Fever in humans occurs as an adaptive response to inflammation resulting from infection, injury, or an immune-mediated response or drug reaction.1-5 The etiologies of fever are categorized as either infectious or noninfectious. (See Examples of infectious and noninfectious etiologies of fever.) Hospital admissions for infection and/or sepsis remain steady and have increased over time.9,10 Fever in ICU patients with infection or sepsis is common, with reported occurrence ranging from 15% to 70%.2,11-15 Higher fever rates are reported from studies of single units and smaller sample sizes, and lower rates are reported from more recent studies; this may be explained by improvements in hospital-acquired infection prevention. Despite the lack of evidence-based guidelines to manage fever in patients with infection or sepsis, clinicians frequently intervene to achieve normothermia in their patients.14,16,17
There has been a longstanding controversy over fever treatment in ICU patients. Some clinicians believe the metabolic response to fever poses risk for poor outcomes, and some believe that the physiologic response to fever is beneficial and adaptive to survival.18-20 The disparate findings from ICU studies evaluating relationships between fever and outcomes and testing of antipyretic interventions may be explained by the heterogeneity of the ICU patient population. More recently, temperature and fever studies have been designed to evaluate subpopulations of ICU patients (neurologic, septic, trauma, acute lung injury, and more) to address this limitation. Recent evidence about the impact of fever suppression on outcomes in ICU patients with infection and/or sepsis may shift the practice of fever management. This article presents an overview of fever and fever suppression interventions, as well as evidence of their impact on outcomes in ICU patients with infection and/or sepsis.
Body temperature terminology
It is important for critical care nurses to understand terminology used to describe body temperature alterations, especially fever, to ensure an accurate evaluation during a critical appraisal of the evidence. (See Body temperature terminology.) Although there are many temperature thresholds used to define fever in the literature, the American College of Critical Care Medicine and the Infectious Disease Society of America define fever as a core body temperature greater than or equal to 38.3° C (101° F) and recommend identification and evaluation of febrile patients in the ICU using this criterion.22
Mechanism of fever
Thermoregulation in humans is the ability of the body to maintain a core body temperature within a hypothalamic-determined range for optimal physiologic functioning, regardless of the variable environmental temperatures. Thermoregulation is a result of the integrated and coordinated work of the nervous, endocrine, circulatory, and pulmonary systems, along with behavioral responses to generate heat, conserve heat, reduce heat production, and lose heat.
As a part of the innate immune response to infectious pathogens, the acute phase response, the resulting inflammation and fever serve as the body's early defense mechanism when infection occurs. Pathogens encounter host immune cells, typically macrophages or monocytes, which synthesize and secrete proinflammatory cytokines to initiate the acute phase response. The acute phase response is a series of complex neuroimmunologic reactions including fever stimulation and the release of cytokines and immunologically activated proteins in response to injury or illness in an attempt to heal the body and reestablish homeostasis.25 Infection activates local inflammation including release of pyrogenic cytokines, which circulate to the hypothalamus, where the thermal set point is increased and body temperature is altered by a series of complex reactions.26-29
Fever and outcomes
Although several studies have reported significant observed associations between fever and higher mortality in ICU patients over the past 20 years, more recent studies are reporting no relationship or a reduced risk for mortality with fever, especially when infection is present. Preservation of the species over the individual is a basic principle of evolution. The strongest evidence that the fever response, including the associated inflammatory response, is adaptive in mammals is the argument that fever would not have been preserved over time with its “metabolically expensive” impact on body systems if there was no survival benefit.21 There have been several studies in the past decade that support the hypothesis that fever is beneficial during infection, as it enhances immune system functions and supports antimicrobial activity.
Fever was an independent predictor of reduced mortality in ICU patients with invasive Candida infections.30 A large multisite trial conducted in Japan and Korea observed no relationship between mortality and fever in the group of patients with sepsis, but did find an increased risk of mortality in febrile patients without sepsis.14 The inability to mount a fever in the early days after injury is an independent predictor of infection and mortality in trauma patients, whereas a fever response was not associated with mortality.31 Body temperature was found to be an independent predictor of mortality (lower mortality with higher temperatures) in a study with surgical patients with blood stream infections and a study of patients with acute respiratory distress syndrome.32,33 Finally, in a recent meta-analysis of 42 studies that evaluated the impact of body temperature on mortality in patients with sepsis, fever predicted the lowest mortality compared with normothermia.34
Fever management can be defined to include identification of fever from body temperature monitoring, application of fever suppression interventions, and evaluation of body temperature and clinical response of patients receiving antipyretic interventions. Fever suppression interventions in ICU patients include administration of antipyretic medications and/or physical cooling interventions to reduce body temperature.14,16,35,36 Acetaminophen is the most common antipyretic medication prescribed for ICU and hospitalized patients.4,37,38 Survey responses from critical care physicians and nurses consistently report that antipyretic medications are the first-line intervention chosen for febrile patients and physical cooling methods are second-line interventions when fevers persist.15,36,39
Acetaminophen. The antipyretic mechanism of action of acetaminophen is not fully understood, yet it appears to block COX-2 enzymes and inhibit prostaglandin-E2 (PGE-2) synthesis in the central nervous system.40,41 This leads to a decrease in the thermal set point in the hypothalamus and the resultant thermoeffector response of cutaneous vasodilation, sweating, and increased respiratory ventilation to promote heat loss.
Until recently, there have been few studies of the antipyretic efficacy of acetaminophen in febrile ICU patients.42 Although most studies with acetaminophen and placebo group comparisons report a lower body temperature in the acetaminophen-treated group, the temperature reduction is modest from a clinical relevance perspective.43-46 In the recently published multisite, randomized controlled trial (RCT), Permissive Hyperthermia through Avoidance of Acetaminophen in Known or Suspected Infection in the ICU (HEAT), which evaluated the impact of intermittent I.V. infusions of acetaminophen on the outcomes of 700 ICU patients with infection, the investigators observed a reduced mean daily average body temperature difference of -0.28° C (95% confidence interval [CI], -0.37 to -0.19).45
A mean difference body temperature reduction of 0.4° C (95% CI, 0.9 to 0.01) was observed 4 hours after I.V. infusion acetaminophen administration compared with placebo in a recent RCT evaluating the effect of acetaminophen on temperature and hemodynamic response in febrile ICU patients.43
Acetaminophen is a relatively safe medication with the known caution of liver dysfunction associated with excessive doses. A less well-known acute adverse reaction to acetaminophen is a significant reduction in BP that has clinical relevance for some ICU patients.43,47-49 There is ongoing research evaluating the potential benefits of acetaminophen after recent findings from a RCT of patients with severe sepsis and detectable levels of cell-free hemoglobin demonstrated reduced oxidative injury after treatment with acetaminophen.50
Nonsteroidal anti-inflammatory drugs. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, are also used as antipyretics in hospitalized patients, though they were used with caution and lower frequency due to the risks of hematologic, kidney, and gastrointestinal adverse reactions in this population.51,52 The antipyretic mechanism of action for NSAIDs also involves a reduction in PGE-2 levels through inhibition and/or downregulation of COX-1 and COX-2 enzyme activity, which results in a decrease of the central thermal set point.51
Although ibuprofen is an effective antipyretic for febrile critically ill patients, it is not commonly used due to the contraindications and warnings for use related to risks for thrombotic stroke, heart failure, myocardial infarction, and gastrointestinal bleeding.53-56 Investigators from the Ibuprofen in Sepsis Study Group observed significantly lower body temperature, heart rate, and minute ventilation in patients with sepsis who received ibuprofen compared with the placebo group, yet survival and duration of shock were not different between groups.55 Randomized, placebo-controlled trials of ibuprofen in febrile burn and malaria-infected patients observed significant body temperature reductions with ibuprofen treatment as well.53,57
Physical cooling interventions include application of surface cooling devices (water-circulating blankets, hydrogel water-circulating pads, air-circulating blankets), intravascular cooling catheter devices, or administration of cold I.V. solutions. Air-circulating cooling devices were found to be more effective than water-circulating blankets for fever suppression in febrile ICU patients.58,59 The more recently designed hydrogel water-flow devices and intravascular cooling devices used for targeted-temperature management are very effective, yet are not typically applied for routine fever suppression due to the expense.60 Nurses report use of fans, baths, ice packs, and cool cloths to treat fever, yet evidence is lacking to support their use as effective antipyretic interventions.
Effectiveness of physical cooling interventions is challenging in patients with intact thermoregulation because the thermal set point is not decreased. When ice packs or cooling blankets are used, the thermal sensors of the skin sense the cold, which conflicts with the pyrogenic cytokine-induced increase of the thermal set point in the hypothalamus. These thermal sensors signal the hypothalamus that signals the heat generation response (for example, shivering), which is counterproductive to the aim of fever suppression. Application of physical cooling to febrile patients causes significant discomfort and can increase oxygen consumption by 57% if shivering is not prevented or managed.61,62 Therefore, the use of antipyretic and shiver-prevention medications in conjunction with physical cooling is more effective and recommended.20,63
Fever suppression and outcomes
To date, the recently published HEAT trial is the largest RCT to evaluate the impact of acetaminophen on outcomes of febrile patients with infection.45 Investigators found no difference in ICU-free days and mortality between the acetaminophen-treated and placebo groups. The publication of this study reignited the discussion among ICU clinicians about whether the routine practice of attempting fever suppression with acetaminophen in this subpopulation of critically ill patients with infection is warranted.19,64,65
Supporting evidence from recent studies has contributed to the recent clinical discussions about whether to treat or not treat fever in ICU patients. A clinical trial investigating outcomes of febrile trauma patients randomized to either permissive fever up to 40° C (104° F) or aggressive antipyretic treatment to keep temperature below 38.5° C (101.3° F) was stopped after early interim analysis due to the higher mortality incidence in the aggressive antipyretic group.66 A large prospective cohort study of 1,425 patients with fever found antipyretic medication (acetaminophen and NSAIDs) treatment to be an independent predictor of mortality in patients with sepsis.14 The findings from a retrospective study of patients with sepsis who had Gram-negative pathogens receiving mechanical ventilation reported a significant association between the use of antipyretic interventions and increased ICU mortality.67 Finally, a recent meta-analysis of eight randomized and eight observational trials evaluated the impact of antipyretic interventions on mortality in patients with sepsis.68 Results from analyses of both trial design cohorts found that antipyretic interventions do not reduce mortality in patients with sepsis.
A recent RCT compared the effect of fever suppression using external cooling to no cooling for 48 hours on vasopressor dose reduction in febrile patients with septic shock.69 The mechanism of improved BP with cooling is related to the cold-induced skin and peripheral vasoconstriction. Investigators observed a significantly higher occurrence of vasopressor dose reduction from baseline to 12 hours in the cooling group, but significance was not sustained to their primary endpoint of 48 hours. Although the study was not powered to detect significant differences in mortality, they reported a lower 14-day mortality in the cooling group, which did not sustain significance at ICU or hospital discharge. It is important to note that achieving fever suppression with this cooling protocol required patients in this study to be mechanically ventilated and receive sedative agents with use of neuromuscular blocking agents in 25% of the sample. Although an effective antipyretic intervention, the feasibility and potential risk of fever suppression with physical cooling versus benefit in ICU patients with sepsis requires further study.
Nurses are the primary decision-makers of fever management as they monitor body temperature, communicate onset of fever to providers, suggest interventions, administer antipyretic medications and other cooling measures as ordered, and evaluate the patient's response to the interventions.16,36,70,71 The recent interest in evaluating the longstanding practice of fever suppression in ICU patients with particular focus on those with infection and sepsis has produced new evidence that nurses can use for clinical decision-making in practice.
Nurses can include assessment of their patient's fever response beyond the body temperature when notifying providers to discuss potential diagnostic workup and whether to apply antipyretic interventions or not. The fever response assessment includes body temperature, respiratory rate (RR), heart rate (HR), BP, mental status, thermal comfort, and any recent immunologic or microbiology lab results. Including the patient's current and comorbid diagnoses with the fever response in the risk-benefit clinical decision-making for fever suppression interventions is a paradigm shift from routine antipyretic intervention for an elevated body temperature. When caring for febrile patients, it is also important to evaluate the patients' responses to antipyretic interventions including body temperature, HR, BP, RR, mental status, thermal comfort, and signs of shivering. Because assessment, management, and evaluation of alterations in body temperature are long-standing fundamentals of nursing care, nurses are essential participants on interprofessional research or performance improvement teams that aim to study and/or implement evidence-based practice initiatives related to fever management.
The current evidence related to fever management in patients with infection and/or sepsis warrants review of routine, tradition-based implementation of antipyretic interventions in this subpopulation of ICU patients. Nurses are optimally positioned to initiate review of current fever management practice on their units and engage their peers in journal clubs or other evidence review forums. As more research on the impact of fever management on acute and long-term outcomes of patients with infection emerges, the importance of critical appraisal of evidence and practice updates, as appropriate, are critical for professional nursing, resource use, and the outcomes of patients we serve.
1. Mulders-Manders CM, Pietersz G, Simon A, Bleeker-Rovers CP. Referral of patients with fever of unknown origin to an expertise center has high diagnostic and therapeutic value. QJM
. [e-pub July 28, 2017].
2. Laupland KB, Zahar JR, Adrie C, et al. Determinants of temperature abnormalities and influence on outcome of critical illness. Crit Care Med
3. Young PJ, Saxena M, Beasley R, et al. Early peak temperature and mortality in critically ill patients with or without infection. Intensive Care Med
4. Young P, Saxena M, Eastwood GM, Bellomo R, Beasley R. Fever and fever management among intensive care patients with known or suspected infection: a multicentre prospective cohort study. Crit Care Resusc
5. Barie PS, Hydo LJ, Eachempati SR. Causes and consequences of fever complicating critical surgical illness. Surg Infect (Larchmt)
6. Rehman T, deBoisblanc BP. Persistent fever in the ICU. Chest
7. Niven DJ, Laupland KB. Pyrexia: aetiology in the ICU. Crit Care
8. Ülger F, Pehlivanlar Küçük M, Öztürk ÇE, Aksoy İ, Küçük AO, Murat N. Non-infectious fever after acute spinal cord injury in the intensive care unit. J Spinal Cord Med
. [e-pub Oct. 13, 2017].
9. Rhee C, Dantes R, Epstein L, et al. Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009-2014. JAMA
10. Lagu T, Rothberg MB, Shieh MS, Pekow PS, Steingrub JS, Lindenauer PK. Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007. Crit Care Med
11. Laupland KB, Shahpori R, Kirkpatrick AW, Ross T, Gregson DB, Stelfox HT. Occurrence and outcome of fever in critically ill adults. Crit Care Med
12. Circiumaru B, Baldock G, Cohen J. A prospective study of fever in the intensive care unit. Intensive Care Med
13. Peres Bota D, Lopes Ferreira F, Mélot C, Vincent JL. Body temperature alterations in the critically ill. Intensive Care Med
14. Lee BH, Inui D, Suh GY, et al. Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study. Crit Care
15. Niven DJ, Laupland KB, Tabah A, et al. Diagnosis and management of temperature abnormality in ICUs: a EUROBACT investigators' survey. Crit Care
16. Thompson HJ, Kagan SH. Clinical management of fever by nurses: doing what works. J Adv Nurs
17. Niven DJ, Stelfox HT, Laupland KB. Antipyretic therapy in febrile critically ill adults: a systematic review and meta-analysis. J Crit Care
18. Young PJ, Saxena M. Fever management in intensive care patients with infections. Crit Care
19. Ray JJ, Schulman CI. Fever: suppress or let it ride. J Thorac Dis
20. Doyle JF, Schortgen F. Should we treat pyrexia? And how do we do it. Crit Care
21. Mackowiak PA, Plaisance KI. Benefits and risks of antipyretic therapy. Ann N Y Acad Sci
22. 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. Crit Care Med
23. Gomez CR. Disorders of body temperature. Handb Clin Neurol
24. Walter EJ, Hanna-Jumma S, Carraretto M, Forni L. The pathophysiological basis and consequences of fever. Crit Care
25. Cray C, Zaias J, Altman NH. Acute phase response in animals: a review. Comp Med
26. Kozak W, Kluger MJ, Tesfaigzi J, et al. Molecular mechanisms of fever and endogenous antipyresis. Ann N Y Acad Sci
27. Leon LR. Invited review: cytokine regulation of fever: studies using gene knockout mice. J Appl Physiol (1985)
28. Romanovsky AA, Almeida MC, Aronoff DM, et al. Fever and hypothermia in systemic inflammation: recent discoveries and revisions. Front Biosci
29. Conti B, Tabarean I, Andrei C, Bartfai T. Cytokines and fever. Front Biosci
30. Leroy O, Gangneux JP, Montravers P, et al. Epidemiology, management, and risk factors for death of invasive Candida infections in critical care: a multicenter, prospective, observational study in France (2005–2006). Crit Care Med
31. Mizushima Y, Ueno M, Idoguchi K, Ishikawa K, Matsuoka T. Fever in trauma patients: friend or foe. J Trauma
32. Schell-Chaple HM, Puntillo KA, Matthay MA, Liu KD, National HeartLung, and Blood Institute Acute Respiratory Distress Syndrome Network. Body temperature and mortality in patients with acute respiratory distress syndrome. Am J Crit Care
33. Swenson BR, Hedrick TL, Popovsky K, Pruett TL, Sawyer RG. Is fever protective in surgical patients with bloodstream infection. J Am Coll Surg
. 2007;204(5):815–821; discussion 822-823.
34. Rumbus Z, Matics R, Hegyi P, et al. Fever is associated with reduced, hypothermia with increased mortality in septic patients: a meta-analysis of clinical trials. PLoS One
35. Kiekkas P, Brokalaki H, Manolis E, Askotiri P, Karga M, Baltopoulos GI. Fever and standard monitoring parameters of ICU patients: a descriptive study. Intensive Crit Care Nurs
36. Saxena MK, Hammond NE, Taylor C, et al. A survey of fever management for febrile intensive care patients without neurological injury. Crit Care Resusc
37. Mohr NM, Fuller BM, Skrupky LP, et al. Clinical and demographic factors associated with antipyretic use in gram-negative severe sepsis and septic shock. Ann Pharmacother
38. Jefferies S, Weatherall M, Young P, Eyers S, Perrin KG, Beasley CR. The effect of antipyretic medications on mortality in critically ill patients with infection: a systematic review and meta-analysis. Crit Care Resusc
39. Rockett H, Thompson HJ, Blissitt PA. Fever management practices of neuroscience nurses: what has changed. J Neurosci Nurs
40. Graham GG, Davies MJ, Day RO, Mohamudally A, Scott KF. The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings. Inflammopharmacology
41. Engström Ruud L, Wilhelms DB, Eskilsson A, et al. Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-2. Neuropharmacology
42. Pierce CA, Voss B. Efficacy and safety of ibuprofen and acetaminophen in children and adults: a meta-analysis and qualitative review. Ann Pharmacother
43. Schell-Chaple HM, Liu KD, Matthay MA, Sessler DI, Puntillo KA. Effects of IV acetaminophen on core body temperature and hemodynamic responses in febrile critically ill adults: a randomized controlled trial. Crit Care Med
44. de Ridder IR, den Hertog HM, van Gemert HM, et al. PAIS 2 (Paracetamol [Acetaminophen] in Stroke 2): Results of a Randomized, Double-Blind Placebo-Controlled Clinical Trial. Stroke
45. Young P, Saxena M, Bellomo R, et al. Acetaminophen for fever in critically ill patients with suspected infection. N Engl J Med
46. den Hertog HM, van der Worp HB, van Gemert HM, et al. The Paracetamol (Acetaminophen) In Stroke (PAIS) trial: a multicentre, randomised, placebo-controlled, phase III trial. Lancet Neurol
47. Cantais A, Schnell D, Vincent F, et al. Acetaminophen-induced changes in systemic blood pressure in critically ill patients: results of a multicenter cohort study. Crit Care Med
48. Chiam E, Weinberg L, Bailey M, McNicol L, Bellomo R. The haemodynamic effects of intravenous paracetamol (acetaminophen) in healthy volunteers: a double-blind, randomized, triple crossover trial. Br J Clin Pharmacol
49. Kang S, Durey A, Suh YJ, Kim AJ. Hemodynamic changes after propacetamol administration in patients with febrile UTI in the emergency department. Am J Emerg Med
. [e-pub Oct. 31, 2017].
50. Janz DR, Bastarache JA, Rice TW, et al. Randomized, placebo-controlled trial of acetaminophen for the reduction of oxidative injury in severe sepsis: the Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis trial. Crit Care Med
51. Aronoff DM, Neilson EG. Antipyretics: mechanisms of action and clinical use in fever suppression. Am J Med
52. Niven DJ, Laupland KB. Pharmacotherapy of fever control among hospitalized adult patients. Expert Opin Pharmacother
53. Promes JT, Safcsak K, Pavliv L, Voss B, Rock A. A prospective, multicenter, randomized, double-blind trial of IV ibuprofen for treatment of fever and pain in burn patients. J Burn Care Res
54. Morris PE, Promes JT, Guntupalli KK, Wright PE, Arons MM. A multi-center, randomized, double-blind, parallel, placebo-controlled trial to evaluate the efficacy, safety, and pharmacokinetics of intravenous ibuprofen for the treatment of fever in critically ill and non-critically ill adults. Crit Care
55. Bernard GR, Wheeler AP, Russell JA, et al. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med
56. FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. 2015. www.fda.gov/Drugs/DrugSafety/ucm451800.htm
57. Krudsood S, Tangpukdee N, Wilairatana P, et al. Intravenous ibuprofen (IV-ibuprofen) controls fever effectively in adults with acute uncomplicated Plasmodium falciparum malaria but prolongs parasitemia. Am J Trop Med Hyg
58. Creechan T, Vollman K, Kravutske ME. Cooling by convection vs cooling by conduction for treatment of fever in critically ill adults. Am J Crit Care
59. Loke AY, Chan HC, Chan TM. Comparing the effectiveness of two types of cooling blankets for febrile patients. Nurs Crit Care
60. Hoedemaekers CW, Ezzahti M, Gerritsen A, van der Hoeven JG. Comparison of cooling methods to induce and maintain normo- and hypothermia in intensive care unit patients: a prospective intervention study. Crit Care
61. Lenhardt R, Negishi C, Sessler DI, et al. The effects of physical treatment on induced fever in humans. Am J Med
62. Shah NG, Cowan MJ, Pickering E, et al. Nonpharmacologic approach to minimizing shivering during surface cooling: a proof of principle study. J Crit Care
63. Hammond NE, Boyle M. Pharmacological versus non-pharmacological antipyretic treatments in febrile critically ill adult patients: a systematic review and meta-analysis. Aust Crit Care
64. Chiumello D, Gotti M, Vergani G. Paracetamol in fever in critically ill patients-an update. J Crit Care
65. Young PJ, Nielsen N, Saxena M. Fever control. Intensive Care Med
66. Schulman CI, Namias N, Doherty J, et al. The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surg Infect (Larchmt)
67. Ye S, Xu D, Zhang C, Li M, Zhang Y. Effect of antipyretic therapy on mortality in critically ill patients with sepsis receiving mechanical ventilation treatment. Can Respir J
68. Drewry AM, Ablordeppey EA, Murray ET, et al. Antipyretic therapy in critically ill septic patients: a systematic review and meta-analysis. Crit Care Med
69. Schortgen F, Clabault K, Katsahian S, et al. Fever control using external cooling in septic shock: a randomized controlled trial. Am J Respir Crit Care Med
70. Grossman D, Keen MF, Singer M, Asher M. Current nursing practices in fever management. Medsurg Nurs
71. O'Donnell J, Axelrod P, Fisher C, Lorber B. Use and effectiveness of hypothermia blankets for febrile patients in the intensive care unit. Clin Infect Dis