CONTENTS
- Definition & classification of fever
- Common causes of fever
- Evaluation
- Management
- Specific fever types
- Podcast
- Questions & discussion
- Pitfalls
definition of a fever
- Fever is a bedrock concept in medicine, yet its precise definition remains a bit elusive.
- The Infectious Disease Society of America defined fever in the ICU as a temperature >38.3/101. (18379262) This is generally a useful rule of thumb. However, a lower threshold for fever (>38/100.4) may be appropriate in some patients:
- Immunocompromised patients (e.g., neutropenic).
- Elderly patients.
- Patients on scheduled acetaminophen or NSAIDs.
- Patients on ECMO or CRRT (continuous renal replacement therapy).
- Once patients have been in the ICU for a few days, their fever curve may be more informative than any single measurement. A consistent trend over multiple time-points may be more likely to reflect a true event. Alternatively, a one-time fever spike which is below 38.9/102 and immediately disappears is less likely to represent infection. (23878765)
method of temperature measurement, ranked by preference:
- Central temperature measurement is ideal (e.g., bladder catheter, esophageal probe). However, most patients will not have such a device in place.
- Rectal temperature is the second most accurate method, but repeated measurement is limited by discomfort and logistics.
- Oral temperature is the third most accurate. However, this may be limited due to lack of patient cooperation, or intubation. (IDSA 2023)
- Other temperature measurements are the least reliable (e.g., axillary, tympanic membrane temperatures). (IDSA 2023)
definition of ICU-acquired fever?
- This chapter explores new-onset fevers which occur after a couple days in the ICU, suggesting that the fever results from a process acquired within the hospital. For patients who develop fevers shortly after ICU admission, the differential diagnosis will be broader (with a greater focus on community-acquired infection).
- ICU-acquired fever should ideally be better defined. Based on definitions of ventilator-associated pneumonia, a fever arising >48 hours after hospital admission might be more likely to have been acquired within the hospital.
recognition of neutropenic fever
- Neutropenia is defined as absolute neutrophil count <500, or between 500-1000 and falling.
- Absolute neutrophil count = (WBC)(% bands + % neutrophils). 🧮
- Fever in the context of neutropenia is defined as either:
- Temperature >38/100.4 for an hour.
- A single temperature >38.3/101.
- Neutropenic fever is critical to recognize, because these patients require empiric broad-spectrum antibiotics.
recognition of hyperthermia
- Hyperthermia is defined as elevated temperature resulting from excess heat generation, rather than from an alteration of the hypothalamic set point.
- Hyperthermia is suggested by the following clinical features:
- Extreme temperature elevation (temperatures >41/105.8).
- Skin may be hot and dry (but not always!).
- Antipyretics are ineffective.
- Hyperthermia has its own differential diagnosis and requires specific treatment.
- The critical distinction between fever versus hyperthermia is explored further in the table below. More on hyperthermia here: 📖
appreciation of spontaneous rigors as a fever-equivalent
- Rigors are shaking chills, which which can be very dramatic. They represent an aggressive attempt by the hypothalamus to rapidly increase body temperature. A rigor will often precede development of a fever.
- Rigors are closely linked to bacteremia. (24298435) Although not supported by evidence specific to the ICU environment, it's logical to investigate a patient with new-onset rigors in the same fashion as a patient with new-onset fever. Overall, evidence linking rigors to bacteremia is more persuasive than evidence linking fever to bacteremia.
infections (~50% of fever in ICU)
- Pneumonia (especially ventilator-associated PNA 📖).
- C. difficile. 📖
- Line infection. 📖
- Surgical site infection.
- Metastatic or local complications from known infection (e.g., empyema, spinal abscess following endocarditis).
- SBP (spontaneous bacterial peritonitis). 📖
- Less often:
- Acalculous cholecystitis. 📖
- Cellulitis, including infected decubitus ulceration.
- CAUTI (catheter-associated urinary tract infection). Note that infection is rare and greatly overdiagnosed in the context of an indwelling, functional Foley catheter. 📖
- Ventriculitis due to an external ventricular drain. 📖
noninfectious
- Procedure-related:
- Hemodialysis.
- Bronchoscopy.
- 🩸 Febrile transfusion reaction (within 6 hours of transfusion).
- 🔪 Benign postoperative fever (post-operative day #1-3; usually <39C/102F).
- Medication-related:
- Sterile pulmonary inflammation:
- Fibroproliferative ARDS.
- Organizing pneumonia.
- Aspiration pneumonitis.
- Pulmonary embolism (usually low-grade fever, <39/102). (10631196)
- Neurogenic fever. 📖
- Disorders which seldom arise in the ICU (yet may remain possible):
- 🦓 Pancreatitis.
- 🦓 Thyroid storm.
- 🦓 Adrenal insufficiency.
- 🦓 Rheumatologic disorders (vasculitis, flare or gout or underlying rheumatologic disease).
- 🦓 Malignancy (especially lymphoma, hepatocellular carcinoma, renal cell carcinoma).
- 🦓 HLH (hemophagocytic lymphohistiocytosis).
basic evaluation
- History:
- Any localizing symptoms? Diarrhea?
- Recent procedures or transfusion?
- Indwelling devices?
- Physical examination:
- Respiratory (if intubated: Sputum? Increasing ventilator support?)
- Abdominal tenderness?
- Skin exam:
- Evaluate any surgical incision.
- Evaluate any line/drain sites.
- Chest radiograph. (IDSA 2023)
- Blood cultures:
- Two sets of peripheral blood cultures at different sites (each set contains an anaerobic bottle and an aerobic bottle).
- Additionally, any line in place >48-72 hours should be cultured. (18379262)
- If central venous catheter cultures are indicated, at least two lumens should be cultured. (IDSA 2023)
- Do not obtain cultures through an old needleless connector (which may increase the risk of contamination). Cultures should be obtained either after removal of the old needleless connector, or through a newly placed needleless connector. (IDSA 2023)
urine culture should usually be avoided 🛑
- Why avoid urinalysis and urine culture?
- These are frequently positive in elderly patients, or anyone with a prolonged Foley catheter.
- In patients with a Foley catheter, it's unusual for urinary tract infection to be a cause of fever in the absence of urological manipulations, neutropenia, or Foley dysfunction. (23878765, 18379262)
- Routinely obtaining urinalysis and urine culture from Foley catheters will lead to overdiagnosis of urinary tract infections.
- Indications to evaluate for urinary tract infection:
- (1) Patient lacks a Foley catheter and has symptoms of urinary tract infection.
- (2) Neutropenic fever.
- (3) Structural urologic abnormality (e.g., recent surgery or urological procedure, or status post renal transplant).
- (4) Persistent fever in a patient with a Foley catheter, without an alternative etiology.
- ⚠️ If the patient has a Foley catheter, it should be changed out prior to obtaining urinalysis and culture (which is obtained via the fresh Foley catheter). (IDSA 2023) The following diagnostic pathway may be used to determine if the patient has a CAUTI (catheter associated urinary tract infection): 📖
tracheal aspirate cultures should usually be avoided 🛑
- Tracheal aspirate cultures will often be positive among patients with structural lung disease (i.e., COPD) or prolonged intubation (often with scary bacteria such as Pseudomonas). However, in the absence of other features of infection, this reflects only colonization and should not affect management.
- Cultures should be obtained only if there is a clinical suspicion of a ventilator-associated pneumonia. If there is a concern for possible VAP (ventilator-associated pneumonia), this should be approached as discussed in the VAP chapter here: 📖
other testing based on clinical scenario:
- Procalcitonin and/or CRP (C-reactive protein) are recommended by IDSA/SCCM guidelines for patients in whom there is a low-to-intermediate likelihood of infection. (IDSA 2023) However, note that elevated levels don't necessarily indicate the presence of septic shock. In general, elevated levels should be an indication to continue further evaluation for possible infection.
- COVID PCR: Depending on levels of community transmission. (IDSA 2023)
- Extended respiratory pathogen PCR: Consider for patients with suspected pneumonia and/or new upper respiratory tract symptoms. (IDSA 2023)
- CT scan(s) may be indicated by:
- Clinical abnormalities (e.g., abdominal pain).
- Recent instrumentation/surgery, persistent fever, and no alternative explanation for the fever.
- Suspected pulmonary embolism.
- Abnormal chest radiograph that requires clarification.
- Clostridioides difficile testing is indicated if this infection is suspected (e.g., otherwise unexplained diarrhea).
- Paracentesis should be considered in the context of ascites, to exclude spontaneous bacterial peritonitis (SBP). 📖
- Leg ultrasonography if DVT is suspected.
- Lumbar puncture is indicated if there is a reason to suspect meningitis (e.g., recent craniotomy or external ventricular drain). However, if an external ventricular drain is in place, fluid may be removed directly from the drain to avoid the risk of lumbar puncture.
indications for empiric antibiotics
- Fever itself isn't an indication for antibiotics.
- (They're antibiotics, not antipyretics.)
- Antibiotics may be indicated in the following situations:
- (a) Neutropenic fever
- (b) Septic shock 📖 (e.g., hypotension, tachycardia, oliguria, delirium, tachypnea).
- (c) High index of suspicion for specific infection (e.g., Clostridioides difficile or ventilator associated pneumonia). In many situations antibiotic initiation for a specific focus of infection is appropriate, while awaiting additional diagnostic information (e.g., culture results).
antipyretic therapy
- Whether fever is a beneficial, adaptive response to infection remains controversial.
- Most fevers don't require treatment. Following the fever curve without antipyretic therapy may provide superior diagnostic information.
- 🧘♀️ A single fever spike which is transient and self-resolving is unlikely to represent true infection. Avoiding the urge to treat with antipyretics or antibiotics allows the wisdom of time to establish the fever's benignity. Isolated fever spikes sometimes result from manipulation of a colonized mucosal surface. (9448975)
- Indications for acetaminophen include:
- Neurologic injury (e.g., stroke, anoxic brain injury). Fever may exacerbate neurologic injury via several mechanisms (including elevation of intracranial pressure, reduction of seizure threshold, and glutamate excitotoxicity).
- Severe fever (e.g., >40C/104F).
- Fever seems to be worsening the patient's clinical condition:
- Altered mental status (fever can cause delirium in some at-risk patients). This is especially true among patients with multiple sclerosis, among whom fever may cause acute neurologic deterioration (known as Uhthoff Phenomenon 🌊).
- Hemodynamic instability or acute myocardial ischemia (tachycardia may exacerbate both of these).
remove central & arterial lines if possible
- Fever alone isn't necessarily an indication to remove a central venous catheter. However, central venous catheter removal should be considered for lines in place >72 hours.
- If the patient is unstable and manifests features of sepsis (e.g., hemodynamic instability), line removal may be more strongly considered.
commonly implicated drugs
- Antimicrobials (most common class):
- Penicillins, cephalosporins, piperacillin, carbapenems.
- Aminoglycosides (rare), fluoroquinolones.
- Vancomycin, daptomycin, linezolid (rare).
- Clindamycin (rare).
- Tetracyclines, macrolides (rare).
- Isoniazid (INH), rifampin.
- Sulfonamides, nitrofurantoin, pentamidine.
- Antiretrovirals.
- Amphotericin B.
- Cardiac/renal:
- Antihypertensives: Captopril, hydralazine, nifedipine.
- Digoxin (rare).
- Sulfa-containing diuretics (e.g., furosemide).
- Antiarrhythmics: Procainamide, quinidine.
- Neurologic / antiseizure agents:
- Barbiturates.
- Phenytoin.
- Carbamazepine.
- Immunologics:
- Interferon.
- Azathioprine.
- Miscellaneous:
- Salicylates, NSAIDs.
- Allopurinol.
- Heparin (but not low molecular-weight heparins).
- Metoclopramide.
- Steroids (rare).
- Colace.
epidemiology
- Exact numbers are hard to track, but drug fever may occur in up to ~10% of admitted patients. (8698996)
- Risk factors for drug fever:
- Sensitivities to multiple medications.
- Polypharmacy.
- HIV infection.
- Cystic fibrosis.
clinical findings
- Fever may occur to any degree, most commonly the temperature is ~102-104F (~38.8-40C).
- Patients can be asymptomatic or may look profoundly ill (e.g., with rigors, myalgias, and hypotension).
- One clue suggesting drug fever may be that a patient looks “inappropriately well” compared to the degree of fever. (23878765)
- Rash is seen only in ~20% of patients (usually a maculopapular central rash, which may involve palms and soles).
- Timing of drug fever is variable. Drug fevers frequently begin 1-2 weeks after starting a medication, but they may emerge after months or years. Upon drug re-challenge, fever may develop within hours.
laboratory abnormalities
- Leukocytosis with left shift may occur in 18% of patients.
- Eosinophilia is seen only in ~18% of patients. If present, consider also whether the patient could have DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms).
diagnosis & treatment
- Definitive diagnosis is often impossible (as drug fever is largely a diagnosis of exclusion).
- After discontinuing the offending agent, fever should resolve within 3-4 days if no rash is present. However, sometimes resolution may take a week.
pathophysiology
- Neurogenic fever (a.k.a. “central fever”) appears to represent a hypothalamic disorder, resulting in elevation of the hypothalamus's target temperature for the body (the “set point”). (26772198)
causes
- Subarachnoid hemorrhage:
- Extremely common, affecting most patients.
- Risk factors include more severe subarachnoid hemorrhage and coexisting intraventricular hemorrhage.
- Intracranial hemorrhage with ventricular extension.
- Traumatic brain injury.
- Surgery or pathology involving the hypothalamus may cause deranged temperature regulation.
- Anti-NMDA receptor encephalitis. 📖
clues supporting a neurogenic fever
- Chronicity: Fever typically starts within 72 hours of admission and has a prolonged duration.
- Poor response to antipyretics (<10% will defervesce).
- Presence of subarachnoid or intraventricular blood.
- Fever usually isn't associated with diaphoresis or tachycardia. (Alternatively, a fever occuring in the context of tachycardia and diaphoresis may suggest paroxysmal sympathetic hyperactivity 📖).
diagnosis of a neurogenic fever
- Ultimately this is largely a diagnosis of exclusion.
- The possibility of paroxysmal sympathetic hyperactivity 📖 should also be considered.
- Neurogenic fever may be likely if:
- (a) A reasonably exhaustive evaluation fails to identify an alternative explanation for the fever.
- (b) Clinical features of the fever are consistent with neurogenic fever (as above).
management
- Neurogenic fever is often resistant to antipyretics.
- Reduction in temperature usually requires physical cooling (e.g., with a cooling blanket or physical temperature control device).
- These patients often have neurologic injury, so treatment of the fever may be important to limit secondary neurologic injury.
- Shivering should be treated aggressively, as this may increase the intracranial pressure. Potential treatments include the following (often more than one therapy will be needed):
- Aggressive IV magnesium repletion.
- Warming of the hands and feet.
- Infusions of dexmedetomidine, propofol, and/or pain-dose ketamine.
- Ondansetron 4 mg IV q8hr.
- Fentanyl boluses (these are preferred over meperidine, due to a superior safety profile).
- Paralysis is a treatment of last resort only.
- Bromocriptine 💉 has been described to be useful in some case reports. (33344618, 28348904)
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- Failure to recognize neutropenic fever as a separate entity that requires immediate treatment.
- Routinely ordering urinalysis and sputum cultures (for most patients, this will only lead to false-positive results and unnecessary antibiotic therapy).
- Failure to recognize a rigors as a fever-equivalent which requires investigation.
- Excessive administration of antibiotics “just to be safe” in situations where they are not indicated.
Guide to emoji hyperlinks
- = Link to online calculator.
- = Link to Medscape monograph about a drug.
- = Link to IBCC section about a drug.
- = Link to IBCC section covering that topic.
- = Link to FOAMed site with related information.
- = Link to supplemental media.
References
- 08698996 Johnson DH, Cunha BA. Drug fever. Infect Dis Clin North Am. 1996;10(1):85-91. doi:10.1016/s0891-5520(05)70287-7 [PubMed]
- 10631196 Stein PD, Afzal A, Henry JW, Villareal CG. Fever in acute pulmonary embolism. Chest. 2000;117(1):39-42. doi:10.1378/chest.117.1.39 [PubMed]
- 18379262 O'Grady NP, Barie PS, Bartlett JG, et al. Guidelines for evaluation of new fever in critically ill adult patients: 2008 update from the American College of Critical Care Medicine and the Infectious Diseases Society of America [published correction appears in Crit Care Med. 2008 Jun;36(6):1992]. Crit Care Med. 2008;36(4):1330-1349. doi:10.1097/CCM.0b013e318169eda9 [PubMed]
- 23878765 Cunha BA. Clinical approach to fever in the neurosurgical intensive care unit: Focus on drug fever. Surg Neurol Int. 2013;4(Suppl 5):S318-S322. Published 2013 May 6. doi:10.4103/2152-7806.111432 [PubMed]
- 26772198 Meier K, Lee K. Neurogenic Fever. J Intensive Care Med. 2017;32(2):124-129. doi:10.1177/0885066615625194 [PubMed]
- 27581757 Niven DJ, Laupland KB. Pyrexia: aetiology in the ICU. Crit Care. 2016;20(1):247. Published 2016 Sep 1. doi:10.1186/s13054-016-1406-2 [PubMed]
- IDSA 2023: O’Grady, Naomi P. MD, FCCM, FIDSA1; Alexander, Earnest PharmD, FCCM2; Alhazzani, Waleed MBBS, MSc, FRCPC3; Alshamsi, Fayez MBBS4; Cuellar-Rodriguez, Jennifer MD5; Jefferson, Brian K. DNP, ACNP-BC, FCCM6; Kalil, Andre C. MD, MPH, FCCM, FIDSA7; Pastores, Stephen M. MD, MACP, FCCP, FCCM8; Patel, Robin MD, FIDSA, FRCPC9,10; van Duin, David MD, PhD, FIDSA11; Weber, David J. MD, FIDSA, FSHEA, FRSM, FAST11; Deresinski, Stanley MD, FIDSA12. Society of Critical Care Medicine and the Infectious Diseases Society of America Guidelines for Evaluating New Fever in Adult Patients in the ICU. Critical Care Medicine 51(11):p 1570-1586, November 2023. | DOI: 10.1097/CCM.0000000000006022