Temperature abnormalities have been recognized as markers of human disease since early civilization, and the value of temperature as a treatment target to cure disease has been hypothesized ever since (1–3). Temperature homeostasis is highly preserved throughout the animal kingdom (4–6). Even small changes in body temperature can lead to changes in inflammation and immune function, with variable-proposed effects on patient outcomes (7,8). Hyperthermia also affects energy utilization. Among febrile critically ill patients, up to one-fifth of energy expenditures are channeled toward raising and maintaining body temperature (9). Any condition that extracts such a metabolic cost and influences so many physiologic pathways remains an attractive therapeutic target in the ICU.
The purpose of this Concise Definitive Review is to detail current evidence on the role of active temperature management in the ICU. We focus on adult ICU medical conditions, such as cardiac arrest, neurologic emergencies, and infection. In this review, we do not cover the role of thermal homeostasis in environmental emergencies (e.g., heat stroke, environmental hypothermia), drug-induced dysthermia (e.g., malignant hyperthermia, serotonin syndrome), or temperature management in children. For the purposes of this review, a core body temperature greater than 38.0°C is commonly used to define fever, and a body temperature less than 36.0°C often defines hypothermia (8).
Perhaps the best studied indication for temperature management in the critically ill is in adults after out-of-hospital cardiac arrest. Cardiac arrest survival is low, and in patients who regain spontaneous circulation, neurologic injury from anoxia is common (10–12). In animal models, mild therapeutic hypothermia was shown to decrease cerebral metabolism, reduce brain tissue inflammation, and prevent neuronal apoptosis (13–23). Therapeutic hypothermia has been used successfully during cardiac surgery as a neuroprotective strategy, leading some to hypothesize that therapeutic hypothermia after cardiac arrest may improve clinical outcomes (24).
Early Clinical Trials
In 2002, two separate, landmark randomized clinical trials in patients with witnessed out-of-hospital cardiac arrest and an initial shockable rhythm showed that mild therapeutic hypothermia (32–34°C) improved favorable neurologic survival (25,26). Both trials were relatively small (combined 352 participants) and limited to patients with witnessed out-of-hospital arrest, but the effect size (absolute risk for favorable neurologic survival increased by 16% and 23%, respectively) was convincing.
Observational Studies Validating Results of Clinical Trials
Multiple observational studies over the next decade replicated the main finding of these trials—hospitals that implemented a postcardiac arrest therapeutic hypothermia protocol observed improvements in risk-adjusted survival (27,28). Based on these findings, the International Liaison Committee on Resuscitation recommended mild therapeutic hypothermia based on level I evidence in 2002 (29).
Some contradictory findings, however, led some to question the mechanism and degree of hypothermia required for neuroprotection (30–32). Despite animal data suggesting that therapeutic hypothermia was highly time-sensitive, more rapid prehospital cooling in clinical trials did not result in incremental benefit (33–36). Patients also seemed to have similar outcomes even if they were cooled to different temperatures (37).
Later Clinical Trials
In 2013, Nielsen et al (38) published the Targeted Temperature Management 33°C versus 36°C after Out-of-Hospital Cardiac Arrest (TTM) trial, a randomized, controlled, dose-finding trial (n = 950) comparing outcomes for out-of-hospital cardiac arrest patients maintained at 33°C vs 36°C for 36 hours, followed by aggressive fever prevention for 72 hours. The TTM trial included patients with out-of-hospital arrest of presumed cardiac etiology, but it included patients with both shockable and nonshockable presenting rhythms. It also had a much larger sample size than prior trials, and it showed no difference in all-cause mortality (hazard ratio, 1.06; 95% CI, 0.89–1.23) or 6-month favorable neurologic outcome (relative risk [RR], 1.02; 95% CI, 0.88–1.16) (38). After the TTM trial was published, however, several observational studies suggested that changes in hospital protocols to allow for postarrest temperatures as high as 36°C were associated with higher prevalence of fever and a reduced percentage of patients with favorable neurologic outcome (39–42). Some questioned whether these observations resulted from heterogeneity of treatment effects or whether clinicians were implementing normothermia with less control than the TTM protocol had mandated. Additionally, severity of illness may have mediated heterogeneous treatment effects, with lower temperatures being associated with better outcomes in the most severely injured patients (43).
Two recent trials have continued to fuel controversy. The Therapeutic Hypothermia after Cardiac Arrest in Nonshockable Rhythm (HYPERION) trial was an open-label randomized controlled trial (RCT) assigning 584 comatose survivors of out-of-hospital or inhospital cardiac arrest with nonshockable rhythms to either mild therapeutic hypothermia (33°C) or induced normothermia (37°C). Prevalence of favorable neurologic outcome was higher in participants allocated to therapeutic hypothermia (10.2% vs 5.7%; p = 0.04) (44). In 2021, the 1,850-participant Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospitals Cardiac Arrest (TTM2) trial was published, which also assigned comatose out-of-hospital cardiac arrest patients to 33°C versus 37°C. Both all-cause mortality (50% vs 48%; RR, 1.04; 95% CI, 0.95–1.23) and poor functional outcome (55% vs 55%; RR, 1.00; 95% CI, 0.92–1.09) at 6 months were similar (45). HYPERION was a study of patients in France with nonshockable arrest (27% inhospital), and a significant proportion of those in the control group had fever. In contrast, TTM2 was a larger trial that included only patients with out-of-hospital arrest, 74% had a shockable rhythm, and 79% had bystander cardiopulmonary resuscitation. These differences in patient population and management of fever in the control groups may have contributed to the seemingly disparate results between the two studies. Some have also questioned whether the fact that it took over 5 hours to achieve goal temperature in TTM2 may have attenuated any effect of therapeutic hypothermia (46). Others have pointed out that the lack of benefit in a superiority trial does not imply statistical equivalence.
At this point, multiple clinical trials have been conducted that lead to contradictory conclusions on the role and dose of therapeutic hypothermia in cardiac arrest, and observational data suggest benefit from standardized temperature management protocols. Based on the early trials, avoiding fever in comatose patients after cardiac arrest remains prudent, and some patients at high risk of poor neurologic outcome may benefit from more aggressive therapeutic hypothermia strategies (47). As an alternative, some centers may choose to use mild therapeutic hypothermia as a practical strategy to avoid fever; this has been shown to be no worse than aggressive, high-reliability maintenance of normothermia because the harm associated with unintentional fever is significant.
Hyperthermia is also common after stroke, and like cardiac arrest patients, stroke patients are susceptible to temperature-induced neurologic injury (48). Fever has been associated with secondary brain injury in patients with ischemic and hemorrhagic strokes, and hyperthermia increases cerebral oxygen consumption, worsens disruption of the blood-brain barrier, increases proinflammatory cytokine release, expands infarct size, and induces neuronal apoptosis (48–52). Fever has been associated with worsened neurologic outcome after ischemic stroke, hemorrhagic stroke, and subarachnoid hemorrhage, but the effect of active temperature management is unclear (53–61). The degree and duration of fever are strongly linked to severity of brain injury, making it difficult to evaluate the role of fever in worsening outcomes from observational studies alone. In a cohort of 38,679 ICU patients with stroke or traumatic brain injury (TBI), patients with temperature over 37.4°C had higher hospital mortality, but increased mortality risk persisted after adjusting for illness severity only in those with peak temperature over 39°C (62). Whether fever is causal in the relationship or is simply an epiphenomenon related to injury severity presents an opportunity for future study.
Multiple small RCTs in ischemic stroke have been conducted to measure the impact of mild therapeutic hypothermia (33–35°C) on improving stroke outcomes. Unfortunately, the trials have been small (18–98 participants), and although none showed clinical benefit, they were underpowered to detect improvement associated with therapeutic hypothermia (63–70). Two large RCTs of cooling in stroke were planned, but the European Multicentre, Randomised, Phase III Clinical Trial of Therapeutic Hypothermia for Acute Ischaemic Stroke was stopped for slow recruitment and withdrawal of funding (98 of 1,500 planned participants), and the Intravascular Cooling in the Treatment of Stroke trial was stopped because of overlap with thrombectomy trials (120 of 1,600 planned participants) (64,70).
Two observational studies with historical controls in hemorrhagic stroke have resulted in limited evidence for benefit, with one study (n = 50) reporting that perihemorrhage edema increased less over the first 2 weeks in patients with large intracerebral hemorrhage (≥25 mL) and induced normothermia but a second study (n = 80) with more variation in hemorrhage size showing no difference in neurologic outcome or survival (71,72).
In patients for whom induced normothermia is used, the impact of pharmacologic antipyretic therapy is modest. Hyperthermia in the context of neurologic injury is different from infectious fever, and physical cooling methods may be required (73–77). The Paracetamol In Stroke trial compared early prophylactic acetaminophen therapy with placebo in 1,400 patients with acute ischemic or hemorrhagic stroke, and neither neurologic improvement (adjusted odds ration [aOR], 1.20; 95% CI, 0.96–1.50) nor favorable neurologic outcome (aOR, 1.02; 95% CI, 0.78–1.32) improved with acetaminophen therapy.
Current guidelines from the American Heart Association (AHA)/American Stroke Association (ASA) recommend treating hyperthermia over 38.0°C (class 1 recommendation), but the role of induced therapeutic hypothermia is uncertain (78). The European Stroke Organization concludes that insufficient evidence exists to recommend either induced hypothermia or treatment of hyperthermia, but antipyretics do not improve functional outcome after stroke (79).
Traumatic Brain Injury
Fever occurs in nearly 70% of patients with TBI and has been associated with increased cerebral blood volume, elevated intracranial pressure, increased metabolism, and worsening of ischemic damage (80–84). A meta-analysis of the impact of fever on outcomes in patients with TBI demonstrated a consistent association between presence of fever and poor outcomes including higher mortality, more disability, and longer ICU and hospital length of stay (48). Thus, although there are no clinical trials showing superiority of fever control, the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC) recommendations for the management of severe TBI recommend fever control in patients with TBI as a tier 0 intervention (85,86), meaning that fever should be controlled regardless of intracranial pressure readings.
Clinical studies of therapeutic hypothermia in TBI have yielded mixed results, and meta-analyses have reached contradictory conclusions (87–93). To date, the largest clinical trial of therapeutic hypothermia in patients with TBI, the Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury—Randomized Clinical Trial, which randomized 511 patients with Glasgow Coma Score less than 9 to normothermia versus prophylactic hypothermia (33–35°C) for 72 hours, found no neurologic benefit (94). Favorable outcomes occurred in 48.8% of patients treated with prophylactic hypothermia versus 49.1% in the normothermia group (risk difference, 0.4%; 95% CI, –9.4% to 8.7%). The most recent Brain Trauma Foundation guidelines for management of severe TBI do not recommend therapeutic hypothermia to improve outcomes (95). The SIBICC consensus treatment algorithms for the management of elevated intracranial pressure, which are based on expert interpretation of available evidence, recommend mild therapeutic hypothermia (35–36°C) as a tier 3 intervention to reduce intracranial pressure in patients with ongoing intracranial hypertension after other tier 1 and tier 2 interventions have been exhausted (85,86).
The benefit of fever control in sepsis has also been debated. Fever is an adaptive response to infection and has both potential beneficial and adverse effects in patients with severe infections (8). Elevated temperatures have been shown to augment innate and adaptive immunity through their effect on macrophage function, heat shock protein response, antibody production, and T cell activation (96–100). Febrile-range hyperthermia also inhibits microorganism growth, reduces viral replication, and enhances antibiotic effectiveness (101–105). Pyrogenic cytokines (e.g., interleukin-1, interleukin-6, tumor necrosis factor-α, and interferon-γ) produced during febrile episodes have been shown to directly potentiate the immune system and provide protection against pathogens (8). However, fever also raises metabolic burden, increases oxygen consumption, and can depress myocardial function (106,107). These deleterious physiologic effects may counter the benefit of increased pathogen clearance and immune effects, especially in patients with septic shock with sepsis-associated hypoperfusion.
Fever Control (Observational Studies)
Observational studies in sepsis patients have demonstrated that fever is associated with improved outcomes. A meta-analysis of 42 studies evaluating body temperature in patients with sepsis showed than mean body temperature was higher in the lowest mortality quartile versus the highest (38.1°C vs 37.1°C) (108). Fever was associated with decreased mortality in patients with CNS infections, despite being associated with worse outcomes in noninfectious neurologic injuries (62). Altogether, these observational data suggest fever could be uniquely beneficial to infected hosts. However, the role of fever in improving outcomes may also mean that patients with more robust immune response and pathogen killing have the greatest febrile response.
Fever Control (Clinical Trials)
Several randomized trials have assessed whether antipyretic therapy improves outcomes (23,109–114). These studies have evaluated pharmacological treatment with acetaminophen and/or ibuprofen, physical cooling to normothermia, and combinations of pharmacological and physical cooling methods. The largest and most recent trial, Permissive Hyperthermia Through Avoidance of Paracetamol in Known or Suspected Infection in the ICU, randomized 700 patients with fever greater than 38.3°C and infection to treatment with IV acetaminophen or placebo. There was no difference in 90-day mortality (RR, 0.96; 95% CI, 0.66–1.39) or 28-day ICU-free days (absolute difference, 0; p = 0.07) (114). Similar findings were seen in a trial of 200 severely ill (median norepinephrine dose 0.5 and 0.65 µg/kg/min in the intervention and control groups, respectively) patients with septic shock randomized to external cooling to normothermia (36.5–37.0°C) for 48 hours versus no cooling (112). Due to severity of their illness, these patients were hypothesized to be the type of patients most likely to benefit from fever control and the concomitant reduction in metabolic burden. Patients who were cooled to normothermia had lower risk of death at 14 days (odds ratio [OR], 0.36; 95% CI, 0.16–0.76), but there was no difference in mortality at ICU or hospital discharge (112).
A meta-analysis subsequently demonstrated no effect of antipyretic therapy on 28-day or hospital mortality in pooled data from eight randomized studies (RR, 0.93; 95% CI, 0.77–1.13) and six observational studies (OR, 0.90; 95% CI, 0.54–1.52), although only five of eight clinical trials and six of eight observational studies had low risk of bias (115). A second, individual patient-level meta-analysis showed no impact of active fever management even in subgroups of patents with higher illness severity or age (116). Therefore, current evidence does not suggest a mortality benefit of routine treatment of fever in patients with sepsis, and individualized treatment based on symptom relief may be preferred.
Induced therapeutic hypothermia has also been hypothesized as a treatment for patients with sepsis due to potential protective effects on the heart, lungs, and liver, and encouraging results in animal models of sepsis (117–119). A randomized trial of 24 hours of therapeutic hypothermia (32–34°C) followed by 48 hours of normothermia versus no temperature management performed in 432 patients with sepsis was stopped early for futility (120). Therapeutic hypothermia did not improve 30-day mortality (44.2% in induced hypothermia vs 35.5% in control; absolute difference, 8.4%, 95% CI, –0.8% to 18%). Therefore, there is no current role for therapeutic hypothermia in patients with sepsis.
Spontaneous hypothermia in sepsis is common, occurring in 15–35% of patients, and spontaneous hypothermia is associated with higher mortality than normothermia or fever, although the reasons for this relationship are unclear (108,121–125). Most clinicians actively warm hypothermic patients with sepsis to normothermia (126), but strong data do not exist to clarify the causal role of temperature on outcomes. In a small pilot trial of 56 afebrile patients with sepsis, therapeutic hyperthermia seemed to be associated with improved survival, but imbalances between the groups and the lack of difference in immune outcomes suggest that further research should be done prior to clinical practice change (127). If spontaneous hypothermia represents a sepsis phenotype, the role of active temperature management to change physiologic pathways and clinical outcomes remains uncertain and is an opportunity for future investigation.
Fever and spontaneous hypothermia are common in critically ill patients, and observational studies have consistently demonstrated that body temperature predicts clinical outcomes in multiple diseases of the critically ill (48,62,108,121–125,128). The strongest data supporting the use of targeted temperature management exist in comatose survivors of cardiac arrest, although more recent trials suggest that aggressive maintenance of normothermia may be adequate to improve neurologic outcomes. Currently, there is little evidence for the routine use of moderate therapeutic hypothermia in patients with acute neurologic injury, and clinical studies of pharmacologic antipyretic therapy have failed to show clinical benefit. Current AHA/ASA guidelines recommend treatment of fever in these patients, largely based on observational association between fever and poorer outcomes. Future work on temperature management in the critically ill may elucidate new signaling mechanisms and therapeutic pathways to inform the more personalized care of critically ill patients in the future.
We thank Nicholas Johnson, MD, FCCM, for his assistance reviewing an early draft of this article, Nathan Kramer, MPH, for editorial assistance, and Paul Casella, MFA, for editorial assistance.
1. Atkins E. Fever: Its history, cause, and function. Yale J Biol Med. 1982;55:283–289
2. Atkins E: Fever: The old and the new. J Infect Dis. 1984; 149:339–348
3. El-Radhi AS. The role of fever in the past and present. Med J Islamic World Acad Sci. 2011; 19:9–14
4. Kluger MJ, Kozak W, Conn CA, et al.: The adaptive value of fever. Infect Dis Clin North Am. 1996; 10:1–20
5. Mackowiak PA: Physiological rationale for suppression of fever. Clin Infect Dis. 2000; 31(Suppl 5):S185–S189
6. Bernheim HA, Kluger MJ: Fever and antipyresis in the lizard Dipsosaurus dorsalis. Am J Physiol. 1976; 231:198–203
7. Evans SS, Repasky EA, Fisher DT: Fever and the thermal regulation of immunity: The immune system feels the heat. Nat Rev Immunol. 2015; 15:335–349
8. Mackowiak PA: Concepts of fever. Arch Intern Med. 1998; 158:1870–1881
9. Frankenfield DC, Smith JS Jr, Cooney RN, et al.: Relative association of fever and injury with hypermetabolism in critically ill patients. Injury. 1997; 28:617–621
10. Laver S, Farrow C, Turner D, et al.: Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med. 2004; 30:2126–2128
11. Yan S, Gan Y, Jiang N, et al.: The global survival rate among adult out-of-hospital cardiac arrest patients who received cardiopulmonary resuscitation: A systematic review and meta-analysis. Crit Care. 2020; 24:61
12. Bloom HL, Shukrullah I, Cuellar JR, et al.: Long-term survival after successful inhospital cardiac arrest resuscitation. Am Heart J. 2007; 153:831–836
13. Dempsey RJ, Combs DJ, Maley ME, et al.: Moderate hypothermia reduces postischemic edema development and leukotriene production. Neurosurgery. 1987; 21:177–181
14. Safar PJ, Kochanek PM: Therapeutic hypothermia after cardiac arrest. N Engl J Med. 2002; 346:612–613
15. Xu L, Yenari MA, Steinberg GK, et al.: Mild hypothermia reduces apoptosis of mouse neurons in vitro
early in the cascade. J Cereb Blood Flow Metab. 2002; 22:21–28
16. Bernard S: Therapeutic hypothermia after cardiac arrest. Neurol Clin. 2006; 24:61–71
17. Yenari MA, Han HS: Neuroprotective mechanisms of hypothermia in brain ischaemia. Nat Rev Neurosci. 2012; 13:267–278
18. Polderman KH: Application of therapeutic hypothermia in the ICU: Opportunities and pitfalls of a promising treatment modality. Part 1: Indications and evidence. Intensive Care Med. 2004; 30:556–575
19. Lemiale V, Huet O, Vigué B, et al.: Changes in cerebral blood flow and oxygen extraction during post-resuscitation syndrome. Resuscitation. 2008; 76:17–24
20. Rosomoff HL, Holaday DA: Cerebral blood flow and cerebral oxygen consumption during hypothermia. Am J Physiol. 1954; 179:85–88
21. Polderman KH: Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet. 2008; 371:1955–1969
22. Sterz F, Safar P, Tisherman S, et al.: Mild hypothermic cardiopulmonary resuscitation improves outcome after prolonged cardiac arrest in dogs. Crit Care Med. 1991; 19:379–389
23. Yenari MA, Wijman CA. Effects of hypothermia on cerebralmetabolism, blood flow, and autoregulation. In
: Therapeutic Hypothermia. Mayer SA, Sessler D (Eds). New York, NY, Marcel Dekker, 2005, pp 141–178
24. Nathan HJ, Wells GA, Munson JL, et al. Neuroprotective effect of mild hypothermia in patients undergoing coronary artery surgery with cardiopulmonary bypass. Circulation. 2001; 104(Suppl_1):I-85–I-91
25. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002; 346:549–556
26. Bernard SA, Gray TW, Buist MD, et al.: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002; 346:557–563
27. Xiao G, Guo Q, Shu M, et al.: Safety profile and outcome of mild therapeutic hypothermia in patients following cardiac arrest: Systematic review and meta-analysis. Emerg Med J. 2013; 30:91–100
28. Kim YM, Yim HW, Jeong SH, et al.: Does therapeutic hypothermia benefit adult cardiac arrest patients presenting with non-shockable initial rhythms?: A systematic review and meta-analysis of randomized and non-randomized studies. Resuscitation. 2012; 83:188–196
29. Nolan JP, Morley PT, Vanden Hoek TL, et al.; International Liaison Committee on Resuscitation: Therapeutic hypothermia after cardiac arrest: an advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation. Circulation. 2003; 108:118–121
30. Nielsen N, Friberg H, Gluud C, et al.: Hypothermia after cardiac arrest should be further evaluated–a systematic review of randomised trials with meta-analysis and trial sequential analysis. Int J Cardiol. 2011; 151:333–341
31. Fisher GC: Hypothermia after cardiac arrest: Feasible but is it therapeutic? Anaesthesia. 2008; 63:885–886
32. Moran JL, Solomon PJ: Therapeutic hypothermia after cardiac arrest–once again. Crit Care Resusc. 2006; 8:151–154
33. Olai H, Thornéus G, Watson H, et al.: Meta-analysis of targeted temperature management in animal models of cardiac arrest. Intensive Care Med Exp. 2020; 8:3
34. Kuboyama K, Safar P, Radovsky A, et al.: Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: a prospective, randomized study. Crit Care Med. 1993; 21:1348–1358
35. Kim F, Nichol G, Maynard C, et al.: Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: A randomized clinical trial. JAMA. 2014; 311:45–52
36. Bernard SA, Smith K, Finn J, et al.: Induction of therapeutic hypothermia during out-of-hospital cardiac arrest using a rapid infusion of cold saline: The RINSE Trial (Rapid Infusion of Cold Normal Saline). Circulation. 2016; 134:797–805
37. Schenone AL, Cohen A, Patarroyo G, et al.: Therapeutic hypothermia after cardiac arrest: A systematic review/meta-analysis exploring the impact of expanded criteria and targeted temperature. Resuscitation. 2016; 108:102–110
38. Nielsen N, Wetterslev J, Cronberg T, et al.; TTM Trial Investigators: Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013; 369:2197–2206
39. Nishikimi M, Ogura T, Nishida K, et al.: Outcome related to level of targeted temperature management in postcardiac arrest syndrome of low, moderate, and high severities: A nationwide multicenter prospective registry. Crit Care Med. 2021; 49:e741–e750
40. Johnson NJ, Danielson KR, Counts CR, et al.: Targeted temperature management at 33 versus 36 degrees: A retrospective cohort study. Crit Care Med. 2020; 48:362–369
41. Salter R, Bailey M, Bellomo R, et al.; Australian and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation (ANZICS-CORE): Changes in temperature management of cardiac arrest patients following publication of the target temperature management trial. Crit Care Med. 2018; 46:1722–1730
42. Bray JE, Stub D, Bloom JE, et al.: Changing target temperature from 33°C to 36°C in the ICU management of out-of-hospital cardiac arrest: A before and after study. Resuscitation. 2017; 113:39–43
43. Callaway CW, Coppler PJ, Faro J, et al.: Association of initial illness severity and outcomes after cardiac arrest with targeted temperature management at 36 °C or 33 °C. JAMA Netw Open. 2020; 3:e208215
44. Lascarrou JB, Merdji H, Le Gouge A, et al.; CRICS-TRIGGERSEP Group: Targeted temperature management for cardiac arrest with nonshockable rhythm. N Engl J Med. 2019; 381:2327–2337
45. Dankiewicz J, Cronberg T, Lilja G, et al.; TTM2 Trial Investigators: Hypothermia versus normothermia after out-of-hospital cardiac arrest. N Engl J Med. 2021; 384:2283–2294
46. Rasmussen TP, Girotra S: A contemporary update on targeted temperature management. 2021. Available at: https://www.acc.org/latest-in-cardiology/articles/2021/11/09/13/16/a-contemporary-update-on-targeted-temperature-management
. Accessed January 2, 2022
47. Morrison LJ, Thoma B: Translating targeted temperature management trials into postarrest care. N Engl J Med. 2021; 384:2344–2345
48. Greer DM, Funk SE, Reaven NL, et al.: Impact of fever on outcome in patients with stroke and neurologic injury: A comprehensive meta-analysis. Stroke. 2008; 39:3029–3035
49. Dietrich WD, Busto R, Valdes I, et al.: Effects of normothermic versus mild hyperthermic forebrain ischemia in rats. Stroke. 1990; 21:1318–1325
50. Dietrich WD, Halley M, Valdes I, et al.: Interrelationships between increased vascular permeability and acute neuronal damage following temperature-controlled brain ischemia in rats. Acta Neuropathol. 1991; 81:615–625
51. Maier CM, Ahern Kv, Cheng ML, et al.: Optimal depth and duration of mild hypothermia in a focal model of transient cerebral ischemia: Effects on neurologic outcome, infarct size, apoptosis, and inflammation. Stroke. 1998; 29:2171–2180
52. Hanstock CC, Boisvert DP, Bendall MR, et al.: In vivo
assessment of focal brain lactate alterations with NMR proton spectroscopy. J Cereb Blood Flow Metab. 1988; 8:208–214
53. Azzimondi G, Bassein L, Nonino F, et al.: Fever in acute stroke worsens prognosis. A prospective study. Stroke. 1995; 26:2040–2043
54. Castillo J, Dávalos A, Marrugat J, et al.: Timing for fever-related brain damage in acute ischemic stroke. Stroke. 1998; 29:2455–2460
55. Schwarz S, Häfner K, Aschoff A, et al.: Incidence and prognostic significance of fever following intracerebral hemorrhage. Neurology. 2000; 54:354–361
56. Leira R, Dávalos A, Silva Y, et al.; Stroke Project, Cerebrovascular Diseases Group of the Spanish Neurological Society: Early neurologic deterioration in intracerebral hemorrhage: Predictors and associated factors. Neurology. 2004; 63:461–467
57. Wartenberg KE, Schmidt JM, Claassen J, et al.: Impact of medical complications on outcome after subarachnoid hemorrhage. Crit Care Med. 2006; 34:617–623
58. Fernandez A, Schmidt JM, Claassen J, et al.: Fever after subarachnoid hemorrhage: Risk factors and impact on outcome. Neurology. 2007; 68:1013–1019
59. Badjatia N, Fernandez L, Schmidt JM, et al.: Impact of induced normothermia on outcome after subarachnoid hemorrhage: A case-control study. Neurosurgery. 2010; 66:696–700
60. Karnatovskaia LV, Lee AS, Festic E, et al.: Effect of prolonged therapeutic hypothermia on intracranial pressure, organ function, and hospital outcomes among patients with aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2014; 21:451–461
61. Oliveira-Filho J, Ezzeddine MA, Segal AZ, et al.: Fever in subarachnoid hemorrhage: Relationship to vasospasm and outcome. Neurology. 2001; 56:1299–1304
62. Saxena M, Young P, Pilcher D, et al.: Early temperature and mortality in critically ill patients with acute neurological diseases: Trauma and stroke differ from infection. Intensive Care Med. 2015; 41:823–832
63. Hemmen TM, Raman R, Guluma KZ, et al.; ICTuS-L Investigators: Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): Final results. Stroke. 2010; 41:2265–2270
64. van der Worp HB, Macleod MR, Bath PM, et al.; EuroHYP-1 investigators: Therapeutic hypothermia for acute ischaemic stroke. Results of a European multicentre, randomised, phase III clinical trial. Eur Stroke J. 2019; 4:254–262
65. Piironen K, Tiainen M, Mustanoja S, et al.: Mild hypothermia after intravenous thrombolysis in patients with acute stroke: A randomized controlled trial. Stroke. 2014; 45:486–491
66. De Georgia MA, Krieger DW, Abou-Chebl A, et al.: Cooling for acute ischemic brain damage (COOL AID): A feasibility trial of endovascular cooling. Neurology. 2004; 63:312–317
67. Bi M, Ma Q, Zhang S, et al.: Local mild hypothermia with thrombolysis for acute ischemic stroke within a 6-h window. Clin Neurol Neurosurg. 2011; 113:768–773
68. Ovesen C, Brizzi M, Pott FC, et al.: Feasibility of endovascular and surface cooling strategies in acute stroke. Acta Neurol Scand. 2013; 127:399–405
69. Els T, Oehm E, Voigt S, et al.: Safety and therapeutical benefit of hemicraniectomy combined with mild hypothermia in comparison with hemicraniectomy alone in patients with malignant ischemic stroke. Cerebrovasc Dis. 2006; 21:79–85
70. Lyden P, Hemmen T, Grotta J, et al.; Collaborators: Results of the ICTuS 2 Trial (Intravascular Cooling in the Treatment of Stroke 2). Stroke. 2016; 47:2888–2895
71. Lord AS, Karinja S, Lantigua H, et al.: Therapeutic temperature modulation for fever after intracerebral hemorrhage. Neurocrit Care. 2014; 21:200–206
72. Staykov D, Wagner I, Volbers B, et al.: Mild prolonged hypothermia for large intracerebral hemorrhage. Neurocrit Care. 2013; 18:178–183
73. Dippel DW, van Breda EJ, van Gemert HM, et al.: Effect of paracetamol (acetaminophen) on body temperature in acute ischemic stroke: A double-blind, randomized phase II clinical trial. Stroke. 2001; 32:1607–1612
74. Dippel DW, van Breda EJ, van der Worp HB, et al.; PISA-Investigators: Effect of paracetamol (acetaminophen) and ibuprofen on body temperature in acute ischemic stroke PISA, a phase II double-blind, randomized, placebo-controlled trial [ISRCTN98608690]. BMC Cardiovasc Disord. 2003; 3:2
75. Kasner SE, Wein T, Piriyawat P, et al.: Acetaminophen for altering body temperature in acute stroke: A randomized clinical trial. Stroke. 2002; 33:130–134
76. den Hertog HM, van der Worp HB, van Gemert HM, et al.; PAIS Investigators: The Paracetamol (Acetaminophen) In Stroke (PAIS) trial: A multicentre, randomised, placebo-controlled, phase III trial. Lancet Neurol. 2009; 8:434–440
77. Broessner G, Beer R, Lackner P, et al.: Prophylactic, endovascularly based, long-term normothermia in ICU patients with severe cerebrovascular disease: Bicenter prospective, randomized trial. Stroke. 2009; 40:e657–e665
78. Powers WJ, Rabinstein AA, Ackerson T, et al.: Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019; 50:e344–e418
79. Ntaios G, Dziedzic T, Michel P, et al.; European Stroke Organisation: European Stroke Organisation (ESO) guidelines for the management of temperature in patients with acute ischemic stroke. Int J Stroke. 2015; 10:941–949
80. Cairns CJ, Andrews PJ: Management of hyperthermia in traumatic brain injury. Curr Opin Crit Care. 2002; 8:106–110
81. Birg T, Ortolano F, Wiegers EJA, et al.; CENTER-TBI Investigators and Participants: Brain temperature influences intracranial pressure and cerebral perfusion pressure after traumatic brain injury: A CENTER-TBI study. Neurocrit Care. 2021; 35:651–661
82. Puccio AM, Fischer MR, Jankowitz BT, et al.: Induced normothermia attenuates intracranial hypertension and reduces fever burden after severe traumatic brain injury. Neurocrit Care. 2009; 11:82–87
83. Mrozek S, Vardon F, Geeraerts T: Brain temperature: Physiology and pathophysiology after brain injury. Anesthesiol Res Pract. 2012; 2012:989487
84. Albrecht RF 2nd, Wass CT, Lanier WL: Occurrence of potentially detrimental temperature alterations in hospitalized patients at risk for brain injury. Mayo Clin Proc. 1998; 73:629–635
85. Hawryluk GWJ, Aguilera S, Buki A, et al.: A management algorithm for patients with intracranial pressure monitoring: The Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC). Intensive Care Med. 2019; 45:1783–1794
86. Chesnut R, Aguilera S, Buki A, et al.: A management algorithm for adult patients with both brain oxygen and intracranial pressure monitoring: The Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC). Intensive Care Med. 2020; 46:919–929
87. Wu X, Tao Y, Marsons L, et al.: The effectiveness of early prophylactic hypothermia in adult patients with traumatic brain injury: A systematic review and meta-analysis. Aust Crit Care. 2021; 34:83–91
88. Olah E, Poto L, Hegyi P, et al.: Therapeutic whole-body hypothermia reduces death in severe traumatic brain injury if the cooling index is sufficiently high: Meta-analyses of the effect of single cooling parameters and their integrated measure. J Neurotrauma. 2018; 35:2407–2417
89. Olah E, Poto L, Rumbus Z, et al.: POLAR study revisited: Therapeutic hypothermia in severe brain trauma should not be abandoned. J Neurotrauma. 2021; 38:2772–2776
90. Kim JH, Nagy Á, Putzu A, et al.: Therapeutic hypothermia in critically ill patients: A systematic review and meta-analysis of high quality randomized trials. Crit Care Med. 2020; 48:1047–1054
91. Chen H, Wu F, Yang P, et al.: A meta-analysis of the effects of therapeutic hypothermia in adult patients with traumatic brain injury. Crit Care. 2019; 23:396
92. Huang HP, Zhao WJ, Pu J: Effect of mild hypothermia on prognosis of patients with severe traumatic brain injury: A meta-analysis with trial sequential analysis. Aust Crit Care. 2020; 33:375–381
93. Lewis SR, Evans DJ, Butler AR, et al.: Hypothermia for traumatic brain injury. Cochrane Database Syst Rev. 2017; 9:CD001048
94. Cooper DJ, Nichol AD, Bailey M, et al.; POLAR Trial Investigators and the ANZICS Clinical Trials Group: Effect of early sustained prophylactic hypothermia on neurologic outcomes among patients with severe traumatic brain injury: The POLAR randomized clinical trial. JAMA. 2018; 320:2211–2220
95. Carney N, Totten AM, O’Reilly C, et al.: Guidelines for the management of severe traumatic brain injury, fourth edition. Neurosurgery. 2017; 80:6–15
96. van Oss CJ, Absolom DR, Moore LL, et al.: Effect of temperature on the chemotaxis, phagocytic engulfment, digestion and O2 consumption of human polymorphonuclear leukocytes. J Reticuloendothel Soc. 1980; 27:561–565
97. Ozveri ES, Bekraki A, Cingi A, et al.: The effect of hyperthermic preconditioning on the immune system in rat peritonitis. Intensive Care Med. 1999; 25:1155–1159
98. Villar J, Ribeiro SP, Mullen JB, et al.: Induction of the heat shock response reduces mortality rate and organ damage in a sepsis
-induced acute lung injury model. Crit Care Med. 1994; 22:914–921
99. Jampel HD, Duff GW, Gershon RK, et al.: Fever and immunoregulation. III. Hyperthermia augments the primary in vitro
humoral immune response. J Exp Med. 1983; 157:1229–1238
100. Jiang Q, Cross AS, Singh IS, et al.: Febrile core temperature is essential for optimal host defense in bacterial peritonitis. Infect Immun. 2000; 68:1265–1270
101. Small PM, Täuber MG, Hackbarth CJ, et al.: Influence of body temperature on bacterial growth rates in experimental pneumococcal meningitis in rabbits. Infect Immun. 1986; 52:484–487
102. Chu CM, Tian SF, Ren GF, et al.: Occurrence of temperature-sensitive influenza A viruses in nature. J Virol. 1982; 41:353–359
103. Kwiatkowski D: Febrile temperatures can synchronize the growth of Plasmodium falciparum in vitro
. J Exp Med. 1989; 169:357–361
104. Mackowiak PA, Marling-Cason M, Cohen RL: Effects of temperature on antimicrobial susceptibility of bacteria. J Infect Dis. 1982; 145:550–553
105. Launey Y, Nesseler N, Mallédant Y, et al.: Clinical review: Fever in septic ICU patients–friend or foe? Crit Care. 2011; 15:222
106. 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; 151:10–14
107. Haupt MT, Rackow EC: Adverse effects of febrile state on cardiac performance. Am Heart J. 1983; 105:763–768
108. 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. 2017; 12:e0170152
109. Bernard GR, Reines HD, Halushka PV, et al.: Prostacyclin and thromboxane A2 formation is increased in human sepsis
syndrome. Effects of cyclooxygenase inhibition. Am Rev Respir Dis. 1991; 144:1095–1101
110. Haupt MT, Jastremski MS, Clemmer TP, et al.: Effect of ibuprofen in patients with severe sepsis
: A randomized, double-blind, multicenter study. The Ibuprofen Study Group. Crit Care Med. 1991; 19:1339–1347
111. 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. 1997; 336:912–918
112. 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; 185:1088–1095
113. Janz DR, Bastarache JA, Rice TW, et al.; Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis
Study Group: 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. 2015; 43:534–541
114. Young P, Saxena M, Bellomo R, et al.; HEAT Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group: Acetaminophen for fever in critically ill patients with suspected infection. N Engl J Med. 2015; 373:2215–2224
115. Drewry AM, Ablordeppey EA, Murray ET, et al.: Antipyretic therapy in critically ill septic patients: A systematic review and meta-analysis. Crit Care Med. 2017; 45:806–813
116. Young PJ, Bellomo R, Bernard GR, et al.: Fever control in critically ill adults. An individual patient data meta-analysis of randomised controlled trials. Intensive Care Med. 2019; 45:468–476
117. Huet O, Kinirons B, Dupic L, et al.: Induced mild hypothermia reduces mortality during acute inflammation in rats. Acta Anaesthesiol Scand. 2007; 51:1211–1216
118. Schwarzl M, Seiler S, Wallner M, et al.: Mild hypothermia attenuates circulatory and pulmonary dysfunction during experimental endotoxemia. Crit Care Med. 2013; 41:e401–e410
119. Scumpia PO, Sarcia PJ, Kelly KM, et al.: Hypothermia induces anti-inflammatory cytokines and inhibits nitric oxide and myeloperoxidase-mediated damage in the hearts of endotoxemic rats. Chest. 2004; 125:1483–1491
120. Itenov TS, Johansen ME, Bestle M, et al.; Cooling and Surviving Septic Shock (CASS) Trial Collaboration: Induced hypothermia in patients with septic shock and respiratory failure (CASS): A randomised, controlled, open-label trial. Lancet Respir Med. 2018; 6:183–192
121. Young PJ, Saxena M, Beasley R, et al. Early peak temperature and mortality in critically ill patients with or without infection. Intensive Care Med. 2012 Jan 31. [online ahead of print]
122. Ramgopal S, Horvat CM, Adler MD: Association of triage hypothermia with in-hospital mortality among patients in the emergency department with suspected sepsis
. J Crit Care. 2020; 60:27–31
123. Kushimoto S, Gando S, Saitoh D, et al.; JAAM Sepsis
Registry Study Group: The impact of body temperature abnormalities on the disease severity and outcome in patients with severe sepsis
: An analysis from a multicenter, prospective survey of severe sepsis
. Crit Care. 2013; 17:R271
124. Drewry AM, Fuller BM, Skrupky LP, et al.: The presence of hypothermia within 24 hours of sepsis
diagnosis predicts persistent lymphopenia. Crit Care Med. 2015; 43:1165–1169
125. Wiewel MA, Harmon MB, van Vught LA, et al.: Risk factors, host response and outcome of hypothermic sepsis
. Crit Care. 2016; 20:328
126. Harmon MBA, Pelleboer I, Steiner AA, et al.: Opinions and management of hypothermic sepsis
: Results from an online survey. Ther Hypothermia Temp Manag. 2020; 10:102–105
127. Drewry AM, Mohr NM, Ablordeppey EA, et al. Therapeutic hyperthermia is associated with improved survival in afebrile critically ill patients with sepsis
: A pilot randomized trial. Crit Care Med. 2022 Feb 7. [online ahead of print]
128. 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:R33