JOURNAL OF NEUROTRAUMA 26:455467 (March 2009) Mary Ann Liebert, Inc. DOI: 10.1089=neu.2008.

0582

Current and Future Role of Therapeutic Hypothermia

Donald Marion1 and M. Ross Bullock2

Abstract

Therapeutic moderate hypothermia has been advocated for use in traumatic brain injury, stroke, cardiac arrestinduced encephalopathy, neonatal hypoxic-ischemic encephalopathy, hepatic encephalopathy, and spinal cord injury, and as an adjunct to aneurysm surgery. In this review, we address the trials that have been performed for each of these indications, and review the strength of the evidence to support treatment with mild=moderate hypothermia. We review the data to support an optimal target temperature for each indication, as well as the duration of the cooling, and the rate at which cooling is induced and rewarming instituted. Evidence is strongest for prehospital cardiac arrest and neonatal hypoxic-ischemic encephalopathy. For traumatic brain injury, a recent meta-analysis suggests that cooling may increase the likelihood of a good outcome, but does not change mortality rates. For many of the other indications, such as stroke and spinal cord injury, trials are ongoing, but the data are insufcient to recommend routine use of hypothermia at this time.
Key words: adult brain injury; cerebral vascular disease; clinical trial; decompressive craniectomy; guidelines; head

trauma; hypothermia; traumatic brain injury

Introduction

herapeutic hypothermia has been used to treat acute diseases of the central nervous system (CNS) for more than 60 years. In the 1950s, Sedzimir and Fay observed that hypothermia was more effective than osmotic diuretics for treating refractory intracranial hypertension following severe traumatic brain injury (TBI), stroke, and a variety of other acute neurological diseases (Sedzimir et al., 1955; Fay, 1959; Sedzimir, 1959). Rosomoff dened the effects of hypothermia on cerebral physiology, metabolism, and swelling in brain injury models (Rosomoff and Holaday, 1954; Rosomoff, 1956, 1959). Lund and colleagues subsequently observed that hypothermia was more effective and longer lasting than hyperventilation for reducing elevated intracranial pressure (ICP) in laboratory studies of TBI (Lund et al., 1965). But these early observations, and particularly the clinical reports, were primarily anecdotal and left clinicians unclear about the optimal target temperature, optimal duration of cooling, safest duration of rewarming, or the common complications associated with hypothermia and how to manage them. As a result, the use of this therapy was occasionally associated with severe or even fatal complications, such as difculty managing hemorrhage during aneurysm surgery, so clinicians did not initially embrace hypothermia as a therapeutic option.

However, Safar and Clifton continued to independently investigate the potential therapeutic benets of hypothermia. During the early 1990s, they published dog and rodent studies that helped dene clinical parameters for the safe and effective use of this therapy (Leonov et al., 1990a,b; Clifton et al., 1991). Importantly, these investigators discovered that target temperatures of 308C or higher for relatively brief periods of time might be sufcient to provide sustained improvement in neurologic outcomes. This was an important observation because the most severe or life-threatening complications of hypothermia (such as refractory cardiac arrhythmias, severe coagulation abnormalities, or life-threatening pneumonias) were associated with prolonged cooling and with temperatures below 308 C. The positive results from these studies led to several small clinical trials of therapeutic moderate hypothermia (32338 C) for the treatment of severe TBI (Clifton et al., 1993; Marion et al., 1993, 1997). When those trials conrmed that moderate hypothermia was not associated with clinically signicant medical complications, clinical trials were initiated for patients with cardiac arrest, hypoxicischemic encephalopathy (HIE) in neonates, stroke, hepatic encephalopathy, and a variety of other acute neurologic diseases. In addition, larger TBI trials were conducted in the United States, and also in Japan and China. Results of many of these clinical trials have now been published, and have

1 2

The Childrens Neurobiological Solutions Foundation, Santa Barbara, California. Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida.

455

456 changed the practice recommendations for several acute diseases that are associated with cerebral ischemia. For patients with out-of-hospital cardiac arrest (OHCA) and neonates with perinatal HIE, therapeutic hypothermia has now been convincingly shown to improve outcomes. The clinical studies for patients with TBI are not as convincing, but there is evidence that even with this disease hypothermia helps control intracranial hypertension. In this article, we will review the current clinical evidence in support of the use of therapeutic hypothermia for the treatment of several of the diseases described above, all of which expose the brain to global or regional ischemia of various duration. Most concur that the likely mechanism whereby hypothermia may limit permanent cerebral injury is through prevention of secondary brain injury. That is, hypothermia is thought to suppress the cascade of physiologic and metabolic events that result in the excitotoxic, oxidative, and=or inammatory injury that occurs following the initial traumatic or physiologic insult. It is important to emphasize that therapeutic hypothermia is not the same as accidental hypothermia. While accidental hypothermia results in signicant physiological stress and depletion of high-energy phosphate stores, induced or therapeutic hypothermia is usually accomplished with the pharmacologic induction of poikilothermia and prevention of shivering, and actually results in preservation of ATP stores (Hildebrand et al., 2004). In addition, it should be claried that most of the studies reviewed in this chapter refer to the use of mild or moderate hypothermia, or cooling to 32358 C. For the purpose of brain protection during complete circulatory arrest, as is used for some aortic, cardiac, or brain aneurysm operations, deep hypothermia (<308 C) also has been used but will not be discussed here. Cardiac Arrest The mortality rate for patients who are brought to the hospital following cardiac arrest and resuscitation in the eld is greater than 50% in most studies. Among those who recover, there often is devastating neurologic damage that leaves survivors severely disabled or in a permanent vegetative state. During the 1990s, several groups initiated multicenter clinical trials to determine if hypothermia could be used to reduce the mortality and neurologic morbidity due to OHCA. In Austria, Fritz Sterz organized a multicenter European trial for patients with OHCA due to ventricular brillation in which patients were randomly assigned to be cooled to a bladder temperature of 32348C for 24 h within 6 h of the arrest, or to be kept normothermic (Hypothermia after Cardiac Arrest Study Group, 2002). Mortality at 6 months after the arrest was 41% for the 137 patients assigned to the hypothermia group and 55% for the 138 patients assigned to the normothermia group (RR 0.74; 95% CI, 0.580.95). Moreover, 55% of the hypothermia group but only 39% of the normothermia patients had a good recovery or moderate disability (RR 1.40; 95% CI, 1.081.81). During that time, Bernard organized a similar prospective clinical trial in Australia, in which comatose patients with OHCA were randomized to normothermia, or to be cooled to 338C within 2 h after return of spontaneous circulation, and kept at that temperature for 12 h (Bernard et al., 2002). Among the 43 patients in the hypothermia group, 49% had a good outcome compared with

MARION AND BULLOCK 26% of the 34 patients assigned to the normothermia group (OR 5.25; 95% CI, 1.4718.76). Sunde et al. (2007) designed a standardized post-resuscitation protocol that included hypothermia and found that 56% of 61 hypothermia patients treated with that protocol survived to discharge with a favorable neurologic outcome compared to only 26% of 58 patients (historical controls) kept normothermic ( p 0.001). In a retrospective study, Oddo et al. (2006) found that 55.8% of 43 hypothermia patients had a good outcome compared to only 25.6% of 43 patients kept normothermic following OHCA ( p 0.004). In that study, the authors found that hypothermia was only benecial for those with arrest due to ventricular brillation, and not when the arrest was due to asystole or pulseless electrical activity. During the past two years, several investigators also have demonstrated that target temperatures are more reliably reached and maintained with the use of intravascular cooling devices rather than conventional surface cooling methods for the induction of hypothermia (Arrich, 2007; Pichon et al., 2007). In a retrospective cohort study, Holzer et al. (2006) evaluated the impact of endovascular cooling versus standard care (normothermia) for patients with OHCA. They found a greater than twofold increase in the likelihood of survival with favorable neurologic recovery in those who were rapidly cooled to 338C and maintained at that temperature for 24 h using endovascular cooling technology as compared to those kept normothermic (adjusted OR 2.56; 95% CI, 1.574.17). With the endovascular device, the hypothermia patients could be cooled at a rate of 1.28C per hour. However, this study was biased in favor of the hypothermia group because signicantly fewer normothermia patients had ventricular brillation (46% vs. 71%) or even a cardiac cause (64% vs. 85%) for their cardiac arrest. In 2005, a meta-analysis was published that included three randomized or quasi-randomized controlled trials of adults who were successfully resuscitated from OHCA, where therapeutic hypothermia was used within 6 h after arrival at the emergency department, and where the neurologic outcome was compared in that group with a prospective normothermia (control) group (Holzer et al., 2005). The clinical trials that met these criteria were identied in a computerized search of all relevant online medical databases. That meta-analysis clearly showed that treatment with hypothermia resulted in a signicantly greater likelihood of being alive at 6 months with a favorable functional neurologic recovery (RR 1.44; 95% CI, 1.111.76). Based on the positive results of these clinical trials, the American Heart Association, and the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation, have published the following Level IIa recommendation: Unconscious adult patients with return of spontaneous circulation after out-of hospital cardiac arrest should be cooled to 328C to 348C (89.68F to 93.28F) for 12 to 24 hours when the initial rhythm is ventricular brillation (VF) (Nolan et al., 2003, 2005). But despite this recommendation, and the extensive clinical evidence in support of it, a 2006 survey of critical care, cardiology, and emergency medicine physicians in the United States, United Kingdom, and Finland found that 74% of U.S. physicians and 64% of non-U.S. physicians were not using hypothermia for these patients (Merchant et al., 2006). The most common reasons cited for nonuse were not enough data, not part of Advanced Cardiac Life Support Guide-

FUTURE OF THERAPEUTIC HYPOTHERMIA lines, and too technically difcult to use. In a separate phone survey of 256 U.K. intensive care units (ICUs), only 28.4% indicated that they had cooled patients after cardiac arrest. Those that hadnt used this therapy cited logistical or resource issues, or lack of evidence or consensus, as reasons for not using hypothermia (Laver et al., 2006). Neonatal Hypoxic-Ischemic Encephalopathy HIE results from perinatal asphyxial insults, such as placenta abruptio or umbilical cord injury, and is a common cause for neonatal death and long-term neurologic disability. Because of the ischemic mechanism for cerebral injury, several investigators have proposed that HIE also might respond to therapeutic moderate hypothermia. A benecial effect on magnetic resonance imaging (MRI) detected basal ganglia, and thalamic injury has been detected in term infants treated with therapeutic hypothermia for 4872 h (Rutherford et al., 2005). However, this effect was only apparent for those infants with moderate, and not severe, amplitude-integrated electroencephalography (EEG) abnormalities. Others have found that hypothermia results in signicantly less MRI-detected cortical gray matter signal abnormality when compared with infants kept normothermic (Inder et al., 2004). In 2005, the results of two major clinical trials were published; signicant improvement in outcomes for HIE infants treated with hypothermia was found. Shankaran et al. (2005) studied 208 infants with a gestational age of 36 weeks or more admitted to the hospital within 6 h of birth with severe acidosis, or perinatal complications and resuscitation that resulted in moderate or severe HIE. These infants were randomly assigned to a normothermia group (n 106), or a group cooled to 33.58C for 72 h (n 102). Death, or moderate to severe disability occurred in 44% of the hypothermia infants and 62% of the normothermia group (RR 0.72; 95% CI, 0.540.95). Eicher et al. (2005) also found benet with hypothermia treatment for 48 h in their study of 65 HIE infants. While 84% of the 33 infants kept normothermic died or were left with severe motor decits, only 52% of the 32 infants treated with hypothermia had such poor outcomes ( p 0.019). Since those trials were completed, two other large clinical trials have conrmed the benecial effects of hypothermia (Wyatt et al., 2007; Gunn et al., 2008). But while those studies document a sustained benet of treatment at 18 months of age, they also show that hypothermia is of little or no benet for those with severe (as opposed to moderate) HIE. Wyatt et al. (2007) also found that a specially designed cooling cap could be used to facilitate rapid head cooling, and that the protective effects of hypothermia may be greater in larger infants. A meta-analysis of the results from eight randomized controlled trials (n 638) also concluded that therapeutic hypothermia was benecial to term newborns with HIE ( Jacobs et al., 2007). For that study, the investigators searched the Oxford Database of Perinatal Trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), MEDLINE (1966 to June 2007), and previous reviews, cross-references, abstracts, conferences, symposia proceedings, and expert informants, to identify all existing prospective randomized, normothermia-controlled, trials in infants with clear evidence of moderate=severe HIE and of intrapartum asphyxia. Their analysis found that treatment with hypothermia led to a statistically signicant and

457 clinically important reduction in the combined outcome of mortality or major neurodevelopmental disability up to 18 months of age, with typical RRs of 0.76 (95% CI, 0.650.89). Cooling also resulted in statistically signicant reductions in mortality, with typical RRs of 0.74 (95% CI, 0.580.94), and in neurodevelopmental disability in survivors (typical RRs 0.68; 95% CI, 0.510.92). The most common adverse effects of hypothermia were an increase in the need for inotrope support and a signicant increase in thrombocytopenia. The authors noted that their analysis was based on less than half of all infants currently known to be enrolled in hypothermia trials for HIE. Data regarding 829 subjects from ongoing and recently completed randomized trials were not available at the time of their publication. They suggested that analysis of some of those trials may help dene optimal methods of cooling, such as whole body vs. selective head cooling. Two other meta-analyses were published in 2007, albeit of smaller numbers, and also concluded that therapeutic hypothermia used for 4872 h immediately after birth was associated with improved outcomes (Schulzke et al., 2007; Shah et al., 2007). Based on the overwhelming positive results of these clinical trials, the Executive Summary of a recent National Institute of Child Health and Human Development Workshop concluded that hypothermia was a potentially promising therapy for newborn HIE (Higgins et al., 2006). And while there remains some controversy about recommending therapeutic hypothermia as a Level I or II Treatment Guideline (Edwards and Azzopardi, 2006), a neurology workgroup on HIE recently concluded that the optimal framework for future clinical trials for this disease will compare patients treated with hypothermia to those treated with hypothermia plus a novel therapy, suggesting that we are nearing a point where hypothermia should be considered part of the current standard of care (Perlman, 2006). If the ongoing clinical trials of this therapy conrm the ndings of the studies already published, it would seem very likely that therapeutic hypothermia treatment guidelines for HIE will be forthcoming in the next 23 years. Traumatic Brain Injury Several of the earliest reports of the use of therapeutic hypothermia were in patients with severe TBI. Investigations by Lundberg and others during the 1950s and 1960s made it clear that a common and often lethal problem associated with severe TBI was brain swelling and intracranial hypertension (Lundberg et al., 1965). Clinicians reasoned that, if they could control the elevated ICP, they might be able to improve outcomes. Some of the early reports did nd that hypothermia was effective in reducing ICP, and that hypothermia treatment was associated with better than expected outcomes (Fay, 1959; Sedzimir, 1959). But subsequent prospective randomized clinical trials have not yielded consistent ndings about the effects of therapeutic hypothermia in TBI. This is primarily because there have been contradictory ndings among several large clinical trials. Prospective clinical trials conducted at single institutions have generally found a benet from hypothermia treatment, but two large multicenter trials did not (Clifton et al., 2001; Shiozaki et al., 2001) (Table 1). There has been much debate about the reasons for the inconsistency of the clinical trial results (Safar and Kochanek, 2002). Most agree that it is difcult to keep all of the metabolic and physiologic variables that could inuence outcomes

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MARION AND BULLOCK Table 1. Clinical Trials of Therapeutic Moderate Hypothermia for Patients with Severe Traumatic Brain Injury Depth=duration of cooling 348C=48 h 32338C=48 h 32338C=24 h 33358C=314 days 348C=48 h 338C=48 h 348C=72 h 32358C=17 days 33358C=35 days 33358C=4 days Good outcome Follow-Up 6 months 3 months 6 months 1 year 3 months 6 months 6 months 6 months 2 years 1 year Hypothermia 38% 52% 56% 46.5% 46% 43% 87% 62% 65% 70% Normothermia 6% 36% 33% 27% 59% 43% 47% 38% 37% 48% p-value >0.05 >0.29 0.05 <0.05 >0.99 0.99 0.08 <0.05 <0.05 <0.05

Reference Shiozaki et al., 1993 Clifton et al., 1993 Marion et al., 1993 Jiang et al., 2000 Shiozaki et al., 2001 Clifton et al., 2001 Gal et al., 2002 Zhi et al., 2003 Qiu et al., 2005 Qiu et al., 2007

Setting Single hospital Single hospital Single hospital Single hospital 11 hospitals 11 hospitals Single hospital Single hospital Single hospital Single hospital (unilateral crani.)

N 33 46 82 87 91 392 30 396 86 80

constant across centers in multicenter trials. In some cases, this can even be challenging within a center when a large number of critical care intensivists are responsible for a study patient. Indeed, a careful analysis of the acute care provided to patients enrolled in the Clifton multicenter trial revealed that there were signicant intercenter differences in the proportion of patients below the critical MAP threshold of 70 mm Hg (range, 2993%), with the greatest intercenter variability occurring in the hypothermia group ( p < 0.001) (Clifton et al., 2001), There also were signicant intercenter differences in the proportion of patients who were dehydrated ( p < 0.001) and who had a CPP less than 50 mm Hg (3253%; p < 0.05). Moreover, there were signicant intercenter differences in the doses of narcotics used ( p < 0.001) and in the use of vasopressor agents ( p < 0.03). The two centers that had Phase I=II experience with the treatment had better outcomes with hypothermia treatment than did the other centers. Virtually all clinical trials that have reported the effect of hypothermia on ICP have found that the treatment helps to reduce elevated ICP (Table 2). In some studies, this effect is diluted when the ICP measurements obtained for several days

after the hypothermia patient is rewarmed are averaged with the data obtained during the actual cooling, in part because some patients have a rebound increase in ICP associated with rewarming. The results of these studies emphasize that, if hypothermia is used to manage intracranial hypertension, withdrawal of the therapy (rewarming) must be accomplished slowly and, ideally, over the course of 1224 h or more. But it also is apparent that ICP control is not a good surrogate for the efcacy of a treatment, since in several of the studies hypothermia resulted in a signicant reduction of ICP but no change in functional outcomes (Clifton et al., 2001; Gal et al., 2002). Despite the ongoing debate about the efcacy of hypothermia for the treatment of severe TBI, clinical trials of this therapy continue to be published, and at least four new clinical trials are ongoing. In 2007, Qiu and colleagues reported a prospective clinical trial in which 80 patients with a severe TBI who had undergone a unilateral craniotomy were randomly assigned to a normothermia group or a group cooled to 33 358C for 4 days (Qiu et al., 2007). At 1 year after the injury, 70% of the hypothermia patients, but only 48% of the normother-

Table 2. Effect of Hypothermia on Intracranial Pressure in Patients with Severe Traumatic Brain Injury Reference Shiozaki et al., 1993 Clifton et al., 1993 Metz et al., 1996 Marion et al., 1997 Nara et al., 1998 Tateishi et al., 1998 Clifton et al., 2001 Takahashi et al., 2000 Jiang et al., 2000 Biswas et al., 2002 Gal et al., 2002 Tokutomi et al., 2003 Zhi et al., 2003 Qiu et al., 2005 Qiu et al., 2007 PRCT Y Y N Y N N Y N Y Y Y N Y Y Y No. of patients 33 46 10 82 23 9 392 9a 87 21a 30 31 396 86 80 Length of cooling 48 h 48 h 25 h 24 h ? Max. of 6 days 48 h 321 days 314 days 48 h 72 h 4872 hours 17 days 35 days 4 days Results Decrease No change Decrease Decrease Decrease Decrease Decrease Decrease Decrease Decrease Decrease Decrease Decrease Decrease Decrease

a Pediatric patients. PRCT, prospective randomized controlled trial.

FUTURE OF THERAPEUTIC HYPOTHERMIA mia group, had achieved a favorable outcome ( p < 0.05). Adelson et al. (2005) completed a Phase I trial in 75 children with severe TBI that demonstrated safety and feasibility, and are now beginning a Phase III multicenter pediatric trial (ClinicalTrials.gov identier: NCT00222742). Clifton has begun a clinical trial focusing on adult patients, younger than 45 years old, with severe TBI (NABIS:HIIR; ClinicalTrials.gov identier: NCT00178711). In addition, a pediatric trial has been initiated in Australia and New Zealand (Hypothermia in Traumatic Brain Injury in Children [HiTBIC], sponsored by the Australia and New Zealand Intensive Care Society; ClinicalTrials.gov identier: NCT00282269), and an adult clinical trial in Japan (Therapeutic Hypothermia for Severe Traumatic Brain Injury in Japan, sponsored by Yamaguchi University Hospital and the Japan Clinical Research Support Unit; ClinicalTrials.gov identier: NCT00134472). In the most recent (3rd edition) of the Guidelines for the Management of Severe Traumatic Brain Injury, a new metaanalysis of hypothermia clinical TBI trials was reported (Brain Trauma Foundation et al., 2007). The analysis included 354 patients assigned to hypothermia groups and 340 patients assigned to normothermia groups from six clinical trials for which sufcient data was available (Clifton et al., 1993, 2001; Marion et al., 1997; Aibiki et al., 2000; Jiang et al., 2000; Qiu et al., 2005). In that analysis, the risk of mortality was not signicantly different between the hypothermia and normothermia groups (RR 0.76; 95% CI, 0.501.05), but hypothermia was associated with a 46% increased chance of good outcome (Glasgow Outcome Scale [GOS] score of 4 or 5; RR 1.46; 95% CI, 1.121.92). Based on this and all other available clinical data, the most appropriate current recommendations are that hypothermia not be considered a standard of care for patients with severe TBI, but that it be used, by clinicians experienced with its use, as one of several medical options for patients with refractory intracranial hypertension. Traumatic Spinal Cord Injury The efcacy of therapeutic hypothermia for spinal cord injury has been tested in preclinical studies nearly as long as it has been for TBI. The history of those investigations is nicely summarized by Inamasu and colleagues in a review article published in 2003 (Inamasu et al., 2003). Recent laboratory studies of spinal cord injury continue to demonstrate signicant histologic preservation (Yu et al., 2000; Shibuya et al., 2004) and improved functional outcomes associated with the use of therapeutic moderate hypothermia (Dimar et al., 2000; Tetik et al., 2002). Moreover, several clinical studies suggest that prophylactic spinal cord cooling may help prevent cord injury during surgery for repair of thoracoabdominal aneurysms (Downey, 2000; Tabayashi et al., 2002). As a result of the positive results from the animal studies, as well as the benets observed from the use of hypothermia for OHCA and neonatal HIE, several experts in the eld have suggested that clinical trials of hypothermia for traumatic spinal cord injury should be initiated (Bernard, 2004; Fehlings and Baptiste, 2005). To date, however, no clinical trials of hypothermia for spinal cord injury have been listed with ClinicalTrials.gov. In the fall of 2007, a professional football player suffered a cervical spine injury and was treated with hypothermia. This case received widespread national news media attention, particularly when the football player regained the ability to

459 walk. But the use of hypothermia in this instance was not based on any clinical trial results, and it prompted the Joint Section on Disorders of the Spine of the American Association of Neurological Surgeons, and Congress of Neurological Surgeons, to publish a formal statement that There is not enough evidence available to recommend for or against the practice of either local or systemic therapeutic hypothermia as a treatment for acute spinal cord injury(Resnick et al., 2007). Stroke The efcacy of therapeutic hypothermia for ischemic stroke has not yet been established by denitive prospective randomized clinical trials (Konstas et al., 2006; den Hertog et al., 2007). The Cool Aid Trial enrolled 40 patients with ischemic stroke presenting within 12 h of symptom onset in a Phase I=II study (De Georgia et al., 2004). Endovascular heat-exchange catheters were used to cool 18 patients to 338C for 24 h, and 22 patients were randomly assigned to a normothermia group. At 1 month after infarct, there was no difference in clinical outcomes, or in lesion growth as measured by diffusionweighted MRI, between the two groups. A Phase I clinical trial of hemicraniectomy with or without mild to moderate hypothermia has been completed, and shows that hypothermia can be safely used together with the radical surgical procedure, but the study was too small to establish any therapeutic benet (Els et al., 2006). In another multicenter study, 50 patients with complete middle cerebral artery infarcts were cooled to 338C for 2472 h to evaluate the safety and feasibility of cooling of patients with large strokes ( Jian et al., 2003). The most common complications attributed to hypothermia were thrombocytopenia, which was documented in 70%, bradycardia in 62%, and pneumonia in 48%. In addition, rebound intracranial hypertension was associated with rewarming in 30% of patients and was most commonly found with rewarming intervals of less than 16 h. Fifteen deaths, out of the 19 that occurred during acute care of these patients, were associated with excessive ICP rise during rewarming. The severity of the rebound brain swelling from rewarming appears to be unique for patients with large cerebral infarcts, though it has been observed to a lesser extent with TBI. Hepatic Encephalopathy It is estimated that 20% of patients with acute liver failure die from increased ICP while awaiting transplantation. Since hypothermia was found to reduce elevated ICP in many of the TBI studies, some began to use this therapy for comatose liver failure patients in an attempt to prevent ICP related brain injury while awaiting liver transplantation. In one study of 14 comatose patients with increased ICP unresponsive to standard medical therapy, core temperature was reduced to 32338C for 10118 h ( Jalan et al., 2004). On average, ICP was reduced from 36.5 to 16.3 mm Hg. Thirteen of these patients were then able to undergo successful orthotopic liver transplantation and had complete neurologic recovery. A mechanistic rationale for the use of therapeutic hypothermia in this setting has been described, and includes the potential for hypothermia to limit the delivery of ammonia to the brain (Vaquero et al., 2005). In 2007, the U.S. Acute Liver Failure Study Group published consensus recommendations that ICP be monitored for all patients with advanced hepatic encephalopathy who are awaiting orthotopic liver

460 transplantation (Stravitz et al., 2007). The Group also observed that the induction of moderate hypothermia appears to be promising as a bridge to orthotopic liver transplantation, but did not make specic recommendation for its use. Other Diseases of the Central Nervous System The potential for intraoperative hypothermia to protect against post-operative neurologic decits has been investigated in a variety of procedures considered at high risk for causing stroke or cerebral ischemia. Deep hypothermia has been shown to extend the time during which the brain can withstand hypoxia or anoxia, and it therefore is commonly used for procedures that involve circulatory arrest and cardiac bypass such as reconstructive procedures for cardiac anomalies, treatment of complex aneurysms of the cerebral vasculature, or aortic surgery, particularly ascending or arch (Gudbjartsson et al., 2003; Boti et al., 2005; Kunihara et al., 2005; Patel et al., 2006; Visconti et al., 2006; Fehrenbacher et al., 2007; Goldberg et al., 2007; Huang et al., 2007). Mild hypothermia also has been used to reduce the risk for neurologic injury during coronary artery stenting following myocardial infarction associated with ST segment elevation (Ly et al., 2005), though it was not found to be neuroprotective in one study of patients undergoing coronary artery bypass surgery (Boodhwani et al., 2007). In a study of 1001 patients undergoing surgical aneurysm clipping who were randomly assigned to intraoperative cooling to 338C, or to be kept at 36.58C during their surgery, there was no difference in neurologic outcome between the two groups as assessed with the GOS at 90 days after surgery (Todd et al., 2005). Techniques for Cooling Surface cooling The most common method for cooling patients treated with therapeutic hypothermia is with surface cooling devices, ice packs, or alcohol baths. Studies from the 1950s and earlier described placing ice packs in the groin and axilla, and keeping the room temperature low. More recently, cooling blankets, through which cold water is circulated in a closed circuit of tubing, have become widely available and routinely used for cooling patients in the ICU. A recent study of 18 patients with acute ischemic stroke found that the target temperature (328C) was reached in a mean of 3.2 h with cooling blankets and alcohol or ice baths, and successfully maintained at that temperature for 1272 h after intubation, sedation, and neuromuscular blockade (Abou-Chebl et al., 2004). Pharmacologic facilitation of cooling is critical, since shivering is a natural physiologic response to hypothermia and will prevent achievement of even mild hypothermia in most unanesthetized patients (Leslie et al., 2004). This typically includes systemic neuromuscular blockade with medications such as vecuronium or pancuronium, and sedation. In addition, at least one clinical trial suggests that surface cooling is most effective when the cooling pads are closely adherent to the skin, at least as compared with conventional, loosely adherent cooling blankets (Mayer et al., 2004). However, shivering is also signicantly more likely with the closely adherent surface cooling system. The Arctic Sun circulating uid adhesive pad is one such system, and was found to be more

MARION AND BULLOCK effective for rewarming patients after off-pump coronary artery bypass than conventional warming methods (Stanley et al., 2003). In most studies, however, ice-packs and conventional cooling blankets are relatively inefcient methods for cooling the patient, and are especially inefcient for large or obese patients. Moreover, surface cooling methods were associated with overshoot, or cooling below the lower limit target of 328C for 1 h or more, in 63% of 32 patients in one study (Merchant et al., 2006). In that study, 13% of the patients had temperatures below 308C and were thereby subjected to an increased risk of hypothermia induced cardiac arrhythmias. Endovascular cooling Intravascular heat-exchange catheters have been developed that can be used to rapidly and precisely reach target temperatures in awake, nonintubated patients with minimal patient discomfort or shivering (Kandzari et al., 2004; Guluma et al., 2006). In preclinical studies, these catheters were found to be safe and not associated with adverse effects on blood elements, blood vessel integrity, or cardiovascular function (Inderbitzen et al., 2002; Dae et al., 2003). The devices appear to be more effective for maintaining the target temperature than water-circulating blankets, water circulating gel-coated pads, cooling with rapid infusion of cold uids followed by cold packs, or air-circulating blankets (Keller et al., 2003; Hoedemaekers, 2007). Compared to surface cooling techniques and antipyretic medications, intravascular heatexchange cooling devices have been shown to signicantly reduce the fever burden, or time the systemic temperature is above 36.58C, acutely following TBI or subarachnoid hemorrhage (SAH) (Diringer, 2004; Hinz et al., 2007), and to be more effective for reaching the target temperature when using therapeutic hypothermia (Feuchtl, 2007). In a retrospective study of therapeutic hypothermia for cardiac arrest, target temperature to 338C was reached at a mean of 3.48 h in all 31 patients cooled using a heat-exchange device, whereas it took 9.2 h to reach a mean minimum temperature of 34.88C in 49 patients cooled using cooling blankets (Flemming, 2006). In a prospective randomized study of anesthetized patients undergoing cranial surgery, endovascular heat-exchange catheters allowed patients to be cooled much faster (4.778C=h) than surface cooling techniques (0.878C=h) (Steinberg et al., 2004). Induction of hypothermia with cold intravenous infusions The induction of hypothermia with cold-uid intravenous infusion, with or without cooling blankets or endovascular cooling devices for sustained cooling, is safe, efcacious, and quick (Kim et al., 2005; Kliegel et al., 2005; Polderman et al., 2005). In one study of 134 patients with postanoxic encephalopathy, SAH, and TBI, infusion of 2.3 L of cold solution over 50 min resulted in a decrease in systemic temperature from 36.98C to 32.98C in 60 min (Polderman et al., 2005). There were no adverse effects on blood pressure, heart rhythm, central venous pressure (CVP), blood gasses, electrolyte and glucose levels, or the platelet or white blood count. Intravenous infusion of cold crystalloid solutions also has been shown to effectively induce hypothermia in the eld after OHCA

FUTURE OF THERAPEUTIC HYPOTHERMIA (Kim et al., 2007; Kliegel et al., 2007), and in TBI patients, this technique has been shown to quickly reduce body temperature when fever is refractory to conventional treatment (Badjatia et al., 2006). The cooling rates for intravenous infusions of a saline=ice slurry were compared to infusion of chilled saline in a swine study (Vanden Hoek et al., 2004). Both of the cold intravenous uids rapidly induced hypothermia, but the two-phase (liquid plus ice) saline slurry cooled more rapidly than an equal volume of cold saline at 08C (decrease of 5.38C vs. 3.48C in 1 h, respectively). Ice slurry could be a signicant improvement over other cooling methods when rate of cooling and limited infusion volumes are important considerations. However, its use is limited because the slurry is technically difcult to produce and must be produced at the point of use. Head cooling versus systemic cooling Since the brain is the intended target of therapeutic hypothermia, selective cranial cooling would be ideal. Theoretically, selective head cooling would avoid the side effects of systemic cooling, such as pneumonia or coagulation abnormalities. But in adults, the scalp and skull are effective insulators, and no study has ever found that surface cooling can consistently reduce deep brain temperatures. Moreover, the brain is well perfused by systemic blood, and this perfusion tends to resist changes in brain temperature caused by scalp cooling, as well as transmit any prolonged temperature changes to the rest of the body. In one study of patients with severe stroke or TBI who had invasive brain temperature monitoring, eigh patients were assigned to therapeutic hypothermia administered with a cooling helmet for 4872 h, and six control patients had conventional care without cooling (Wang et al., 2004). The mean change in temperature at 0.8 cm below the cortical surface was 1.68C in the cooled group and 0.228C in the control group. It took 3.4 h to achieve supercial brain temperatures lower than 348C, but by 6.67 h, there was systemic hypothermia with body temperatures below 368C. A signicant cranial=systemic temperature gradient was maintained throughout the period of cooling. Selective head cooling may be more appropriate for newborn infants than adults, because the scalp and skull are very thin in newborns, and there are large anterior and posterior fontanelles where the bony skull has not yet formed. In one study, selective head cooling was actually found to be more effective in reducing the incidence of severe cortical lesions following neonatal HIE than was whole body cooling (Rutherford et al., 2005). Head cooling also was found to be effective for reducing mortality and severe disability at 18 months for infants with neonatal encephalopathy in prospective randomized controlled clinical trials (Gluckman et al., 2005; Wyatt et al., 2007). In addition to scalp caps and other techniques for surface cooling of the head, some investigators have evaluated a technique for directing chilled air into the nasal cavity and found it to help maintain normal brain temperature in a group of brain-injured patients who had brain temperature monitors in place (Dohi et al., 2006). In a swine model, cold-saline perfusion of the epidural space through a exible doublelumen catheter also has been shown to be feasible and effec-

461 tive for reducing deep brain temperatures to as low as 278C within 5 min (Cheng et al., 2006). Optimal Target Temperature It is possible that just the prevention of fever, rather than hypothermia, is the reason for improved outcomes in many of the clinical trials of therapeutic hypothermia. While fever is a normal physiologic response to infection, inammation, and several other conditions, there are also signicant detrimental effects of fever in patients with ischemic brain injury and potential benets of normalizing body temperature (Axelrod and Diringer, 2006). In preclinical studies of induced brain hyperthermia following rodent cerebral ischemia, a 10-fold increase in cell death was associated with each 18C-increase above 398C (Morimoto et al., 1997). But fever is common in the Neurological Intensive Care Unit (neuro-ICU) and occurs in more than 90% of those in the ICU for 2 or more weeks (Kilpatrick et al., 2000). In addition, deep brain temperature often is higher than systemic temperature, at least after a severe TBI (Henker et al., 1998). Fever is particularly common and difcult to control following SAH, and there is an inverse relationship between fever and outcome in these patients (Badjatia et al., 2004; Fernandez et al., 2007). However, while this association is well dened, it is not clear if effective fever reduction will improve outcomes. Others have suggested that the optimal target temperature may be 34358C rather than 32338C. In their study of 22 patients with severe TBI, Shiozaki et al. (2003) found that, if intracranial hypertension could not be controlled with mild hypothermia (348C) and conventional treatment, reducing the temperature further was unlikely to be benecial. In 19 of the 22 patients, the ICP was not reduced by temperature reduction below 348C, and the remaining three patients died of multiple organ failure. These investigators observed that, as the temperature declined from 348C to 318C, there was a signicant increase in the use of intravenous uids and vasopressors (dopamine), and a signicant decrease in the blood pressure, heart rate, serum potassium levels, and white blood count compared to when the temperature was decreased from 378C to 348C. In their cohort of 31 patients with severe TBI, Tokutomi et al. (2003) also found that there was a signicant decrease in ICP as the temperature was reduced from 378 to 35368C, but for most of the patients, a further reduction of the temperature did not lower the ICP. In that cohort, the highest mean CPP was observed at temperatures of 3535.98C, and decreased with further decreases in temperature, suggesting that 3535.58C may be the optimal target temperature. Adverse Effects of Hypothermia Hypothermia has well-known physiologic effects on the heart and cardiac output, blood pressure, and intravascular volume. Electrocardiographic manifestations such as the presence of J (or Osborn) waves, prolonged PR, QRS, and QT intervals, and atrial arrhythmias are well known. However, most of these changes are only seen with body temperatures below 308C. Gebauer et al. (2006) found that mild to moderate hypothermia (32338C) reduced cardiac output by as much as 33% and stroke volume by 23%, though these changes were of no apparent clinical signicance. There also is some evidence that hypothermia may cause the cerebral vasculature to

462 be more spastic following TBI. In one study, four of ve TBI patients who had angiographically conrmed vasospasm had undergone hypothermic therapy for treatment of intracranial hypertension (Yanagawa et al., 2007). But all of these subjects also had Fisher Grade II SAH. Of greater concern, and particularly for trauma patients who may be a risk for intraabdominal or intracranial hemorrhage because of contused or lacerated tissues, is the effect of hypothermia on blood coagulation. Hypothermia has been associated with bleeding diathesis and decreased liver function (Aslam et al., 2006). While these complications were most likely found with temperatures below 308C, a meta-analysis of 14 studies found that perioperative mild to moderate hypothermia was associated with increased blood loss by approximately 16% (426%), and a relative risk for transfusion of approximately 22% (337%) (Rajagopalan et al., 2008). Some have even argued that the benecial effects of hypothermia may in part be due to inhibition of platelet aggregation, and thereby improved perfusion of damaged or ischemic tissues (Frelinger et al., 2003). But the effect of mild to moderate hypothermia on coagulation abnormalities is controversial. Kettner et al. (2003) carefully evaluated the effect of moderate hypothermia (328C) in 16 anesthetized elective intracranial surgery patients. During several hours of hypothermia, there was no change in the activated partial thromboplastin time (aPTT) or hematocrit, and only a small and clinically insignicant change in the prothrombin time (PT) and platelet count. It is important to note that blood tests for coagulation factors typically are done at 378C, and that the change in temperature from 328 to 378C is likely to affect test results (Watts et al., 1998). As a result, the in vivo bleeding time is considered by some to be one of the most reliable determinates of the coagulation status in hypothermic patients (Kheirabadi et al., 2007). Hemorrhage and coagulation abnormalities are problems frequently encountered even in normothermic patients with hemorrhagic stroke or trauma, and the administration of recombinant factor VIIa has recently been found to help in achieving hemostasis or limiting the hemorrhage in those patients (Rizoli et al., 2006; Mayer, 2007; Sachs et al., 2007). Concerns have been raised about how hypothermia might affect the activity of this drug. In an ex vivo study, Kheirabadi et al. (2007) evaluated the effect of factor VIIa on blood samples from eight healthy adults that were incubated with the factor VIIa at various temperatures from 378 to 288C for 30 min. Mild to moderate hypothermia to 328C delayed the initial clot reaction and reduced clot formation rate without affecting ultimate clot strength, and their study found that administration of factor VIIa should be benecial in enhancing hemostasis in hypothermic patients without the need for prior correction of the patients body temperature. Others also have found that, in the absence of acidosis, recombinant factor VIIa should be effective in enhancing hemostasis in hypothermic (338C) patients (Meng et al., 2003). Hypothermia has systemic effects that have implications for the acute medical management of the cooled patient. Cooling suppresses the inammatory response and leaves the patient at greater risk for infections, particularly with prolonged cooling for several days or more. Hypothermia also decreases the systemic clearance of cytochrome P450 metabolized drugs between approximately 7% and 22% per 1-8C below 378C (Tortorici et al., 2007). In addition, hypothermia

MARION AND BULLOCK decreases the potency and efcacy of certain drugs. Thus, the therapeutic index of drugs is narrowed during hypothermia. A 28C reduction of body temperature can double the duration of pharmacologic neuromuscular blockade (Heier and Caldwell, 2006). Further research is essential to delineate precise dosing guidelines and mechanisms of the effect of hypothermia on drug disposition and response for many of the drugs currently used for resuscitation and acute care of these patients. In addition, cooling to 338C also has been associated with a signicant prolongation of the latencies of all waves of both somatosensory-evoked potentials and brainstem auditory evoked potentials, so the clinical interpretation of these studies must be modied to account for temperature (Tiainen et al., 2005). Conclusion Therapeutic mild to moderate hypothermia has been evaluated in numerous clinical trials for several different neurologic diseases, and much has been learned about its efcacy and safety. To date, there is strong support for the use of hypothermia to treat patients with OHCA, particularly if their initial resuscitation rhythm is ventricular brillation. For neonates with HIE, eight randomized controlled clinical trials that enrolled 638 infants also concluded that therapeutic hypothermia improves outcomes for at least 18 months after birth. The clinical data supporting the use of hypothermia for severe TBI remains controversial, though the most recent edition of the Guidelines for the Management of Traumatic Brain Injury found a signicantly greater likelihood of a good outcomes for patients treated with hypothermia. And with few exceptions, most studies have found that cooling helps reduce otherwise refractory ICP. Further studies are needed to determine the potential benet of hypothermia for stroke, hepatic encephalopathy, or spinal cord injuries. The technology for intravascular cooling is rapidly evolving, and this cooling method currently appears to be superior to surface cooling techniques for achieving and maintaining the target temperature. Rapid intravenous infusions of cold crystalloid solutions also can help reach the target temperature quickly. The optimal target temperature is not clear, however, and some of the studies of brain tissue pO2 and cerebral perfusion pressure suggest it may not be lower than 348C. Alternatively, important benets may be due to the prevention of fever alone. Cooling to 32338C for 2 days or more is generally safe and not associated with clinically signicant adverse effects. A decrease in cardiac output and serum potassium levels is common and usually well tolerated. Most studies do not nd an increase in bleeding or hemorrhagic complications. Infections are more likely with hypothermia but generally are treatable and are most common with cooling for more than 48 h. References
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