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Point: Should Antipyretic Therapy Be Given Routinely to Febrile Patients in Septic Shock? YesAntipyretic Therapy in Septic Shock FREE TO VIEW

Nicholas M. Mohr, MD; Kevin C. Doerschug, MD, FCCP
Author and Funding Information

From the Department of Emergency Medicine, Division of Critical Care, Department of Anesthesia (Dr Mohr), and the Division of Pulmonary Diseases, Critical Care, and Occupational Medicine, Department of Internal Medicine (Dr Doerschug), University of Iowa Carver College of Medicine.

Correspondence to: Nicholas M. Mohr, MD, University of Iowa Hospitals and Clinics, 200 Hawkins Dr, 1008 RCP, Iowa City, IA 52242; e-mail: nicholas-mohr@uiowa.edu


Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;144(4):1096-1098. doi:10.1378/chest.13-0916
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Published online

Fever is a highly conserved response to infection in animal species. The presence of fever implies immune competence, and although some postulate the ability to mount fever portends survival advantages, the magnitude of fever has been associated with higher mortality in sepsis.1 Unfortunately, the pathophysiologic derangements accompanying septic shock overcome the protective value of fever, and in some cases fever contributes to a cycle of vasodilatory shock, myocardial dysfunction, and organ failure that precedes death. Critical care physicians should strongly consider external cooling to minimize the harmful effects of fever, especially among the most seriously ill patients. We base this position upon the following arguments:

  • 1. A physiologic rationale exists to support fever therapy;

  • 2. Contradictory conclusions in the literature result primarily from heterogeneity of studies (eg, severity of illness, methods of cooling, and timing of interventions); and

  • 3. The strongest clinical trial supports fever treatment.

Fever intuitively seems like it should have value. For a mechanism that comprises 23% of the metabolic requirement in a critically ill human,2 it is amazingly prevalent among nonhuman species. Cold-blooded lizards, rabbits, mice, and sheep mount fever, and fever seems important in these animals’ ability to fight infection.3 The conservation of this response across species suggests a great importance of fever, so impairing natural immune function through antipyretic therapy seems counterintuitive. Several human series have demonstrated faster viral clearance and improved vaccine response in the presence of fever.4,5 Febrile-range hyperthermia has been associated with several protective mechanisms, including decreased bacterial replication, increased antimicrobial effects, enhanced immune function, leukocyte activation, negative feedback on proinflammatory cytokines, and increased expression of heat shock protein chaperones.3

Unfortunately, fever also imparts deleterious physiology. First, fever places an incredibly expensive metabolic load on patients in whom oxygen delivery is already compromised. In a series of 12 critically ill patients, treating fever decreased oxygen consumption, CO2 production, and energy expenditure.2 Second, fever has been shown to be a direct depressant of myocardial function, and it contributes to vasodilatory shock.6,7 Third, hyperthermia may worsen oxygen exchange in patients with lung injury. Among 27 septic patients with ARDS, Pao2/Fio2 was inversely associated with temperature.8 A subsequent study of mild therapeutic hypothermia in 19 patients with sepsis and ARDS demonstrated that those assigned to hypothermia had improved oxygenation (Pao2/Pao2, 0.27 vs 0.15; P < .01) and mortality (67% vs 100%, P < .05) compared with those assigned to normothermia.9

Despite decades of looking for a universal survival advantage from withholding antipyretic therapy, convincing evidence has been elusive. Multiple animal studies, observational studies, and seven randomized clinical trials7,10-15 have been performed to evaluate the safety and effectiveness of fever control, with conflicting results. Although most have been underpowered to evaluate clinical outcomes, few have shown clear harm from antipyretic therapy. Yet heterogeneity persists regarding the benefits of fever control. Why do studies disagree on the value of fever control?

Severity of Illness

The heterogeneous effects of antipyretic therapy are partially a result of variations in severity of illness across studies. In a rat model of intraabdominal sepsis, therapeutic hypothermia resulted in an increased survival time and decreased organ injury in those animals with severe septic shock (cecal incision with peritoneal spillage, control group mortality 100%), whereas no such benefit existed for moderately severe septic shock (cecal puncture only with no spillage, control group mortality 67%).16 Thus, it is quite relevant that of all the clinical trials of fever control, the one that most strongly supports fever control also enrolled the most seriously ill cohort.7

External Cooling vs Drug Therapy

The existing literature reports different methods of antipyretic therapy, largely categorized as studies of external cooling or of pharmacologic therapy. The strongest evidence supporting fever control uses external cooling; drug therapy is not as well supported. Many studies used antipyretic medication, but physical cooling allows for temperature control without the potential inhibition of protective inflammatory responses inherent in pharmacologic antipyretics. For example, in febrile rabbits infected with Pasteurella multocida, a sodium salicylate infusion for fever control increased mortality from 29% to 100% (P < .005),17 whereas physical cooling in a separate model decreased mortality from 90% to 46% (P < .03).18 The largest human trial examining the use of ibuprofen therapy in sepsis (n =455) showed no significant difference in mortality (37% vs 40%, P = .56) despite a significant decrease in oxygen consumption and lactate. This study enrolled a cohort that were not as sick (only 64% of patients required vasopressor therapy at study enrollment; mean APACHE [Acute Physiology and Chronic Health Evaluation] II score, 15), but ibuprofen therapy did not show an improvement in survival.11

Timing of Treatment

Antipyretic studies start antipyretic therapy at various times in the development of sepsis, with some initiating therapy prior to infection. This also contributes to the heterogeneity of results. Some fever studies prevent fever in patients who are not infected, oftentimes before experimental models of septic shock are induced. These models are likely different from patients with septic shock, who often have had significant fever prior to receiving medical care. Several animal studies illustrate that applying heat stress prior to the experimental induction of life-threatening infection can improve survival.19 A small trial (N = 82) of febrile trauma patients that randomized primarily noninfected patients to aggressive fever control vs permissive temperature management (using mostly pharmacologic therapy) was stopped at an interim safety analysis because of a significantly higher mortality in the group being aggressively cooled.15 A randomized trial of preoperative local warming (N = 421) also showed significant protection at preventing wound infections when the operative site was warmed prior to clean surgery.20 Although these models can teach us about the role of fever in conditioning a host for infection, they do not inform us about patients presenting with septic shock.

The largest clinical trial using external cooling in patients with septic shock supports induced normothermia in septic shock. A recently published French trial randomized 200 febrile patients with septic shock to external cooling (36.5°C to 37°C) vs no cooling for 48 h. The patients studied all had septic shock (median norepinephrine dose in placebo group was 0.65 μg/kg/min), with a placebo group ICU mortality of 43%. External cooling was effective at reducing temperature (P <.01), decreasing vasopressor dose by > 50% at 12 h (54% vs 20%, P < .01), and avoiding dialysis (10% vs 21%, P = .03). Most importantly, ICU mortality showed a trend toward benefit with external cooling (35% vs 43%, P = .26).7 Febrile patients with septic shock should be cooled using external cooling to normothermia to optimize clinical outcome.

In summary, fever is clearly an important adaptive response to infection. Similar native responses to septic shock include capillary leak, hypotension, myocardial dysfunction, overwhelming inflammatory response, organ failure, and death. For patients with the highest mortality, the benefit of controlling fever outweighs the harm from impairing fever-dependent immune function. Data opposing fever control are drawn primarily from patient populations having lower severity of illness, using drug therapy for antipyresis, or controlling temperature prior to infection. The only quality clinical trial that tests external cooling in patients with septic shock supports fever control for improving resolution from shock and for decreasing mortality. Hyperthermia therapy was popular in the early 20th century as a pre-antibiotic treatment of infection. Is interest in the therapeutic value of fever in critical illness based on clinical data, or do we think that fever is important only because “it must be”? Emerging data are clear—our most seriously ill patients do not tolerate fever well, and we should use temperature management as an additional therapy to optimize sepsis physiology.

Lee BH, Inui D, Suh GY, et al; Fever and Antipyretic in Critically ill Patients Evaluation (FACE) Study Group. Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study. Crit Care. 2012;16(1):R33. [CrossRef] [PubMed]
 
Manthous CA, Hall JB, Olson D, et al. Effect of cooling on oxygen consumption in febrile critically ill patients. Am J Respir Crit Care Med. 1995;151(1):10-14. [CrossRef] [PubMed]
 
Hasday JD, Fairchild KD, Shanholtz C. The role of fever in the infected host. Microbes Infect. 2000;2(15):1891-1904. [CrossRef] [PubMed]
 
Graham NM, Burrell CJ, Douglas RM, Debelle P, Davies L. Adverse effects of aspirin, acetaminophen, and ibuprofen on immune function, viral shedding, and clinical status in rhinovirus-infected volunteers. J Infect Dis. 1990;162(6):1277-1282. [CrossRef] [PubMed]
 
Prymula R, Siegrist CA, Chlibek R, et al. Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials. Lancet. 2009;374(9698):1339-1350. [CrossRef] [PubMed]
 
Haupt MT, Rackow EC. Adverse effects of febrile state on cardiac performance. Am Heart J. 1983;105(5):763-768. [CrossRef] [PubMed]
 
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. 2012;185(10):1088-1095. [CrossRef] [PubMed]
 
Pernerstorfer T, Krafft P, Fitzgerald R, et al. Optimal values for oxygen transport during hypothermia in sepsis and ARDS. Acta Anaesthesiol Scand Suppl. 1995;39(s107):223-227. [CrossRef]
 
Villar J, Slutsky AS. Effects of induced hypothermia in patients with septic adult respiratory distress syndrome. Resuscitation. 1993;26(2):183-192. [CrossRef] [PubMed]
 
Niven DJ, Stelfox HT, Léger C, Kubes P, Laupland KB. Assessment of the safety and feasibility of administering antipyretic therapy in critically ill adults: a pilot randomized clinical trial. J Crit Care. 2013;28(3):296-302. [CrossRef] [PubMed]
 
Bernard GR, Wheeler AP, Russell JA, et al; The Ibuprofen in Sepsis Study Group. The effects of ibuprofen on the physiology and survival of patients with sepsis. N Engl J Med. 1997;336(13):912-918. [CrossRef] [PubMed]
 
Gozzoli V, Schöttker P, Suter PM, Ricou B. Is it worth treating fever in intensive care unit patients? Preliminary results from a randomized trial of the effect of external cooling. Arch Intern Med. 2001;161(1):121-123. [CrossRef] [PubMed]
 
Gozzoli V, Treggiari MM, Kleger GR, et al. Randomized trial of the effect of antipyresis by metamizol, propacetamol or external cooling on metabolism, hemodynamics and inflammatory response. Intensive Care Med. 2004;30(3):401-407. [CrossRef] [PubMed]
 
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. 2010;14(3):R125. [CrossRef] [PubMed]
 
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). 2005;6(4):369-375. [CrossRef] [PubMed]
 
Rim KP, Kim K, Jo YH, et al. Effect of therapeutic hypothermia according to severity of sepsis in a septic rat model. Cytokine. 2012;60(3):755-761. [CrossRef] [PubMed]
 
Vaughn LK, Veale WL, Cooper KE. Antipyresis: its effect on mortality rate of bacterially infected rabbits. Brain Res Bull. 1980;5(1):69-73. [CrossRef] [PubMed]
 
Vaughn LK, Veale WL, Cooper KE. The effect of venous blood stream cooling on survival of bacterially infected rabbits. Pflugers Arch. 1987;409(6):635-637. [CrossRef] [PubMed]
 
Hotchkiss R, Nunnally I, Lindquist S, Taulien J, Perdrizet G, Karl I. Hyperthermia protects mice against the lethal effects of endotoxin. Am J Physiol. 1993;265(6 pt 2):R1447-R1457. [PubMed]
 
Melling AC, Ali B, Scott EM, Leaper DJ. Effects of preoperative warming on the incidence of wound infection after clean surgery: a randomised controlled trial. Lancet. 2001;358(9285):876-880. [CrossRef] [PubMed]
 

Figures

Tables

References

Lee BH, Inui D, Suh GY, et al; Fever and Antipyretic in Critically ill Patients Evaluation (FACE) Study Group. Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study. Crit Care. 2012;16(1):R33. [CrossRef] [PubMed]
 
Manthous CA, Hall JB, Olson D, et al. Effect of cooling on oxygen consumption in febrile critically ill patients. Am J Respir Crit Care Med. 1995;151(1):10-14. [CrossRef] [PubMed]
 
Hasday JD, Fairchild KD, Shanholtz C. The role of fever in the infected host. Microbes Infect. 2000;2(15):1891-1904. [CrossRef] [PubMed]
 
Graham NM, Burrell CJ, Douglas RM, Debelle P, Davies L. Adverse effects of aspirin, acetaminophen, and ibuprofen on immune function, viral shedding, and clinical status in rhinovirus-infected volunteers. J Infect Dis. 1990;162(6):1277-1282. [CrossRef] [PubMed]
 
Prymula R, Siegrist CA, Chlibek R, et al. Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials. Lancet. 2009;374(9698):1339-1350. [CrossRef] [PubMed]
 
Haupt MT, Rackow EC. Adverse effects of febrile state on cardiac performance. Am Heart J. 1983;105(5):763-768. [CrossRef] [PubMed]
 
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. 2012;185(10):1088-1095. [CrossRef] [PubMed]
 
Pernerstorfer T, Krafft P, Fitzgerald R, et al. Optimal values for oxygen transport during hypothermia in sepsis and ARDS. Acta Anaesthesiol Scand Suppl. 1995;39(s107):223-227. [CrossRef]
 
Villar J, Slutsky AS. Effects of induced hypothermia in patients with septic adult respiratory distress syndrome. Resuscitation. 1993;26(2):183-192. [CrossRef] [PubMed]
 
Niven DJ, Stelfox HT, Léger C, Kubes P, Laupland KB. Assessment of the safety and feasibility of administering antipyretic therapy in critically ill adults: a pilot randomized clinical trial. J Crit Care. 2013;28(3):296-302. [CrossRef] [PubMed]
 
Bernard GR, Wheeler AP, Russell JA, et al; The Ibuprofen in Sepsis Study Group. The effects of ibuprofen on the physiology and survival of patients with sepsis. N Engl J Med. 1997;336(13):912-918. [CrossRef] [PubMed]
 
Gozzoli V, Schöttker P, Suter PM, Ricou B. Is it worth treating fever in intensive care unit patients? Preliminary results from a randomized trial of the effect of external cooling. Arch Intern Med. 2001;161(1):121-123. [CrossRef] [PubMed]
 
Gozzoli V, Treggiari MM, Kleger GR, et al. Randomized trial of the effect of antipyresis by metamizol, propacetamol or external cooling on metabolism, hemodynamics and inflammatory response. Intensive Care Med. 2004;30(3):401-407. [CrossRef] [PubMed]
 
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. 2010;14(3):R125. [CrossRef] [PubMed]
 
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). 2005;6(4):369-375. [CrossRef] [PubMed]
 
Rim KP, Kim K, Jo YH, et al. Effect of therapeutic hypothermia according to severity of sepsis in a septic rat model. Cytokine. 2012;60(3):755-761. [CrossRef] [PubMed]
 
Vaughn LK, Veale WL, Cooper KE. Antipyresis: its effect on mortality rate of bacterially infected rabbits. Brain Res Bull. 1980;5(1):69-73. [CrossRef] [PubMed]
 
Vaughn LK, Veale WL, Cooper KE. The effect of venous blood stream cooling on survival of bacterially infected rabbits. Pflugers Arch. 1987;409(6):635-637. [CrossRef] [PubMed]
 
Hotchkiss R, Nunnally I, Lindquist S, Taulien J, Perdrizet G, Karl I. Hyperthermia protects mice against the lethal effects of endotoxin. Am J Physiol. 1993;265(6 pt 2):R1447-R1457. [PubMed]
 
Melling AC, Ali B, Scott EM, Leaper DJ. Effects of preoperative warming on the incidence of wound infection after clean surgery: a randomised controlled trial. Lancet. 2001;358(9285):876-880. [CrossRef] [PubMed]
 
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