (odds ratio 2.07, 95% CI 1.68-2.55) [24].

DIFFERENTIAL DIAGNOSIS — Sources of fever in the ICU may be infectious or noninfectious. The relative frequency of infectious and noninfectious fevers varies according to the population being studied and the definition of infection that is used [15]. The most common infectious etiologies (table 2) include ventilator-associated pneumonia, intravascular catheter-related infections, surgical site infections, catheter-related urinary tract infections, and bacteremia from these and other sources [9]. There are many noninfectious sources of fever in the ICU (table 3), among which benign postoperative fever, drugs, transfusion reactions, and possibly venous thromboembolism are the most common. Distinguishing among these etiologies is discussed below. (See 'Diagnostic approach' below.)

DIAGNOSTIC APPROACH — The evaluation is focused on identifying the likely cause of the fever so that targeted investigations can be performed and empiric therapy appropriately administered or withheld [25]. In some patients, low-grade fevers (eg, <38.3°C [101°F]) that appear during the ICU course are not necessarily addressed unless the patient is immunocompromised. However, all fevers >38.3°C (101°F) should be investigated, especially when the fever is new, recurrent, or persistent.

During the evaluation, clinicians should remain mindful that critically ill patients often have more than one infection. In addition, evidence of infection and inflammation (eg, leukocytosis, pus) may be altered if the patient is immunosuppressed, and medical technologies (eg, continuous renal replacement therapy or extracorporeal membrane oxygenation [ECMO]) can modify or mask a fever.

Targeted history and examination — Whenever a patient develops a fever in the ICU, a thorough review of the medical history and a full physical examination should be performed looking for common, as well as serious, causes of fever (table 2 and table 3).

The clinician should assess for new or altered quality of sputum/endotracheal secretions (color, odor, amount, and consistency) and perform a lung examination to look for the development of new pneumonia. They should also assess for the presence of devices, in particular intravascular catheters, urinary catheters, or chest and abdominal drains, and question whether diarrhea is present to suggest possible Clostridioides difficile infection. Clinicians should also perform a detailed chest and abdominal examination looking for tenderness or rigidity to suggest evidence of an abscess, acalculous cholecystitis, pancreatitis, or mesenteric ischemia. Heart sounds should be listened to carefully for new murmurs to suggest endocarditis. The mouth, skin, joints, and lower limbs should also be examined looking for evidence of poor dental hygiene, wound infections and cellulitis, lymphadenitis, septic arthritis, or osteomyelitis; or swelling, erythema, or tenderness to suggest deep venous thrombosis. A medication, total parenteral nutrition, transfusion, and previous microbiologic history should also be assessed. Dressings or plaster should be removed from all covered wounds and the wounds inspected and examined.

While fever can be caused by numerous etiologies, the magnitude of the fever may be helpful in distinguishing some possible underlying etiologies [9,26,27]. For example:

Fevers between 38.3°C (101°F) and 38.8°C (101.8°F) may be infectious or noninfectious. The differential diagnosis is longest in this range.

Fevers between 38.9°C (102°F) and 41°C (105.8°F) can be assumed to be infectious.

Fevers ≥41.1°C (106°F) are usually noninfectious. Examples include drug fever, transfusion reactions, adrenal insufficiency, thyroid storm, neuroleptic malignant syndrome, heat stroke, and malignant hyperthermia. (See "Severe nonexertional hyperthermia (classic heat stroke) in adults" and "Neuroleptic malignant syndrome" and "Malignant hyperthermia: Diagnosis and management of acute crisis".)

In the ICU patient, all infections (table 2) have the potential to progress to sepsis and septic shock (ie, typically distributive shock). Noninfectious causes of fever that may also be accompanied by distributive shock include adrenal crisis [28,29], thyroid storm [30], and an acute hemolytic transfusion reaction, although these three etiologies are rare in critically ill patients. Most of the other noninfectious causes of fever are rarely associated with shock including non-hemolytic transfusion reactions, drug fever, and certain intra-abdominal conditions (eg, acalculous cholecystitis, pancreatitis). (See "Definition, classification, etiology, and pathophysiology of shock in adults", section on 'Distributive' and "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis", section on 'Definitions'.)

Initial investigations — Since there are no rigorous data to support a protocolized approach to investigating fever in ICU patients [15,31-34], we prefer one that is clinically driven and cost conscious. In most patients, we perform the following initial tests. Such testing is considered inexpensive, easy to perform, and targeted at the common and more serious etiologies of fever in the ICU patient:

Blood cultures – Blood cultures from two different sites (aerobic and anaerobic bottles) should be drawn before initiation of antimicrobials. When central intravascular catheters are present, blood cultures from the catheter should also be drawn, preferably from at least two ports. If infection with fungus is suspected, blood should be used to additionally inoculate fungal culture bottles.

Respiratory tract sampling – Endotracheal aspirate/sputum Gram stain and culture are indicated for febrile patients, provided sampling is feasible. The value of additional testing including viral testing (for severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] or other viruses), invasive respiratory tract sampling, and quantitative cultures in patients with suspected ventilator-associated pneumonia (VAP) should be considered and is discussed separately. (See "Clinical presentation and diagnostic evaluation of ventilator-associated pneumonia".)

Urinalysis and urine culture – Urinalysis and urine culture are indicated for febrile patients in the ICU, particularly those who are catheterized, have renal pathology (eg, obstructing stones, trauma), or are immunosuppressed. (See "Sampling and evaluation of voided urine in the diagnosis of urinary tract infection in adults".)

Chest imaging – A chest radiograph may detect a new or progressive pulmonary infiltrate, distinguish pneumonia from tracheobronchitis, or identify a respiratory source of fever other than pneumonia or tracheobronchitis that would otherwise be missed because it is not associated with sputum production (eg, development of a pleural effusion/empyema in a patient with community acquired pneumonia). However, chest radiographs (particularly portable and supine radiographs) are insensitive, especially in those with existing radiologic abnormalities (eg, acute respiratory distress syndrome, interstitial lung disease) since new findings may not be easily detectable; in such cases, chest computed tomography (CT) may be needed to detect new infiltrates or lung abnormalities responsible for fever. Bedside ultrasonography may also be useful for the detection of new pleural effusions if CT is not feasible. (See "Clinical presentation and diagnostic evaluation of ventilator-associated pneumonia", section on 'Chest imaging'.)

Microbiologic cultures from suspected sites of infection – Many patients in the ICU have several potential sites for infection including wounds, catheters, fluid collections, joints, stool (eg, for C. difficile), or sinuses. When indicated, collecting samples from such potential sites for culture is prudent. If empyema is suspected, cultures should be drawn directly from the pleural space rather than from the catheter. If fever occurs during transfusion and the transfusion is ceased, the transfusion bag and its contents should also be sent for culture. (See "Complications of the endotracheal tube following initial placement: Prevention and management in adult intensive care unit patients", section on 'Sinusitis'.)

Laboratory studies – Routine complete blood count and chemistries including lactate measurements should be obtained. For example, a leukocytosis, left shift and elevated lactate may indicate sepsis, hyponatremia, hyperkalemia, and hypoglycemia may indicate adrenal insufficiency, and high urea and creatinine may suggest a renal tract infection or obstruction. We also obtain transaminases, bilirubin, and alkaline phosphatase (to look for acalculous cholecystitis or biliary pathology) as well as amylase and lipase (to look for pancreatitis), particularly in patients with abdominal pain or in those whose abdominal exam cannot be reliably assessed due to sedation or coma.

Others — Other tests that are commonly considered include the following:

Abdominal imaging – Abdominal imaging is indicated for patients with symptoms or signs of an intra-abdominal process (distension, tenderness, absent bowel sounds). It is also indicated for patients who have a reason to have an intra-abdominal infection (eg, recent abdominal surgery) and no alternative source of the fever has been identified, even if there are no symptoms or signs of an abdominal process. Finally, abdominal imaging may be indicated if laboratory testing suggests a possible intra-abdominal process, but the results are insufficient to identify the exact abnormality.

The type of abdominal imaging varies depending on the suspected etiology. As an example, in a patient with fever, transaminitis, and hyperbilirubinemia, a right upper quadrant ultrasound exam may determine whether there is acalculous cholecystitis, choledocholithiasis, or a primary hepatic condition. Alternatively, CT angiography may be indicated in patients with suspected mesenteric ischemia. Bedside ultrasonography may also be useful as an initial step to plan additional testing.

Other laboratory tests – Other laboratory tests are directed at specific suspected etiologies. For example:

-Suspected thyroid storm thyroid-stimulating hormone (TSH), T3, and T4 levels (see "Thyroid storm", section on 'Diagnosis')

-Suspected acute hemolytic transfusion reaction (eg, direct antiglobulin test, plasma free hemoglobin, haptoglobin, repeat blood type and cross-match) (see "Hemolytic transfusion reactions")

-Suspected adrenal insufficiency (eg, random cortisol level or a cosyntropin test performed if necessary) (see "Determining the etiology of adrenal insufficiency in adults" and "Glucocorticoid therapy in septic shock in adults", section on 'Should adrenal reserve be assessed?')

While many experts utilize procalcitonin (PCT) as a diagnostic indicator of infection, we do not routinely use it since we believe that the diagnostic value of PCT in critically ill patients who become febrile during their ICU course is unproven. Moreover, if the clinical suspicion for bacterial infection is moderate or high, then empiric antibiotics should be considered irrespective of the PCT level. (See "Procalcitonin use in lower respiratory tract infections", section on 'Ventilator-associated pneumonia'.)

The value of endotoxin activity assay and C-reactive protein (CRP) have also been studied as biomarkers for identifying infection, but appear less promising because they lack specificity [35,36] and do not correlate as well with severity of disease [37]. However, some experts obtain CRP in patients with a low suspicion for bacterial infection. If the CRP level is unexpectedly high, it may prompt administration of empiric antibiotics [2].

Sinus evaluation – Evaluation for sinusitis is appropriate for mechanically ventilated patients who have purulent nasal drainage or whose evaluation has otherwise been completely negative. (See "Complications of the endotracheal tube following initial placement: Prevention and management in adult intensive care unit patients", section on 'Sinusitis'.)

Establishing a provisional clinical diagnosis — In most patients, following clinical examination and initial testing, a provisional diagnosis (or diagnoses) is typically made and treated accordingly. In challenging cases, involving an infectious disease or other specialist is prudent. Only common and serious diagnoses are briefly discussed below, but the potential for other etiologies always needs to be considered. Further details are provided in the linked topics.

Ventilator-associated pneumonia (VAP) – In most cases, VAP is a clinical diagnosis based upon the identification of a new or progressive lung infiltrate on imaging with clinical evidence that the infiltrate is of infectious origin (eg, fever, purulent sputum, leukocytosis, increased respiratory rate, increased minute volume, decreased tidal volume, decreased oxygenation, or the need for more ventilatory support or inspired oxygen), together with the identification of a pathogen in a respiratory specimen. (See "Clinical presentation and diagnostic evaluation of ventilator-associated pneumonia".)

Intravascular catheter-related infection – Intravascular catheter-related infections (venous, arterial) commonly present as a fever without localizing symptoms or signs. Alternative presentations include cellulitis at the insertion site, purulent drainage from the insertion site, incidentally detected bacteremia, sepsis (fever, tachycardia, tachypnea, leukocytosis), or septic shock. Rarely, a patient may present with suppurative thrombophlebitis, endocarditis, or septic abscesses. The diagnosis may be confirmed by ruling out other potential sources and identifying typical offending micro-organisms in peripheral and catheter-related cultures (eg, Staphylococcus or Streptococcus species). (See "Intravascular catheter-related infection: Epidemiology, pathogenesis, and microbiology", section on 'Epidemiology' and "Intra-arterial catheterization for invasive monitoring: Indications, insertion techniques, and interpretation", section on 'Local or systemic infection' and "Central venous catheters: Overview of complications and prevention in adults", section on 'Catheter-related infection'.)

Surgical site infection – A surgical site infection (wound or internal organ) should be considered in any postoperative patient with a fever and/or signs of shock. Abdominal signs may be masked by analgesia or sedation but surgical drains may reveal increased output or discharge of purulent material. Most surgical site infections occur one to four weeks after surgery, although they may occasionally occur during the first postoperative week or more than a month after surgery. The clinical manifestations and likely pathogen depend upon the surgical site (eg, Gram negative infections from abdominal surgery). (See "Fever in the surgical patient".)

Catheter-related urinary tract infections (UTIs) – Catheter-related UTIs may present as a fever without localizing symptoms or signs. They may also present with symptoms and signs of cystitis (suprapubic pain, hematuria, pyuria) or pyelonephritis (flank pain, costovertebral angle tenderness, nausea, and vomiting), which may be hard to determine in mechanically ventilated patients. Occasionally, they present with the systemic signs of sepsis. The identification of bacteriuria together with the clinical features of a UTI facilitate the diagnosis. (See "Catheter-associated urinary tract infection in adults", section on 'Diagnosis'.)

Bacteremia – Bacteremia may be secondary to any infection. Fever may be the only sign of bacteremia, although it can rapidly progress to septic shock. Transfusion-transmitted bacterial infection is a rare, but life-threatening, complication of hospital care that does not always occur during transfusion. Bacteremia by pathogenic micro-organisms (eg, Staphylococcus aureus) rather than by contaminants, should prompt a search for a source and warrants empiric treatment with antibiotics. (See "Transfusion-transmitted bacterial infection".)

Sinusitis – In mechanically ventilated patients, sinusitis most typically manifests as fever without an obvious source and without localizing symptoms and signs; purulent nasal drainage is occasionally present. It is typically diagnosed by supportive imaging and sinus fluid culture.

Non-hemolytic transfusion reaction – Fever is the most common sign of a non-hemolytic transfusion reaction (table 4). It generally occurs within one to six hours after the initiation of a transfusion of red blood cells or platelets and may be accompanied by chills and mild dyspnea. Non-hemolytic reactions are benign with no lasting sequelae. The diagnosis is made by clinically excluding other causes of fever in a patient receiving a transfusion (algorithm 1), the details of which are discussed separately. (See "Immunologic transfusion reactions", section on 'Febrile nonhemolytic transfusion reactions'.)

Drug fever – Drug fever is a diagnostic challenge. It can occur several days after the initiation of the drug, can take several days to subside after cessation of the drug, and can produce high fevers (ie, >38.9°C [102°F]) without other signs. It is essentially a diagnosis of exclusion unless other signs of hypersensitivity (eg, rash) are present. (See "Drug fever".)

Acalculous cholecystitis – Acalculous cholecystitis is associated with a variety of clinical conditions (table 5). It generally presents with fever, leukocytosis, and vague abdominal discomfort. A right upper quadrant mass may be palpable. An insidious presentation is associated with gallbladder gangrene and perforation. The diagnosis is based upon a constellation of symptoms and signs (eg, critically ill patients with sepsis without a clear source or jaundice) in the setting of supportive imaging findings, and the exclusion of alternative diagnoses. (See "Acalculous cholecystitis: Clinical manifestations, diagnosis, and management".)

Mesenteric ischemia – Fever is a late sign in both arterial and venous mesenteric ischemia. It usually signifies bowel infarction, by which time other signs have usually developed, such as abdominal tenderness, hematochezia, or lactic acidosis [38,39]. The abdominal tenderness is typically periumbilical, may be severe and out of proportion to the physical examination findings, and may be accompanied by nausea and vomiting; however, abdominal signs may be masked in older adults and by sedation. The diagnosis is usually made using a constellation of clinical findings with supportive abdominal imaging, typically, CT angiography, and occasionally by endoscopy or visual inspection in the operating room. (See "Overview of intestinal ischemia in adults".)

Acute pancreatitis – Acute pancreatitis is typically accompanied by abdominal pain, tenderness, and distension, as well as nausea and vomiting. The diagnostic criteria are similar to those who are not critically ill and typically requires the presence of two of the following three criteria: acute onset of persistent, severe, epigastric pain, elevation in serum lipase or amylase to three times or greater than the upper limit of normal, and characteristic findings of acute pancreatitis on imaging (contrast-enhanced CT, magnetic resonance imaging [MRI], or transabdominal ultrasonography). (See "Clinical manifestations and diagnosis of acute pancreatitis".)

Venous thromboembolism (VTE) – Deep vein thrombosis (DVT) and pulmonary embolism (PE), while common in ICU patients, are rare causes of fever. DVT should be suspected in those with asymmetric extremity edema, pain, or erythema, and may be associated with catheter placement, particularly in those with cancer. DVT is usually diagnosed using compressive ultrasonography. PE may present as unexplained fever and hypoxemia, hypotension, or atrial fibrillation. The diagnostic approach to PE should be similar to those who are not critically ill, although testing can be challenging due to the high incidence of renal dysfunction that may increase the risk of contrast administration. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity" and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)

Acute hemolytic transfusion reaction – An acute hemolytic transfusion reaction is a medical emergency and is fortunately a rare cause of fever in the ICU patient. It is usually due to ABO incompatibility that results in the rapid destruction of donor red blood cells by recipient antibodies (or rarely autoantibodies) and typically occurs within 24 hours of the transfusion. Common clinical manifestations include fever, chills, distributive shock, disseminated intravascular coagulation, and acute kidney injury. Flank pain, red or brown urine, and bleeding occur less often. It is diagnosed by identifying the features of hemolysis and repeat cross matching of blood. (See "Immunologic transfusion reactions".)

Adrenal crisis – Adrenal crisis is rare in critically ill patients. It usually occurs in patients with previously undiagnosed adrenal insufficiency who are subjected to a serious infection or other major stress, patients with known adrenal insufficiency who do not take more glucocorticoid during a serious infection or other major stress, patients with acute bilateral adrenal infarction or hemorrhage, or patients whose chronic glucocorticoid therapy is abruptly withdrawn [28,29]. Distributive shock is the predominant manifestation of an adrenal crisis, but fever, nausea, vomiting, abdominal pain, weakness, fatigue, lethargy, hypoglycemia, confusion, or coma, hyponatremia, and hyperkalemia may also be present. (See "Clinical manifestations of adrenal insufficiency in adults", section on 'Adrenal crisis'.)

Thyroid storm – Thyroid storm, which is also a rare cause of fever, refers to severe, life-threatening thyrotoxicosis [30]. It is often precipitated by an acute stressor, such as surgery, infection, trauma, or an acute iodine load. Clinical manifestations may include severe fever (>40°C [>104°F]), distributive shock, severe tachycardia (>140 beats/min), congestive heart failure, nausea, vomiting, diarrhea, agitation, delirium, psychosis, stupor, and coma. The diagnosis of thyroid storm is based upon the presence of severe and life-threatening symptoms in a patient with biochemical evidence of hyperthyroidism (elevation of free T4 and/or T3 and suppression of TSH). (See "Thyroid storm".)

MANAGEMENT — The cornerstone of management is to treat the underlying cause of the fever. In addition, the clinician may need to decide whether antimicrobials, catheter or device removal, and/or treatment of the fever are indicated.

Treat suspected underlying cause — Treatment of fever should be directed at the suspected underlying cause, which are discussed in separate topic reviews:

(See "Treatment of hospital-acquired and ventilator-associated pneumonia in adults".)

(See "Central venous catheters: Overview of complications and prevention in adults", section on 'Catheter-related infection'.)

(See "Fever in the surgical patient", section on 'Initial treatment'.)

(See "Catheter-associated urinary tract infection in adults", section on 'Treatment'.)

(See "Transfusion-transmitted bacterial infection", section on 'Immediate interventions'.)

(See "Immunologic transfusion reactions".)

(See "Drug fever".)

(See "Acalculous cholecystitis: Clinical manifestations, diagnosis, and management".)

(See "Overview of intestinal ischemia in adults", section on 'Initial management'.)

(See "Management of acute pancreatitis".)

(See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults".)

(See "Treatment of adrenal insufficiency in adults".)

(See "Thyroid storm", section on 'Initial management'.)

(See "Complications of the endotracheal tube following initial placement: Prevention and management in adult intensive care unit patients", section on 'Sinusitis'.)

Choosing to start empiric antibiotics — In some cases, empiric antibiotic therapy is started while in others it is delayed until the fever returns, a decision that is subject to considerable judgment and weighs the risks of delaying therapy against the unnecessary use of antimicrobials [25]. In general, we suggest empiric antimicrobials when infection is suspected, especially in patients with temperature ≥38.9°C (≥102°F) and in patients who present with sepsis, shock, or neutropenia; are immunosuppressed; and/or have devices that are suspected to be infected [40-43]. For most other patients, further diagnostic work-up with ongoing clinical assessment prior to the initiation of antimicrobial therapy is reasonable.

Deciding to remove catheters — Whether or not to remove an intravascular catheter (or other device) in a febrile patient is challenging. Considerations in the decision to remove an intravascular catheter include the severity of illness, age of the catheter, probability that the catheter is the source of fever, and consequences of catheter removal. For example, in a patient with sepsis, removal of an intravascular catheter where the insertion site looks infected is appropriate while removal may not be necessary if the insertion site is clean and the catheter has only recently been inserted. Removal is also appropriate if the catheter is known to be infected or patients have evidence of metastatic infection or persistent bacteremia or fungemia from the catheter (eg, endocarditis), particularly with pathogens including Staphylococcus aureus, Pseudomonas aeruginosa, drug resistant organisms, and Candida species. The management of a catheter in the setting of possible intravascular catheter-related infections is discussed separately. (See "Intravascular non-hemodialysis catheter-related infection: Treatment".)

The decision to remove longer term intravascular devices (eg, infusion ports) or life-sustaining devices (eg, ventricular assist devices, aneurysmal grafts) or artificial joints is much more difficult and is beyond the scope of this topic.

Treatment of fever — There is variation in practice regarding the routine treatment of fever. We do not routinely treat every fever because protocols that systematically prevent and treat fever in the intensive care unit appear to offer no benefit [44]. Most experts agree that aggressive or prolonged cooling with external cooling blankets or ice packs and use of such mechanical methods to prevent fever recurrence is not generally necessary unless the fever itself is considered harmful (eg, patients with increased intracranial pressure) or excessively high (eg, fever ≥41°C [≥105.8°F]) [45-50]. For example, if body temperature exceeds the "critical thermal maximum," which is thought to be between 41.6 and 42°C (106.9 to 107.6 °F), life-threatening complications can ensue (eg, rhabdomyolysis) [51]. The management of severe hyperthermia, including external cooling, and targeted temperature management following cardiac arrest are discussed separately. (See "Severe nonexertional hyperthermia (classic heat stroke) in adults" and "Pathophysiology and treatment of fever in adults", section on 'Treatment of fever and hyperpyrexia' and "Initial assessment and management of the adult post-cardiac arrest patient", section on 'Temperature management'.)

When treating fever, most experts choose acetaminophen rather than nonsteroidal anti-inflammatories (NSAIDs) or aspirin. Whether intravenous or enteral acetaminophen should be used is unknown, although our preference is for enteral (oral) administration, when feasible. Several studies reported that the incidence of hypotension (systolic blood pressure ≤90 mmHg or ≥20 percent decrease from baseline) was higher after parenteral acetaminophen compared with enteral administration [52,53]. (See "Pain control in the critically ill adult patient", section on 'Acetaminophen'.)

Data describing the aggressive use of antipyretics and cooling in ICU patients with fever are conflicting and most of these studies are subject to methodologic flaws [48,54-57]. As examples:

In a meta-analysis of 13 randomized trials enrolling 1963 non-neurocritically ill adult patients, despite temperature reduction, antipyretic therapy had no impact on 28-day mortality, length of stay, or shock reversal compared with placebo [57].

In a randomized controlled trial of external cooling applied to patients with septic shock, a reduction in vasopressor requirements and 14-day mortality was seen in the treatment group (19 versus 34 percent), although this difference in outcome was not sustained at later follow-up [55].

Another randomized study of 698 critically ill patients with fever suspected to be due to infection reported that compared with placebo, intravenous acetaminophen administered until resolution of fever, cessation of antibiotics, ICU discharge, or death did not increase the number of ICU-free days or mortality although this outcome was inadequately assessed [56].

FOLLOW-UP AND ADDITIONAL STUDIES — In some cases, this approach results in improvement or resolution of the fever. In such cases, patients should be followed up and antibiotics, if administered, tailored according to culture results.

However, in a small number of cases, the fever persists or worsens, in which case additional studies targeted at a suspected etiology (eg, persistent bacteremia from an infected device, drug fever, osteomyelitis, pulmonary vasculitides, tumor, or venous thromboembolism) should be considered. These investigations range from bronchoscopy to lung biopsy, and may also involve extensive radiologic imaging, lumbar puncture, bone biopsy, and serologic testing. In rare cases a cause is not found. (See "Fever of unknown origin in adults: Evaluation and management" and "Fever of unknown origin in adults: Etiologies".)

SPECIAL POPULATIONS — The etiology and management of fever may require special attention in the following populations:

Patients with acute neurological conditions (see "Initial assessment and management of acute stroke", section on 'Fever' and "Management of acute moderate and severe traumatic brain injury", section on 'Temperature management')

Surgical patients (see "Fever in the surgical patient" and "Perioperative temperature management")

Pregnant women (see "Intrapartum fever")

Immunosuppressed patients (see "Diagnostic approach to the adult cancer patient with neutropenic fever" and "Approach to the immunocompromised patient with fever and pulmonary infiltrates")

Patients with malignant hyperthermia (see "Malignant hyperthermia: Diagnosis and management of acute crisis")

Patients with neuroleptic malignant syndrome (see "Neuroleptic malignant syndrome")

Patients with serotonin syndrome (see "Serotonin syndrome (serotonin toxicity)")

Neutropenic patients (see "Overview of neutropenic fever syndromes" and "Diagnostic approach to the adult cancer patient with neutropenic fever")

Patients with fever of unknown origin (see "Fever of unknown origin in adults: Evaluation and management" and "Fever of unknown origin in adults: Etiologies")

Fever in returning travelers (see "Evaluation of fever in the returning traveler")

Patients with impaired splenic function (see "Clinical features, evaluation, and management of fever in patients with impaired splenic function")

SUMMARY AND RECOMMENDATIONS

Definition and epidemiology – Fever is common in the intensive care unit (ICU) patient and may be associated with increased morbidity and mortality. For the purposes of this review, we discuss the evaluation of patients who develop new fever during their ICU admission rather than those who were admitted with fever and we define a fever as a body temperature of 38.3°C (101°F) or higher. (See 'Introduction' above and 'Definition' above and 'Epidemiology' above.)

Temperature measurement – While central sites are more accurate, peripheral sites are more commonly used for monitoring the body temperature of ICU patients. Importantly, regardless of which method is chosen, the same method and site of measurement should be used repeatedly to facilitate the trending of serial measurements. (See 'Temperature measurement' above.)

Differential diagnosis – Sources of fever in the ICU may be infectious or noninfectious. The most common infectious etiologies (table 2) include ventilator-associated pneumonia, intravascular catheter-related infections, surgical site infections, catheter-related urinary tract infections, and bacteremia from these and other sources. Among the noninfectious sources of fever (table 3) benign postoperative fever, drugs, transfusion reactions, and possibly venous thromboembolism are the most common. (See 'Differential diagnosis' above.)

Diagnostic approach – In general, a thorough history and examination targeted at common and serious sources of fever together with initial testing helps narrow the differential and allows a provisional diagnosis to be made and, if indicated, targeted therapy to be administered. We prefer an approach that is clinically driven and cost-conscious. Initial testing should include blood cultures and may also include respiratory tract sampling, urinalysis and culture, chest radiography, cultures from suspected sites of infection (eg, skin, wounds, stool) as well as routine laboratory studies including complete blood count, chemistries, liver function tests, amylase, lipase, and a lactate level. Additional studies are targeted at specific suspected etiologies (eg, abdominal imaging, thyroid function tests, repeat blood type and cross match, cortisol). Some experts measure procalcitonin to help manage duration of antibiotics. (See 'Diagnostic approach' above and 'Establishing a provisional clinical diagnosis' above.)

Management – The cornerstone of management is to treat the underlying cause of the fever. In addition, the clinician may need to decide whether antimicrobials, catheter or device removal, and/or treatment of the fever are indicated. (See 'Management' above and 'Treat suspected underlying cause' above.)

In some cases, empiric therapy is started immediately while in others it is delayed until the investigations return.

-Empiric antimicrobials are appropriate when infection is suspected, especially those who present with a fever ≥38.9°C (≥102°F), sepsis or shock, have neutropenia, are immunosuppressed, and/or have devices that are suspected to be infected. (See 'Choosing to start empiric antibiotics' above.)

The decision to remove a catheter or device depends upon several factors including the severity of illness, age of the catheter/device, probability that the catheter/device is the source of fever, and consequences of catheter/device removal. (See 'Deciding to remove catheters' above.)

There is variation in practice regarding the routine treatment fever. While we do not routinely treat every fever, some clinicians treat fever with an antipyretic (eg, acetaminophen) on initial presentation and follow the course of the fever over the next six to twelve hours while investigations and cultures are ongoing. Aggressive or prolonged cooling with external cooling blankets or ice packs and use of such mechanical methods to prevent fever recurrence is not generally necessary unless the fever itself is considered harmful (eg, patients with increased intracranial pressure) or is excessively high (eg, fever ≥41°C [≥105.8°F]). (See 'Treatment of fever' above.)

Follow-up – In some cases, this approach results in improvement or resolution of the fever; patients should be followed up and antibiotics tailored according to culture results. However, in a small number of cases, the fever persists or worsens, in which case additional studies targeted at a suspected etiology (eg, drug fever, osteomyelitis, pulmonary vasculitides, tumor or venous thromboembolism) should be considered. (See 'Follow-up and additional studies' above.)

Special populations – Individual populations of patients may require special attention including patients with acute neurological conditions, surgical patients, pregnant women, immunosuppressed patients, patients with malignant hyperthermia, neuroleptic malignant syndrome, and serotonin syndrome, neutropenic patients, patients with fever of unknown origin, fever in travelers, and patients with impaired splenic function. (See 'Special populations' above.)

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Topic 1624 Version 32.0

References

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