REVIEW URRENT C OPINION
Fever and therapeutic normothermia in severe brain injury: an update Leif-Erik Bohman a and Joshua M. Levine b
Purpose of review Fever is common in the ICU among patients with severe brain injury. Fever has been consistently shown to exacerbate brain injuries in animal models and has been consistently associated with poor outcome in human studies. However, whether fever control improves outcome and the ideal means of fever control remain unknown. This review will address recent literature on the impact of fever on severe brain injury and on interventions to maintain normothermia. Recent findings Current guidelines generally recommend maintenance of normothermia after brain injury but have scant recommendations on methods to do this. Observational trials have continued to demonstrate the association between fever and poor outcome after severe brain injury. Recent trials have shown the efficacy of more aggressive approaches to fever reduction, whereas a large randomized trial showed the relative ineffectiveness of acetaminophen alone for fever control. Several studies have also described the impact of fever and of fever control on brain physiology. Summary The value of therapeutic normothermia in the neurocritical care unit (NCCU) is increasingly accepted, yet prospective trials that demonstrate a functional benefit to patients are lacking. Keywords fever control, induced normothermia, normothermia, targeted temperature management
INTRODUCTION Fever (variously defined as core body temperatures exceeding 37.58C–38.58C) is common in patients with severe brain injuries, including hypoxic-ischemic encephalopathy from cardiac arrest, traumatic brain injury (TBI), ischemic stroke, haemorrhagic stroke and subarachnoid haemorrhage (SAH) [1–5]. A large body of experimental and human evidence, which has been well summarized in several prior reviews [6–11], suggests an association between fever and poor neurological outcome after severe brain injury. The present review is intended to update that of Badjatia from 2009 [10], and focuses on subsequent publications. Although there have been several updates to the relevant disease-specific guidelines since 2009, relatively few substantive changes have been made regarding therapeutic normothermia. Current guidelines by disease type are detailed in Table 1. Generally, guidelines acknowledge the association of fever with poor outcome, however, with the exception of the Neurocritical Care Society Guidelines for SAH, stop short of making specific therapeutic recommendations [12–19]. www.co-criticalcare.com
Recent evidence regarding fever and therapeutic normothermia in severe brain injury may be categorized into observational and interventional studies. Recent observational studies have provided further evidence of an association between fever, even after therapeutic hypothermia for cardiac arrest, and poor outcome. They also have shed light on the frequency of fever after severe brain injury and on rates of fever control in clinical practice. Interventional studies may be further subclassified into those that compare the efficacy of interventions in controlling fever, and those that investigate the effects of fever control on physiology or functional outcome. Increasing evidence a
Department of Neurosurgery and bDepartment of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA Correspondence to Joshua M. Levine, MD, Division of Neurocritical Care, Department of Neurology, Hospital of the University of Pennsylvania, 3 W Gates, 3400 Spruce Street, Philadelphia, PA 19104, USA. E-mail: [email protected] Curr Opin Crit Care 2014, 20:182–188 DOI:10.1097/MCC.0000000000000070 Volume 20 Number 2 April 2014
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Fever and therapeutic normothermia Bohman and Levine
KEY POINTS
centre in Copenhagen recently examined the association of post rewarming fever (T >38.58C) on outcome [21 ]. Of note, patients with posthypothermia fevers were not aggressively cooled to normothermia. Among these patients, posthypothermia fever was associated with increased mortality at 30 days and worsened neurological outcome at 1-year follow-up. &
Although the association between fever and worse neurological outcome after severe brain injury is robust, there is little direct proof in humans that the relationship between fever and exacerbation of brain injury is causal. Nonetheless, fever control remains an important element in the care of patients with severe brain injury. Although cooling patients with cardiac arrest to 338C is currently recommended, a recent study suggests that cooling to 368C confers similar benefit. Further studies are needed to define the optimal methods of temperature control, the safest and most effective treatments for shivering, and the ideal depth and duration of cooling in patients with acute brain injury.
demonstrates that intensive cooling devices, particularly intravascular devices, provide faster and more durable temperature control than the traditional methods of fever management, antipyretics and air-cooled blankets.
OBSERVATIONAL STUDIES In this section, we review data from recent observational studies in the areas of stroke and cardiac arrest.
Acute ischemic stroke: total fever burden and maximum temperature are more important than admission temperature Despite the consistent association between fever and poor outcome, little study has been devoted to the temporal profile of temperature elevation after ischemic stroke. To address this, Karaszewski et al. [20] prospectively followed 44 patients with anterior circulation infarcts and recorded temperature every 4 h for 120 h. Maximum and final temperatures, as well as the temperature area under the curve, were associated with both National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Score (mRS) at 3 months, whereas admission temperature was not. The peak temperature in this ischemic stroke population was a median of 35.5 h after stroke onset, and most patients were normothermic on admission.
Cardiac arrest: fever after therapeutic hypothermia is associated with increased mortality A prospective cohort study including 270 patients treated with therapeutic hypothermia at a single
INTERVENTIONAL STUDIES: TECHNIQUE SELECTION In this section, we review data from recent interventional studies that address methods to achieve temperature control.
Further evidence that advanced temperature control techniques appear superior to traditional methods A variety of techniques have been used to cool patients, ranging from antipyretic medications (particularly acetaminophen and NSAIDs) to surface cooling devices (air or water-circulating blankets or gel-cooled systems) and intravascular cooling methods (injection of cold 0.9% sodium chloride or central venous heat exchange systems). Despite their position as the initial treatment of choice, antipyretic medications are notoriously ineffective, particularly in the brain-injured population [9]. Previous studies have suggested that advanced cooling systems (surface or intravascular devices) that incorporate a servomechanism with constant core temperature monitoring are more effective than traditional air-cooled blankets or ice packs alone in patients with acetaminophen-refractory fevers [22–24]. In these studies, however, advanced cooling devices were used for a relatively brief duration (1–3 days), and in each, only a single device was compared with a control group. Hoedemaekers et al. [25] performed a head-tohead comparison of cooling techniques in 50 ICU patients. In 25 patients (predominantly cardiac arrest), the goal was hypothermia, and in the other 25 patients (predominantly TBI/SAH), the goal was normothermia [25]. Patients were randomized to five groups: conventional treatment (antipyretics and ice packs); air-cooled blankets; water-cooled blankets; water-cooled gel pads; or intravascular heat exchange. In this small study, water-cooled gel pads and intravascular heat exchange allowed the fastest cooling in both normothermia and hypothermia groups; however, the intravascular system was superior in maintenance of target temperature. Patients treated with intravascular heat exchange catheters spent less than 5% of time out of target
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Neuroscience Table 1. Current guidelines for fever control in severe brain injury Disease
Guideline source/date
Cardiac arrest
AHA (2010) [12]
Recommendations
Strength of recommendations
Strength of evidence
Focus on TH when not contraindicated
I
C
Not stated
Not stated
I
C
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Hyperthermia ‘can impair brain recovery’ Recommends active intervention to avoid hyperthermia both postresuscitation and postrewarming after TH Cites lack of trials on specific treatment methods or benefits of treatment ENLS (2012) [13]
Focus on TH when not contraindicated Patients not eligible for TH ‘may benefit from fever prevention’
Ischemic stroke
Haemorrhagic stroke
Traumatic brain injury
AHA/ASA (2013) [14]
AHA/ASA (2010) [15]
BTF (2007) [16]
Recommends identifying sources of fever and treating any temperature above 388C with antipyretic medication ‘Mechanical interventions’ can be used, but makes no recommendation on their use Notes experimental/clinical data ‘provide a rationale for aggressive treatment to maintain normothermia’ No formal recommendations provided, citing lack of evidence on outcome and/or specific interventions Virtually no mention of ‘fever’ or ‘hyperthermia’ Inadequate evidence to recommend TH
Subarachnoid haemorrhage
ENLS (2012) [17]
Recommends ‘temperature 36.08C–38.38C’ in list of physiologic parameters for goal-directed care
Not stated
Not stated
AHA (2009) [18]
‘It is imperative to avoid systemic and metabolic insults’, including hyperthermia, however, ‘no definitive prospective trials exist to support these common-sense recommendations’
n/a
n/a
NCS (2011) [19]
‘Temperature should be monitored frequently; infectious causes of fever should always be sought and treated’
Strong
High
‘During the period of risk for DCI control of fever is desirable; intensity should reflect the individual patient’s relative risk of ischemia’
Strong
Low
‘While the efficacy of most antipyretic agents (acetaminophen, ibuprofen) is low, they should be used as the first line of therapy’
Strong
Moderate
‘Surface cooling or intravascular devices are more effective and should be employed when antipyretics fail in cases where fever control is highly desirable’
Strong
High
‘Use of [surface cooling or intravascular] devices should be accompanied by monitoring for skin injury and venous thrombosis’
Strong
Weak
‘Patients should be monitored and treated for shivering’
Strong
High
AHA, American Heart Association; ASA, American Stroke Association; BTF, Brain Trauma Foundation; ENLS, Emergency Neurological Life Support; NCS, Neurocritical Care Society; TH, therapeutic hypothermia.
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Fever and therapeutic normothermia Bohman and Levine
temperature range, whereas patients in all other groups spent 40% or more of study time out of the normal range. Intravascular cooling may be safely maintained for durations of at least 1–2 weeks. In a recent prospective study, 102 patients with SAH, ischemic stroke and haemorrhagic stroke, treated at two centres in Germany and Austria, were randomized to either intravascular cooling or standard therapy (antipyretics and a water-circulating cooling blanket) [26]. A temperature of 36.58C was maintained for 7 days in patients with intracranial haemorrhage or stroke and for 14 days in SAH patients. Catheterbased intravascular cooling resulted in marked reductions in fever burden and nursing intensity. Aside from a high (near universal) incidence of nonbloodstream infections in the intravascular cooling group, there was no difference in adverse events between groups. There was no difference in functional outcome at 6 months between groups, but given the heterogeneity in the diseases and severity enrolled, the study was underpowered to detect a change in outcome.
INTERVENTIONAL STUDIES: IMPACT OF NORMOTHERMIA ON PHYSIOLOGY In this section, we review data from recent interventional studies that address physiology.
Induced normothermia improves neurophysiology in severe brain injury Two recent studies suggest an association between induced normothermia and improved brain physiology. In a retrospective single-centre series, 21 patients with severe TBI and fever (T 388C) who were treated with induced normothermia using intravascular heat exchange catheters were compared with 21 historical controls with fever (matched by age, sex and GCS) who were treated with antipyretics, surface cooling and intraperitoneal ice lavage [27]. The patients managed with intravascular cooling not only had significant reductions in fever burden but also had lower mean ICP and spent less time with an ICP more than 25 mmHg compared with controls. Interestingly, the authors also reported that brain temperatures in the induced normothermia group tended to be lower than core temperatures. This contrasts with many earlier reports that suggest that brain temperature generally exceeds core temperature by as much as 28C [28,29]. In another study [30] of the effects of temperature management on brain physiology, 18 patients with SAH and fevers refractory to antipyretics were
monitored with cerebral microdialysis during therapeutic normothermia (using ice packs and water-cooled blankets or gel pads). When microdialysis samples from these patients during afebrile and febrile periods were compared, normothermia was associated with lower lactate to pyruvate ratio (LPR) and fewer episodes of metabolic crisis (LPR >40) than fever. This finding was evident during periods of normal and elevated ICP. In addition, elevated LPR was associated with poor outcome. This study demonstrated an association between fever control and reduced cerebral biochemical distress and therefore provides indirect evidence in humans of a causal relationship between fever and brain injury.
Shivering is common during induced normothermia and may reduce the physiologic benefits of temperature control Shivering is a frequent occurrence during induced normothermia, particularly during intensive surface cooling [23]. A small study [31] showed that in patients with severe brain injury treated with therapeutic normothermia who developed shivering, there was no improvement in systemic oxygen consumption (VO2), whereas patients who did not develop shivering showed a significant reduction in VO2 with normothermia. A more recent study [32] in patients with severe brain injuries managed with intensive surface cooling who developed shivering found marked reductions in the brain tissue tension of oxygen (PbtO2) during shivering episodes compared with the period prior to the shivering episode. ICP was also modestly elevated during shivering episodes, consistent with previous reports.
INTERVENTIONAL STUDIES: IMPACT ON OUTCOME In this section, we review data from recent interventional studies that address clinical outcomes.
Acute ischemic stroke: prophylactic administration of paracetamol (acetaminophen) does not improve outcome The largest study intended to examine how normothermia may affect outcome was the Paracetamol (Acetaminophen) in Stroke (PAIS) trial, a multicentre, randomized, double-blind, placebocontrolled trial conducted in the Netherlands [33]. Patients were eligible if they were at least 18 years old, had either ischemic or hemorrhagic stroke, had an admission T 368C–398C and could receive the study drug within 12 h of symptom onset. Patients were excluded if they had a contraindication to
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Neuroscience
receiving paracetamol or a significant baseline neurological deficit. Patients in the experimental arm received 6 g/day of paracetamol for 3 days. Patients were followed up at 14 days and 3 months postictus. The study was stopped early due to financial reasons after 1400 patients were enrolled. For this reason, the primary outcome was revised from a binary outcome based on mRS to a sliding dichotomy based on improvement beyond expectations. The PAIS trial failed to show any benefit in its revised primary outcome (improvement beyond expectations) or quality of life in any of its prespecified analyses. An unplanned posthoc subgroup analysis showed a modest benefit among patients with higher baseline temperatures (378C– 398C) [33]. A critique of the article pointed out that this effect on functional outcome, even if real, would be small in absolute terms [34]. Consistent with previous studies, paracetamol’s effect on body temperature was modest, with temperature 24 h after admission only 0.268C (0.188C–0.318C) lower in the paracetamol than in the control group. For reasons not discussed in the manuscript, the trial only reported patient temperature at two time points and did not define fever or report the incidence of fever over the treatment period in either group. The trial findings indicate that early and prophylactic acetaminophen administration is not useful in stroke patients; however, little may be inferred about the value of therapeutic normothermia in this population.
Subarachnoid haemorrhage: induced normothermia may improve functional outcome Badjatia et al. [35] recently published a series of 40 consecutive febrile SAH patients compared with 80 historical controls (matched for age, Hunt Hess score, and SAH sum score) selected from their SAH patient registry. All patients were initially treated with acetaminophen. In the treatment cohort, patients with fever (defined as T >38.38C) were treated with a water-circulating gel pad cooling system (one was also cooled with an intravascular device). In the control cohort, fever was treated with water-cooled blankets. Induced normothermia was initiated at variable time points (median day 3, range 0–6) and maintained for a median of 7 days. Patients in the advanced fever control (AFC) group had higher rates of hyperglycemia and cardiac arrhythmias but otherwise did not have an excess of adverse effects compared with controls. Of note, shivering was not considered an adverse effect and shivering rates were not reported, although their group and others have reported higher rates 186
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of shivering with the AFC surface cooling systems [23,31]. The AFC group was more likely to have received sedative medications, which may have partly reflected the antishivering protocol mentioned by the authors, and the AFC group tended to have longer ICU stay and a higher tracheostomy rate [35]. In spite of these differences, however, the use of AFC was associated with a reduced risk of poor outcome [odds ratio (OR) 0.2, 95% confidence interval (95% CI) 0.1–0.6, P ¼ 0.004] in multivariable regression analyses adjusting for Hunt Hess Score, age, pneumonia, anaemia and arrhythmia. These findings are corroborated by a retrospective study of 183 patients with aneurysmal SAH that reported a dose–response relationship between days of fever and chance of a poor functional outcome. This relationship persisted in multivariable regression analysis that adjusted for the incidence of infection [36].
Are the benefits seen in the trials of therapeutic hypothermia after cardiac arrest due, at least in part, to fever control? Despite being recommended by major guidelines and supported by a Cochrane review, the practice of therapeutic hypothermia after cardiac arrest remains controversial [12,13,37]. A recent metaanalysis that applied strict evidentiary criteria and a trials sequential analysis concluded that the overall quality of the evidence for therapeutic hypothermia after cardiac arrest was low [38]. Nielsen et al. [38] point out that median temperatures in the normothermia groups of the therapeutic hypothermia trials ranged from 378C to 388C, indicating that as many of half of the patients may have been febrile, and cite data from previous observational studies that found the OR for poor outcome was more than 2 for every degree of temperature greater than 378C [39] and nearly 3 for temperatures greater than 37.88C [40]. These methodological limitations and relatively small size of earlier therapeutic hypothermia trials for cardiac arrest led to a recent, large, multicentre trial in which 950 patients with out-of-hospital cardiac arrest were randomized to a target temperature of 338C or of 368C [41]. Data were analysed from 939 patients (473 in the 338C group and 466 in the 368C group). There were few significant differences in baseline characteristics between the two treatment groups, and similar methodologies were used to achieve target temperatures, although these were left to the discretion of the study centres. The difference between groups in the primary end-point, all-cause mortality, was not statistically significant (50% in the 338C group vs. 48% in the Volume 20 Number 2 April 2014
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Fever and therapeutic normothermia Bohman and Levine &&
368C group) [42 ]. There were also no significant differences in any of the secondary neurologic outcomes or major complications, except hypokalemia, which was more common in the 338C group. The study was rigorously conducted with blinded assessment of outcome and data analysis, though the treating practitioners were not blinded to treatment group. The authors concluded that cooling to 338C has no benefit over cooling to 368C. The impact of this study on future practice has yet to be determined but may imply that induced normothermia may be as beneficial as therapeutic hypothermia.
CONCLUSION Although prospective evidence that links induced normothermia to improved outcome is limited, the association between fever and poor outcome after severe neurological injury is strong. Moreover, a growing body of experimental and clinical evidence suggests that fever reduction improves brain metabolism. To date, data about the physiological effects and the impact on outcome of induced normothermia are largely derived from small, single-centre, nonrandomized, retrospective trials, and must be interpreted judiciously. However, these studies provide a compelling evidentiary basis for further study. Critical unanswered questions remain. What are the ideal strategies to achieve normothermia? What is the ideal way to minimize shivering? Which patients should be selected for therapeutic normothermia and what is the appropriate threshold temperature? To what extent is the association of fever with outcome in observational studies an epiphenomenon vs. a contributor to pathogenesis? Clinical trials.gov lists several recently completed or ongoing trials of normothermia in TBI, ICH, stroke and severe brain injury, in addition to several ongoing trials on the effects of hypothermia in these disorders. Acknowledgements None. Conflicts of interest Drs Bohman and Levine have no conflicts of interest to report.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Circiumaru B, Baldock G, Cohen J. A prospective study of fever in the intensive care unit. Intensive Care Med 1999; 25:668–673.
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Clinical trial of a novel surface cooling system for fever control in neurocritical care patients. Crit Care Med 2004; 32:2508–2515. 24. Mayer S, Commichau C, Scarmeas N, et al. Clinical trial of an air-circulating cooling blanket for fever control in critically ill neurologic patients. Neurology 2001; 56:292–298. 25. 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 2007; 11:R91. 26. 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. 27. 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. 28. 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37. Arrich J, Holzer M, Havel C, et al. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane database Syst Rev 2012; 9:CD004128. 38. Nielsen N, Friberg H, Gluud C, et al. Hypothermia after cardiac arrest should be further evaluated: a systematic review of randomised trials with metaanalysis and trial sequential analysis. Int J Cardiol 2011; 151:333–341. 39. Zeiner A, Holzer M, Sterz F, et al. Hyperthermia after cardiac arrest is associated with an unfavorable neurologic outcome. Arch Intern Med 2001; 161:2007–2012. 40. Langhelle A, Tyvold SS, Lexow K, et al. In-hospital factors associated with improved outcome after out-of-hospital cardiac arrest. A comparison between four regions in Norway. Resuscitation 2003; 56:247–263. 41. Nielsen N, Wetterslev J, al-Subaie N, et al. Target temperature management after out-of-hospital cardiac arrest – a randomized, parallel-group, assessorblinded clinical trial – rationale and design. Am Heart J 2012; 163:541–548. 42. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management && at 338c versus 368c after cardiac arrest. N Engl J Med 2013; 369:2197– 2206. The largest, randomized trial of therapeutic hypothermia (338C vs. 368C) that found no difference in outcomes between treatment groups, challenging the current paradigm for postcardiac arrest temperature management.
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Fever and therapeutic normothermia in severe brain injury: an update Leif-Erik Bohman a and Joshua M. Levine b
Purpose of review Fever is common in the ICU among patients with severe brain injury. Fever has been consistently shown to exacerbate brain injuries in animal models and has been consistently associated with poor outcome in human studies. However, whether fever control improves outcome and the ideal means of fever control remain unknown. This review will address recent literature on the impact of fever on severe brain injury and on interventions to maintain normothermia. Recent findings Current guidelines generally recommend maintenance of normothermia after brain injury but have scant recommendations on methods to do this. Observational trials have continued to demonstrate the association between fever and poor outcome after severe brain injury. Recent trials have shown the efficacy of more aggressive approaches to fever reduction, whereas a large randomized trial showed the relative ineffectiveness of acetaminophen alone for fever control. Several studies have also described the impact of fever and of fever control on brain physiology. Summary The value of therapeutic normothermia in the neurocritical care unit (NCCU) is increasingly accepted, yet prospective trials that demonstrate a functional benefit to patients are lacking. Keywords fever control, induced normothermia, normothermia, targeted temperature management
INTRODUCTION Fever (variously defined as core body temperatures exceeding 37.58C–38.58C) is common in patients with severe brain injuries, including hypoxic-ischemic encephalopathy from cardiac arrest, traumatic brain injury (TBI), ischemic stroke, haemorrhagic stroke and subarachnoid haemorrhage (SAH) [1–5]. A large body of experimental and human evidence, which has been well summarized in several prior reviews [6–11], suggests an association between fever and poor neurological outcome after severe brain injury. The present review is intended to update that of Badjatia from 2009 [10], and focuses on subsequent publications. Although there have been several updates to the relevant disease-specific guidelines since 2009, relatively few substantive changes have been made regarding therapeutic normothermia. Current guidelines by disease type are detailed in Table 1. Generally, guidelines acknowledge the association of fever with poor outcome, however, with the exception of the Neurocritical Care Society Guidelines for SAH, stop short of making specific therapeutic recommendations [12–19]. www.co-criticalcare.com
Recent evidence regarding fever and therapeutic normothermia in severe brain injury may be categorized into observational and interventional studies. Recent observational studies have provided further evidence of an association between fever, even after therapeutic hypothermia for cardiac arrest, and poor outcome. They also have shed light on the frequency of fever after severe brain injury and on rates of fever control in clinical practice. Interventional studies may be further subclassified into those that compare the efficacy of interventions in controlling fever, and those that investigate the effects of fever control on physiology or functional outcome. Increasing evidence a
Department of Neurosurgery and bDepartment of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA Correspondence to Joshua M. Levine, MD, Division of Neurocritical Care, Department of Neurology, Hospital of the University of Pennsylvania, 3 W Gates, 3400 Spruce Street, Philadelphia, PA 19104, USA. E-mail: [email protected] Curr Opin Crit Care 2014, 20:182–188 DOI:10.1097/MCC.0000000000000070 Volume 20 Number 2 April 2014
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Fever and therapeutic normothermia Bohman and Levine
KEY POINTS
centre in Copenhagen recently examined the association of post rewarming fever (T >38.58C) on outcome [21 ]. Of note, patients with posthypothermia fevers were not aggressively cooled to normothermia. Among these patients, posthypothermia fever was associated with increased mortality at 30 days and worsened neurological outcome at 1-year follow-up. &
Although the association between fever and worse neurological outcome after severe brain injury is robust, there is little direct proof in humans that the relationship between fever and exacerbation of brain injury is causal. Nonetheless, fever control remains an important element in the care of patients with severe brain injury. Although cooling patients with cardiac arrest to 338C is currently recommended, a recent study suggests that cooling to 368C confers similar benefit. Further studies are needed to define the optimal methods of temperature control, the safest and most effective treatments for shivering, and the ideal depth and duration of cooling in patients with acute brain injury.
demonstrates that intensive cooling devices, particularly intravascular devices, provide faster and more durable temperature control than the traditional methods of fever management, antipyretics and air-cooled blankets.
OBSERVATIONAL STUDIES In this section, we review data from recent observational studies in the areas of stroke and cardiac arrest.
Acute ischemic stroke: total fever burden and maximum temperature are more important than admission temperature Despite the consistent association between fever and poor outcome, little study has been devoted to the temporal profile of temperature elevation after ischemic stroke. To address this, Karaszewski et al. [20] prospectively followed 44 patients with anterior circulation infarcts and recorded temperature every 4 h for 120 h. Maximum and final temperatures, as well as the temperature area under the curve, were associated with both National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Score (mRS) at 3 months, whereas admission temperature was not. The peak temperature in this ischemic stroke population was a median of 35.5 h after stroke onset, and most patients were normothermic on admission.
Cardiac arrest: fever after therapeutic hypothermia is associated with increased mortality A prospective cohort study including 270 patients treated with therapeutic hypothermia at a single
INTERVENTIONAL STUDIES: TECHNIQUE SELECTION In this section, we review data from recent interventional studies that address methods to achieve temperature control.
Further evidence that advanced temperature control techniques appear superior to traditional methods A variety of techniques have been used to cool patients, ranging from antipyretic medications (particularly acetaminophen and NSAIDs) to surface cooling devices (air or water-circulating blankets or gel-cooled systems) and intravascular cooling methods (injection of cold 0.9% sodium chloride or central venous heat exchange systems). Despite their position as the initial treatment of choice, antipyretic medications are notoriously ineffective, particularly in the brain-injured population [9]. Previous studies have suggested that advanced cooling systems (surface or intravascular devices) that incorporate a servomechanism with constant core temperature monitoring are more effective than traditional air-cooled blankets or ice packs alone in patients with acetaminophen-refractory fevers [22–24]. In these studies, however, advanced cooling devices were used for a relatively brief duration (1–3 days), and in each, only a single device was compared with a control group. Hoedemaekers et al. [25] performed a head-tohead comparison of cooling techniques in 50 ICU patients. In 25 patients (predominantly cardiac arrest), the goal was hypothermia, and in the other 25 patients (predominantly TBI/SAH), the goal was normothermia [25]. Patients were randomized to five groups: conventional treatment (antipyretics and ice packs); air-cooled blankets; water-cooled blankets; water-cooled gel pads; or intravascular heat exchange. In this small study, water-cooled gel pads and intravascular heat exchange allowed the fastest cooling in both normothermia and hypothermia groups; however, the intravascular system was superior in maintenance of target temperature. Patients treated with intravascular heat exchange catheters spent less than 5% of time out of target
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Neuroscience Table 1. Current guidelines for fever control in severe brain injury Disease
Guideline source/date
Cardiac arrest
AHA (2010) [12]
Recommendations
Strength of recommendations
Strength of evidence
Focus on TH when not contraindicated
I
C
Not stated
Not stated
I
C
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Hyperthermia ‘can impair brain recovery’ Recommends active intervention to avoid hyperthermia both postresuscitation and postrewarming after TH Cites lack of trials on specific treatment methods or benefits of treatment ENLS (2012) [13]
Focus on TH when not contraindicated Patients not eligible for TH ‘may benefit from fever prevention’
Ischemic stroke
Haemorrhagic stroke
Traumatic brain injury
AHA/ASA (2013) [14]
AHA/ASA (2010) [15]
BTF (2007) [16]
Recommends identifying sources of fever and treating any temperature above 388C with antipyretic medication ‘Mechanical interventions’ can be used, but makes no recommendation on their use Notes experimental/clinical data ‘provide a rationale for aggressive treatment to maintain normothermia’ No formal recommendations provided, citing lack of evidence on outcome and/or specific interventions Virtually no mention of ‘fever’ or ‘hyperthermia’ Inadequate evidence to recommend TH
Subarachnoid haemorrhage
ENLS (2012) [17]
Recommends ‘temperature 36.08C–38.38C’ in list of physiologic parameters for goal-directed care
Not stated
Not stated
AHA (2009) [18]
‘It is imperative to avoid systemic and metabolic insults’, including hyperthermia, however, ‘no definitive prospective trials exist to support these common-sense recommendations’
n/a
n/a
NCS (2011) [19]
‘Temperature should be monitored frequently; infectious causes of fever should always be sought and treated’
Strong
High
‘During the period of risk for DCI control of fever is desirable; intensity should reflect the individual patient’s relative risk of ischemia’
Strong
Low
‘While the efficacy of most antipyretic agents (acetaminophen, ibuprofen) is low, they should be used as the first line of therapy’
Strong
Moderate
‘Surface cooling or intravascular devices are more effective and should be employed when antipyretics fail in cases where fever control is highly desirable’
Strong
High
‘Use of [surface cooling or intravascular] devices should be accompanied by monitoring for skin injury and venous thrombosis’
Strong
Weak
‘Patients should be monitored and treated for shivering’
Strong
High
AHA, American Heart Association; ASA, American Stroke Association; BTF, Brain Trauma Foundation; ENLS, Emergency Neurological Life Support; NCS, Neurocritical Care Society; TH, therapeutic hypothermia.
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Fever and therapeutic normothermia Bohman and Levine
temperature range, whereas patients in all other groups spent 40% or more of study time out of the normal range. Intravascular cooling may be safely maintained for durations of at least 1–2 weeks. In a recent prospective study, 102 patients with SAH, ischemic stroke and haemorrhagic stroke, treated at two centres in Germany and Austria, were randomized to either intravascular cooling or standard therapy (antipyretics and a water-circulating cooling blanket) [26]. A temperature of 36.58C was maintained for 7 days in patients with intracranial haemorrhage or stroke and for 14 days in SAH patients. Catheterbased intravascular cooling resulted in marked reductions in fever burden and nursing intensity. Aside from a high (near universal) incidence of nonbloodstream infections in the intravascular cooling group, there was no difference in adverse events between groups. There was no difference in functional outcome at 6 months between groups, but given the heterogeneity in the diseases and severity enrolled, the study was underpowered to detect a change in outcome.
INTERVENTIONAL STUDIES: IMPACT OF NORMOTHERMIA ON PHYSIOLOGY In this section, we review data from recent interventional studies that address physiology.
Induced normothermia improves neurophysiology in severe brain injury Two recent studies suggest an association between induced normothermia and improved brain physiology. In a retrospective single-centre series, 21 patients with severe TBI and fever (T 388C) who were treated with induced normothermia using intravascular heat exchange catheters were compared with 21 historical controls with fever (matched by age, sex and GCS) who were treated with antipyretics, surface cooling and intraperitoneal ice lavage [27]. The patients managed with intravascular cooling not only had significant reductions in fever burden but also had lower mean ICP and spent less time with an ICP more than 25 mmHg compared with controls. Interestingly, the authors also reported that brain temperatures in the induced normothermia group tended to be lower than core temperatures. This contrasts with many earlier reports that suggest that brain temperature generally exceeds core temperature by as much as 28C [28,29]. In another study [30] of the effects of temperature management on brain physiology, 18 patients with SAH and fevers refractory to antipyretics were
monitored with cerebral microdialysis during therapeutic normothermia (using ice packs and water-cooled blankets or gel pads). When microdialysis samples from these patients during afebrile and febrile periods were compared, normothermia was associated with lower lactate to pyruvate ratio (LPR) and fewer episodes of metabolic crisis (LPR >40) than fever. This finding was evident during periods of normal and elevated ICP. In addition, elevated LPR was associated with poor outcome. This study demonstrated an association between fever control and reduced cerebral biochemical distress and therefore provides indirect evidence in humans of a causal relationship between fever and brain injury.
Shivering is common during induced normothermia and may reduce the physiologic benefits of temperature control Shivering is a frequent occurrence during induced normothermia, particularly during intensive surface cooling [23]. A small study [31] showed that in patients with severe brain injury treated with therapeutic normothermia who developed shivering, there was no improvement in systemic oxygen consumption (VO2), whereas patients who did not develop shivering showed a significant reduction in VO2 with normothermia. A more recent study [32] in patients with severe brain injuries managed with intensive surface cooling who developed shivering found marked reductions in the brain tissue tension of oxygen (PbtO2) during shivering episodes compared with the period prior to the shivering episode. ICP was also modestly elevated during shivering episodes, consistent with previous reports.
INTERVENTIONAL STUDIES: IMPACT ON OUTCOME In this section, we review data from recent interventional studies that address clinical outcomes.
Acute ischemic stroke: prophylactic administration of paracetamol (acetaminophen) does not improve outcome The largest study intended to examine how normothermia may affect outcome was the Paracetamol (Acetaminophen) in Stroke (PAIS) trial, a multicentre, randomized, double-blind, placebocontrolled trial conducted in the Netherlands [33]. Patients were eligible if they were at least 18 years old, had either ischemic or hemorrhagic stroke, had an admission T 368C–398C and could receive the study drug within 12 h of symptom onset. Patients were excluded if they had a contraindication to
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Neuroscience
receiving paracetamol or a significant baseline neurological deficit. Patients in the experimental arm received 6 g/day of paracetamol for 3 days. Patients were followed up at 14 days and 3 months postictus. The study was stopped early due to financial reasons after 1400 patients were enrolled. For this reason, the primary outcome was revised from a binary outcome based on mRS to a sliding dichotomy based on improvement beyond expectations. The PAIS trial failed to show any benefit in its revised primary outcome (improvement beyond expectations) or quality of life in any of its prespecified analyses. An unplanned posthoc subgroup analysis showed a modest benefit among patients with higher baseline temperatures (378C– 398C) [33]. A critique of the article pointed out that this effect on functional outcome, even if real, would be small in absolute terms [34]. Consistent with previous studies, paracetamol’s effect on body temperature was modest, with temperature 24 h after admission only 0.268C (0.188C–0.318C) lower in the paracetamol than in the control group. For reasons not discussed in the manuscript, the trial only reported patient temperature at two time points and did not define fever or report the incidence of fever over the treatment period in either group. The trial findings indicate that early and prophylactic acetaminophen administration is not useful in stroke patients; however, little may be inferred about the value of therapeutic normothermia in this population.
Subarachnoid haemorrhage: induced normothermia may improve functional outcome Badjatia et al. [35] recently published a series of 40 consecutive febrile SAH patients compared with 80 historical controls (matched for age, Hunt Hess score, and SAH sum score) selected from their SAH patient registry. All patients were initially treated with acetaminophen. In the treatment cohort, patients with fever (defined as T >38.38C) were treated with a water-circulating gel pad cooling system (one was also cooled with an intravascular device). In the control cohort, fever was treated with water-cooled blankets. Induced normothermia was initiated at variable time points (median day 3, range 0–6) and maintained for a median of 7 days. Patients in the advanced fever control (AFC) group had higher rates of hyperglycemia and cardiac arrhythmias but otherwise did not have an excess of adverse effects compared with controls. Of note, shivering was not considered an adverse effect and shivering rates were not reported, although their group and others have reported higher rates 186
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of shivering with the AFC surface cooling systems [23,31]. The AFC group was more likely to have received sedative medications, which may have partly reflected the antishivering protocol mentioned by the authors, and the AFC group tended to have longer ICU stay and a higher tracheostomy rate [35]. In spite of these differences, however, the use of AFC was associated with a reduced risk of poor outcome [odds ratio (OR) 0.2, 95% confidence interval (95% CI) 0.1–0.6, P ¼ 0.004] in multivariable regression analyses adjusting for Hunt Hess Score, age, pneumonia, anaemia and arrhythmia. These findings are corroborated by a retrospective study of 183 patients with aneurysmal SAH that reported a dose–response relationship between days of fever and chance of a poor functional outcome. This relationship persisted in multivariable regression analysis that adjusted for the incidence of infection [36].
Are the benefits seen in the trials of therapeutic hypothermia after cardiac arrest due, at least in part, to fever control? Despite being recommended by major guidelines and supported by a Cochrane review, the practice of therapeutic hypothermia after cardiac arrest remains controversial [12,13,37]. A recent metaanalysis that applied strict evidentiary criteria and a trials sequential analysis concluded that the overall quality of the evidence for therapeutic hypothermia after cardiac arrest was low [38]. Nielsen et al. [38] point out that median temperatures in the normothermia groups of the therapeutic hypothermia trials ranged from 378C to 388C, indicating that as many of half of the patients may have been febrile, and cite data from previous observational studies that found the OR for poor outcome was more than 2 for every degree of temperature greater than 378C [39] and nearly 3 for temperatures greater than 37.88C [40]. These methodological limitations and relatively small size of earlier therapeutic hypothermia trials for cardiac arrest led to a recent, large, multicentre trial in which 950 patients with out-of-hospital cardiac arrest were randomized to a target temperature of 338C or of 368C [41]. Data were analysed from 939 patients (473 in the 338C group and 466 in the 368C group). There were few significant differences in baseline characteristics between the two treatment groups, and similar methodologies were used to achieve target temperatures, although these were left to the discretion of the study centres. The difference between groups in the primary end-point, all-cause mortality, was not statistically significant (50% in the 338C group vs. 48% in the Volume 20 Number 2 April 2014
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Fever and therapeutic normothermia Bohman and Levine &&
368C group) [42 ]. There were also no significant differences in any of the secondary neurologic outcomes or major complications, except hypokalemia, which was more common in the 338C group. The study was rigorously conducted with blinded assessment of outcome and data analysis, though the treating practitioners were not blinded to treatment group. The authors concluded that cooling to 338C has no benefit over cooling to 368C. The impact of this study on future practice has yet to be determined but may imply that induced normothermia may be as beneficial as therapeutic hypothermia.
CONCLUSION Although prospective evidence that links induced normothermia to improved outcome is limited, the association between fever and poor outcome after severe neurological injury is strong. Moreover, a growing body of experimental and clinical evidence suggests that fever reduction improves brain metabolism. To date, data about the physiological effects and the impact on outcome of induced normothermia are largely derived from small, single-centre, nonrandomized, retrospective trials, and must be interpreted judiciously. However, these studies provide a compelling evidentiary basis for further study. Critical unanswered questions remain. What are the ideal strategies to achieve normothermia? What is the ideal way to minimize shivering? Which patients should be selected for therapeutic normothermia and what is the appropriate threshold temperature? To what extent is the association of fever with outcome in observational studies an epiphenomenon vs. a contributor to pathogenesis? Clinical trials.gov lists several recently completed or ongoing trials of normothermia in TBI, ICH, stroke and severe brain injury, in addition to several ongoing trials on the effects of hypothermia in these disorders. Acknowledgements None. Conflicts of interest Drs Bohman and Levine have no conflicts of interest to report.
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37. Arrich J, Holzer M, Havel C, et al. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane database Syst Rev 2012; 9:CD004128. 38. Nielsen N, Friberg H, Gluud C, et al. Hypothermia after cardiac arrest should be further evaluated: a systematic review of randomised trials with metaanalysis and trial sequential analysis. Int J Cardiol 2011; 151:333–341. 39. Zeiner A, Holzer M, Sterz F, et al. Hyperthermia after cardiac arrest is associated with an unfavorable neurologic outcome. Arch Intern Med 2001; 161:2007–2012. 40. Langhelle A, Tyvold SS, Lexow K, et al. In-hospital factors associated with improved outcome after out-of-hospital cardiac arrest. A comparison between four regions in Norway. Resuscitation 2003; 56:247–263. 41. Nielsen N, Wetterslev J, al-Subaie N, et al. Target temperature management after out-of-hospital cardiac arrest – a randomized, parallel-group, assessorblinded clinical trial – rationale and design. Am Heart J 2012; 163:541–548. 42. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management && at 338c versus 368c after cardiac arrest. N Engl J Med 2013; 369:2197– 2206. The largest, randomized trial of therapeutic hypothermia (338C vs. 368C) that found no difference in outcomes between treatment groups, challenging the current paradigm for postcardiac arrest temperature management.
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