Continuing Education Activity

Temperature is one of the most important vital signs for all patients, including intensive care units (ICU). Fever or hypothermia often necessitates further physical evaluations, investigations, and changes in treatment in the ICU. Fever in ICU is defined as a temperature of = 101 degrees F (38.3 degrees C ). It can be either infectious or non-infectious in origin. The fever in the ICU could merely be a continued manifestation of the disease/disorder that prompted the ICU admission or could result from certain unique etiologies in the ICU. Prompt evaluation, source identification, and treatment are crucial. This activity describes the pathways in the assessment and treatment of fever in ICU and highlights the importance of close interaction and coordination between various healthcare professional team members in ensuring a positive outcome.

Objectives:

• Review the pathophysiology of fever in ICU.
• Summarize the etiology of fever in ICU, including the infectious and non-infectious causes.
• Explain the role of antipyretics.
• Outline the different treatment modalities based on the etiology of fever.

Introduction

Temperature is one of the most important vital signs for all patients, including intensive care units (ICU). Fever or hypothermia often necessitates further physical evaluations, investigations, and changes in treatment in the ICU.  

The definition of fever in the ICU is different from the usual definition of fever. Fever in an ICU patient is defined as a single temperature of ≥101 degrees F or ≥38.3 C, as per the American College of Critical Care Medicine (ACCCM) and Infectious Disease Society of America (IDSA) joint task force.[1] Also, the ACCCM and IDSA recommend that fever in ICU should be investigated only if the temperature is ≥101 degrees F. Hyperpyrexia or hyperthermia is a temperature of more than 105.8 degrees F (or 41 degrees C) and is uncommonly encountered in intensive care settings.

In immunocompromised or neutropenic patients, a lower threshold should be considered for fever diagnosis as these patients do not mount an appropriate febrile response. Also, the clinical, laboratory, and radiological manifestations of inflammation/infection would be scanty or absent in these patients, at least in the initial stages. Fever in a neutropenic ICU patient is defined as a single temperature more than 101 F (38.3 C) or a  temperature more than 100.4 F (38.0 C) sustained for more than one hour in a patient with an absolute neutrophil count (ANC) less than 500 cells/mm.[2][3] One also needs to be aware that extracorporeal therapies, including continuous renal replacement therapy or extracorporeal membrane oxygenation, could mask or alter the febrile response.

Fever is expected to provide a protective effect and help the host eliminate the invading organisms. Also, fever is associated with increased mortality and morbidity in ICU patients and forms part of mortality prediction scores, including APACHE II & III. However, studies on fever and mortality in ICU patients have been unequivocal. A large 2008 epidemiological study had shown that a temperature more than ≥ 39.5 degrees C was associated with increased mortality in critically ill patients, and the mere presence of a temperature ≥38.3 degrees C failed to produce any association with mortality.[4] A subsequent study (FACE) published in 2012 reported that higher 28-day mortality observed with temperature more than ≥ 39.5 degrees C occurred in non-septic patients and not in patients with sepsis.[5] Certain studies have also shown an inverse relation between fever and mortality in ICU and emergency patients.[6][7]

The fever in the ICU could merely be a continued manifestation of the disease/disorder that prompted the ICU admission or could result from certain unique etiologies in the ICU, and very rarely due to the flare-up or manifestation of an underlying dormant disease or disorder. The fever unique to the ICU settings could result from interventions or therapies provided during ICU care or the patient manifesting new-onset fever due to SIRS, septic, metabolic or neuroendocrine response. This review predominantly discusses the fever in non-neutropenic or non-immunocompromised ICU patients. However, clinical and/or management-related overlaps between different patient groups are not unexpected.

Etiology

The etiology could be either infective or non-infective. Most episodes of fever in the ICU are due to infections. In the multicenter prospective observational study, it was found that 63% of the critically ill patients who had a fever had sepsis.[7] Common infectious causes include ventilator-associated pneumonia,catheter-related bloodstream infections, surgical site infections, urinary tract infections related to catheters, and bacteremias of various origins, including the above causes. The common causes of fever are listed in the table below:

Fever etiology unique or exclusive to the ICU setting include:

1. Ventilator-associated pneumonia
2. Catheter-related bloodstream infection
3. Catheter-associated urinary tract infection
4. Clostridoides difficile colitis
5. Pressure ulcer
6. Surgical wound-related infection

Epidemiology

The incidence of fever in ICU varies between 26 to 88% depending on the type of ICU, patient cohort & definition of fever used.[8][7] A large study by Laupland et al. showed that the incidence of fever and high fever in medical and surgical ICUs was 44% and 8%, respectively.[4] Barie et al. found that the incidence of fever in surgical ICU was 26%.[9] A similar incidence of infectious and noninfectious fever has been reported.[10]

An observational study of 24,204 adult ICU admissions revealed fever ≥39.5 C (103 F) was associated with an increase in mortality (20% vs. 12%), compared with a fever below 39.5 C (103 F).[4] Fever has also been associated with an increased length of stay and cost of care. It may also result in poor outcomes in patients with pancreatitis, traumatic head injury, or subarachnoid hemorrhage.[11]

Pathophysiology

Fever is due to cytokines like IL1, IL6, and TNFα produced by the white cells due to exogenous stimuli.[12][13] These cytokines stimulate receptors located at the organum vasculosum of the lamina terminalis, resulting in prostaglandins production. The prostaglandins (PG), mainly PGE2, increase the production of cAMP, which resets the thermoregulatory set point of the hypothalamus & raises the body temperature.[14][15] There is an ongoing perception in the available literature that the pathophysiology of neutropenic fever and neutropenic sepsis differs entirely from non-neutropenic patients.

History and Physical

A detailed history is necessary, and a thorough physical examination should be performed whenever a patient with a fever is encountered in the ICU. Infectious and non-infectious causes need to be considered, with the former being a more crucial diagnosis resulting in a change of ongoing management.

Vascular access sites, urinary catheters, drain sites, and surgical incision sites should be examined. Heart sounds should be carefully auscultated to rule out a clue for infective endocarditis. Tracheal secretions should be assessed for color, odor, purulence, and quantity. The skin and soft tissue evaluation for cellulitis, furunculosis, and paronychia are routinely performed in all patients. The subtle or silent sources of infection commonly encountered are sinusitis, decubitus ulcers, dental or tonsillar infections, perineal wounds, and abscesses, all of which often need a high degree of clinical suspicion. Drug history should be reviewed, and drug fever is almost always a diagnosis of exclusion.

One also needs to be aware that in immunocompromised or neutropenic patients, the clinical symptoms and signs of infection or inflammation would be scanty or absent. Only a high degree of suspicion gives a clue to the site of infection causing the fever. Skin findings such as ulcers, nodules, vesicles, pilonidal sinus, and lesions such as erythema multiforme & ecthyma gangrenosum might be the subtle sign of infectious etiology and need to look for in neutropenic or immunosuppressed patients specifically. Perianal infections are often missed in neutropenic patients.

Measurement of Body Temperature

Core body temperature should be measured in ICU. The thermistor of a pulmonary artery catheter is considered the gold standard for measuring core body temperature but is not commonly used as it is invasive. Nasopharyngeal, esophageal, and bladder thermistors are preferred, followed by rectal and tympanic membrane measurements.[16] Axillary, oral, and forehead measurements should not be used in ICU. Some experts opine that probable causes could be ascertained based on the severity of the fever.[17][18][19] 

Based on these assumptions, a temperature between 38.3 degrees C and 38.8 degrees C can result from infectious and non-infectious etiologies, encompassing a huge list of differentials. Fevers above 38.9 C (102 F) and below 41 C are mostly infectious, and a fever ≥ 41.1 C (105.8 F) is considered non-infectious.

Evaluation

Laboratory Investigations: Biochemistry & Microbiology

Lactate should be routinely measured as high lactate levels are usually seen in sepsis. A lactate level of > 2 mmol/liter is a component of the 2016 third international consensus definition of septic shock.[20] This is due to the increased lactate production due to anaerobic metabolism and reduced clearance. Complete blood count and kidney and liver function tests should be checked. Serum amylase and lipase should be done to rule out pancreatitis in patients with abdominal pain. Diagnosis of transfusion reactions may require a direct antiglobulin test, haptoglobin, free hemoglobin in the plasma, and repeat blood grouping and cross-matching in the appropriate settings.

The thyroid profile requires evaluation in patients where thyroid storm is suspected. Free cortisol measurement or ACTH test must be done to evaluate adrenal insufficiency. Fresh cultures should be obtained before the initiation or changing of antibiotics. Blood cultures should be obtained in all patients with fever. Additional cultures should be obtained based on the suspected foci of infection, e.g., tracheal secretions, BAL in case of pneumonia, urine cultures in suspected UTI, and CSF culture in suspected meningitis. 

Role of CRP and Procalcitonin

The CRP is an acute-phase reactant used as a biomarker for sepsis. CRP is found to increase inflammatory pathology; hence, its role in sepsis is limited due to low specificity. Procalcitonin is another biomarker of sepsis that is a better indicator of the severity of the illness than CRP. It mainly correlates with bacterial infections. Procalcitonin can be used in antibiotic stewardship to reduce the unnecessary use of antibiotics in the ICU.[21][22] There is no sufficient evidence for the use of procalcitonin to initiate antibiotic therapy. It is to be noted that elevated procalcitonin levels can also present in patients with non-infective etiologies, including trauma, major surgery, multiorgan failure(even in the absence of infection), and myocardial infarction. High procalcitonin levels may be associated with increased mortality in patients with sepsis.[23]

Imaging Studies

Chest radiograph helps to look for the respiratory cause of fever and differentiates pneumonia from tracheobronchitis. The sensitivity of chest x-rays is significantly decreased in neutropenic patients. For example, about 50% of neutropenic patients with bone marrow suppression and blood stem cell transplant recipients had a normal x-ray chest when the HRCT thorax was abnormal.[24]

Ultrasound lung and abdomen/pelvis also help to rule out sources of infection. Ultrasound chest has a high sensitivity in detecting consolidations in the lung, though with a lesser specificity. Ultrasound abdomen will not be able to detect retroperitoneal collections accurately. Air, if present, will obscure the ultrasonic vision significantly. Compression ultrasound & Doppler study of deep veins are performed whenever deep vein thrombosis is suspected. An arterial doppler may be required to diagnose early/subtle limb ischemia as a cause for fever.

CT thorax may help diagnose empyema thoraces unclear or invisible on routine X-ray chest, aiding its prompt drainage. A Contrast-Enhanced Abdominal CT  is sometimes needed to evaluate an undetected intra-abdominal source of fever. Acalculous cholecystitis, liver abscess, and post-operative abdominal collection can be identified with CT abdomen. Suspected mesenteric ischemia will require a CT angiogram. Evaluation for sinusitis is important, especially in neutropenic patients and non-neutropenic patients without any other known infection source. This involves a high degree of clinical suspicion and a CT scan of the paranasal sinuses. Whole-body positron emission tomography (PET) scan is rarely required to diagnose the source of fever in an ICU patient.

Endoscopic Interventions

Fibreoptic bronchoscopy and BAL help diagnose certain uncommon pulmonary etiologies (infectious and non-infectious) causing fever in an ICU patient. Fibreoptic gastrointestinal endoscopies are sometimes utilized to rule out a  gastrointestinal cause (infectious or non-infectious) cause for fever. Colonoscopy may be rarely required to confirm the pseudomembrane formation in strongly suspected Clostridioides difficile colitis if conventional tests are negative.

Blood cultures

Blood cultures from two different sites (aerobic and anaerobic bottles) should be drawn before starting treatment with antimicrobials. In the presence of central intravascular catheters, blood cultures from the catheter should also be drawn. Moreover, blood should be used to additionally inoculate fungal culture bottles if infection with fungus is suspected.

Respiratory tract sampling

When appropriate, endotracheal aspirate/sputum Gram stain and culture are also indicated for febrile patients.

Treatment / Management

Antibiotics

Empirical antibiotic therapy should be started in patients with suspected infections after sending appropriate cultures. The antibiotics must be initiated at the earliest possible in all suspected sepsis cases, especially in septic shock. The antibiotics/antimicrobials are selected based on the pathogen's suspected nature, the source of sepsis, the local antibiogram, and the risk of encountering drug resistance in a particular patient. Antibiotics need to be given in the correct dose for the appropriate duration. Deescalation involves substituting the ongoing antibiotic with a narrower spectrum antibiotic as per the culture report, converting IV antibiotics to oral ones, and finally stopping the ongoing antibiotic once the course is over. Deescalation is expected to combat the increasing antibiotic resistance in ICUs all over the globe.

Source Control

The source of infection should be identified, and source control should be enacted immediately. This includes removing intravascular devices, urinary catheters, and drainage of empyema/abscesses.

Role of Antipyretics

Antipyretics reduce the threshold of body temperature control in the hypothalamus and hence reduce the body temperature. Fever is said to have a protective role in patients with infection by reducing bacterial growth, increasing the synthesis of cytokines, and activating neutrophils, macrophages, and T cells.[25][26] However, fever has some deleterious effects. It has been shown to increase metabolism and hence oxygen consumption.[27] Lowering the temperature has been shown to reduce lactate levels in septic patients.[28] Whether the cost of pyrexia relates to unfavorable outcomes remains unknown. Also, it has been proven without a doubt that in neurological injury, fever increases mortality.[29][30][31][32] 

The REACTOR study randomly evaluated 184 ICU patients with fever who did not have any acute CNS pathology. They studied the difference between systematic active and ordinary temperature management and observed no difference in ICU-free days or 90-day survival.[33] The available studies and data regarding aggressive temperature control measures using external cooling or acetaminophen are met with significant methodological flaws and are inconclusive at this stage.[34][35]

So if the question is, "should the fever be treated in all the patients?" A fever >40 C is associated with increased mortality in patients without evidence of infection and should be controlled aggressively.[6] Moderate fever (37.5 to 38.4 C) was associated with decreased mortality in septic patients.[5] A meta-analysis showed that antipyretics do not reduce mortality or show any difference in the acquisition of nosocomial infection in critically ill patients with sepsis.[36]

Most experts prefer acetaminophen over aspirin for temperature control in the ICU. The bioavailability of enteral acetaminophen is excellent, and the enteral/oral route is preferred over intravenous preparation unless the enteral route is contraindicated. Many studies reported incidence of fall in systolic blood pressure ≤90 mmHg or ≥20% from baseline were higher with intravenous acetaminophen than with oral preparations.[37][38]

Differential Diagnosis

Though most fevers in the ICU are of infective etiology, the possibility of non-infective etiology also needs to be considered in any setting to prevent abuse or misuse of antibiotics.

Postoperative Fever

Fever is quite frequently seen in the first 48 hours after surgery. Early postoperative fever is usually noninfectious due to an inflammatory response to surgery. This does not require evaluation. Fever after 72-96 hours post-surgery is usually infectious and needs further evaluation. The surgical wound should be evaluated for infection. The other causes of fever are atelectasis, urinary tract infection, deep vein thrombosis, suppurative phlebitis, and pulmonary embolism.

Ventilator-associated Pneumonia (VAP)

Ventilator-associated pneumonia is pneumonia occurring 48 hours after endotracheal intubation. Pneumonia is defined as the presence of lung infiltrates and evidence that it is infectious as indicated by the new onset of fever, purulent sputum, leukocytosis, and decline in oxygenation.[39] Diagnosis is based on clinical suspicion, chest radiograph, and microbiological cultures from lower respiratory tract secretions.[40] Prevention of VAP plays a crucial role. VAP prevention includes the implementation of infection control practices and VAP bundles. Treatment is with IV antibiotics. Per the hospital antibiogram, empirical antibiotic therapy should be started and then changed to pathogen-specific therapy once the culture results are obtained.[39]

Catheter-related BloodstreamIinfection (CRBSI)

CRBSI is a bloodstream infection attributed to an intravenous catheter. It is the commonest cause of nosocomial bacteremia. A definitive diagnosis of CRBSI is made if the same organism grows from at least one percutaneous blood sample culture and the catheter tip.[41] Treatment includes the removal of catheters and antibiotics.

Fever Due to Indwelling Catheter (CAUTI)

Catheter-associated urinary tract infection (CAUTI) is a urinary tract infection in a patient on a urinary catheter or was catheterized in the last 48 hours. The urinary samples should be obtained directly from the catheter's sampling port to diagnose catheter-associated urinary tract infections. If the catheter has been in place for >2 weeks, it should be replaced, and the sample should be taken from a new catheter.[42]

Pressure Ulcers

A pressure ulcer is a non-infective cause of fever in the ICU. However, it is commonly associated with infection and sepsis. The incidence of pressure ulcers varies between different clinical settings. Literature shows a wide range of variations in pressure sore prevalence between 5% to 40%.[43][44][45] Pressure ulcers prolong the hospital stay and patient suffering, increase mortality, and are an economic burden.

Acalculous Cholecystitis

Acalculous cholecystitis is an inflammatory disease of the gall bladder which occurs without a gallstone. It results due to dysfunction of the gall bladder emptying. It occurs in approximately 1.5% of critically ill patients. It occurs in critically ill patients due to other medical or surgical conditions. The common clinical features include fever with sepsis, jaundice, and right upper quadrant pain and tenderness. Abdominal ultrasound is required for diagnosis. CT abdomen may be required if the diagnosis is not clear.[46] In an unstable patient, treatment consists of percutaneous drainage or ERCP with stent placement to decompress the gall bladder. Cholecystectomy is the definitive treatment.

Nosocomial Sinusitis

Nosocomial sinusitis is usually overlooked as a source of infections in critically ill patients. Predisposing nosocomial sinusitis factors include nasogastric or nasotracheal tubes, facial fractures, nasal packing, and steroids.[47] Diagnosis is usually difficult as the patient is usually on the ventilator, and the clinical signs and symptoms cannot be elicited. A CT scan makes the diagnosis of the paranasal sinuses.[48] Microbial diagnosis can be made by antral puncture or endoscopic tissue culture. Nosocomial sinusitis is often associated with ventilator-associated pneumonia. Treatment includes removing the foreign body, like the nasogastric tube, nasal vasoconstrictors, and antibiotics.

Nosocomial Diarrhea

The most common cause for febrile diarrhea is Clostridioides (previously Clostridium) difficile infection, infecting patients who have recently been treated with antibiotics. The antibiotic most commonly associated with Clostridioides difficile infection is clindamycin. The criteria for diagnosis include diarrhea, defined as an increase in stool liquidity and an increased frequency of bowel motions, and the presence of toxins produced by Clostridioides difficile in the stools. Treatment includes supportive measures, stoppage of the ongoing antibiotic therapy, and antibiotics to eradicate Clostridioides difficile. E.g., metronidazole, oral vancomycin, fidaxomicin.[49] Hand washing with soap and water is recommended as the alcohol-based hand rubs are ineffective against Clostridioides difficile.

Drug Fever

3-5% of febrile episodes in ICU are attributed to drugs.[50] It is a diagnosis of exclusion. Diagnosis can be established by the temporal relation between the fever and starting or stopping the medication. The common drugs causing drug fever are antibiotics, especially beta-lactams; antiepileptic drugs, especially phenytoin; antiarrhythmics like quinidine and procainamide; diuretics, allopurinol, and heparin.[16] The approximate time between initiation of the drug and the appearance of fever is around 7 to 10 days, and fever generally subsides within 72 hours of withdrawal of the drug.[51]

Hyperthermia Syndromes

Hyperthermia is a high core body temperature > 41 degrees C. It differs from fever because body temperature is elevated above the thermoregulatory set point. Hyperthermia does not respond to pharmacological therapy. Hyperthermia syndromes include heat stroke, malignant hyperthermia, neuroleptic malignant syndrome, and serotonin syndrome. Endocrine conditions like thyrotoxicosis, adrenal crisis, and pheochromocytoma also cause hyperthermia.

Pertinent Studies and Ongoing Trials

The HEAT trial compared acetaminophen with a placebo in patients with fever (body temperature ≥38 C) and known or suspected infection. There was a moderate reduction in temperature but no difference in mortality at 28 or 90 days or the ICU-free days.[35] A meta-analysis of randomized control trials showed that more active fever management did not show any survival benefit in critically ill patients.[52] Another meta-analysis showed that antipyretics reduce the temperature in non-neurocritical ill patients but do not reduce mortality or impact other outcomes.[53]

Prognosis

In patients with stroke and neurologic injuries, fever per se, irrespective of the cause, has been shown to have worse outcomes in terms of functional outcome and length of stay.[32] However, in non-neurological patients, there is no clear evidence that fever increases mortality. Depending on the etiology of the fever, outcomes vary.

Complications

Deleterious effects of fever include an increase in cardiac output, an increase in oxygen consumption, and an increase in carbon dioxide production.[54] Febrile convulsions are common in children between 3 months and six years of age and are often noted to have an associated family history. Fever worsens neurological outcomes in patients with traumatic brain injury and cerebrovascular accidents.[55][32] 

A drop in GCS commonly occurs in patients with traumatic brain injury or stroke whenever a new onset fever sets in. Maternal fever is associated with fetal malformations & spontaneous abortion.[56] 

Persistent high fevers also cause rhabdomyolysis and acute kidney injury, necessitating renal replacement therapy. Fever could have significant indirect impacts too. Apart from the cost implication of any fever evaluation and treatment, unexplained fevers often prompt misuse or overuse of antibiotics (empiric use even in non-infectious causes), which could result in economic burden and promote the development of multidrug resistance.

Consultations

An infectious disease consult may help evaluate and manage fever in an ICU patient, especially when it is persistent, even after appropriate management. Fever with an unknown etiology with non-resolving sepsis/septic shock could be challenging and require urgent multidisciplinary interaction and aggressive evaluation. Constant interaction with the radiology team may provide an early clue for diagnosis, ensuring early diagnostic and therapeutic interventions. Pulmonologists, rheumatologists, endocrinologists, and surgeons are a few other specialists required based on the suspected etiology of fever.

Deterrence and Patient Education

The patient’s family/ guardian or the patient should be adequately counseled regarding the battery of investigations and evaluations required whenever a new onset fever occurs in a patient already admitted to the ICU. The concern is much more whenever an undiagnosed new-onset fever sets in, especially with sepsis/septic shock features. The family/guardian should be aware of the potential complications, expected morbidity, including a prolonged ICU stay, and the mortality involved in such instances of secondary sepsis.

Enhancing Healthcare Team Outcomes

Fever in ICU can sometimes pose a diagnostic dilemma. Hence an interprofessional healthcare team approach involving good interaction and coordination between various healthcare specialists can bring out the best outcomes in these patients. Education of the entire health care team (including clinicians, mid-level practitioners, nursing, pharmacists, and paramedical staff), with the implementation of stringent infection control measures to prevent secondary ICU infections, forms another major strategy in these cases, thereby improving patient outcomes. [Level 5]