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Fever suppression in patients with infection

State of the evidence

Schell-Chaple, Hildy PhD, RN, CCNS, FAAN

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doi: 10.1097/01.CCN.0000534921.93547.1a
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Figure

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.

Table
Table:
Examples of infectious and noninfectious etiologies of fever1,6-8

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

Table
Table:
Body temperature terminology6-8,21-24

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

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

Pharmacologic antipyretics

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

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.

Nursing considerations

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.

Conclusion

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.

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                      Keywords:

                      antipyretics; critical illness; fever; hyperthermia; hypothermia; infection; normothermia; sepsis; thermoregulation

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