Chapter 8: Controversies in Therapeutic Hypothermia

Induced TH is currently used in several medical conditions. However, it is by far more commonly employed in today's clinical practice to prevent or diminish hypoxic-ischemic encephalopathy (HIE) and its deleterious outcomes in postcardiac arrest patients.

HIE is a syndrome of acute global brain injury resulting from critical reduction or loss of blood flow and supply of oxygen and nutrients. Some of the terms used to describe this clinical syndrome include anoxic encephalopathy, postcardiac arrest brain injury, and other terms denoting a diminution of blood or oxygen to the whole brain. The pathologic injury to the brain results in cell injury and death from an intracellular energetic crisis that selectively affects vulnerable areas such as CA-1 of the hippocampus, caudate, putamen and neocortex, and relative sparing of brain stem. High-quality cardiopulmonary resuscitation (CPR) with prompt restoration of spontaneous circulation is crucial to survival. The mainstay of postresuscitation care is TH. ICU management also includes optimizing hemodynamic status, diagnosing and treating seizures, and other supportive care.

The most common cause of HIE is cardiac arrest, which is commonly secondary to cardiac etiologies (infarction or arrhythmia). Each year over half a million cardiac arrests occur in the United States. Approximately 380,000 of these occur outside of health care facilities, and another 210,000 occur in hospital every year.

Outcomes of Postanoxic Brain Injury After Cardiac Arrest

The outcome of patients experiencing SCA is poor. The primary cause of mortality after SCA is primarily related to the effects of anoxic brain injury and not necessarily from cardiac complications.

Outcomes differ based on initial rhythm found at scene of SCA. For example, outcomes are poorer with so-called “nonshockable” rhythms (asystole, pulseless electrical activity [PEA]) compared to “shockable” rhythms (ventricular tachycardia [VT] or ventricular fibrillation [VF]). Improved survival may be best when initial rhythm is VF, but still dependent on prompt delivery of effective CPR. Clinical factors identified as predictors of greater likelihood of survival to hospital discharge are witnessed arrest, VT or VF as initial rhythm, return to spontaneous circulation (ROSC) during first 10 minutes, and longer duration of overall resuscitation efforts.¹

The Controversies

Since the development of modern CPR techniques in the 1950s, numerous pharmacologic trials with putative neuroprotective effects have failed to improve survival and quality of life of patients resuscitated from cardiac arrest. Mild TH has become a standard component of postcardiac arrest to prevent or mitigate various types of neurologic injury. The ultimate goal of resuscitation is to improve survival with good neurologic outcome. The evidence supporting this practice came from two randomized trials published consecutively in 2002—one small-sized Australian study done by Bernard et al that showed good neurologic outcome in 49% survivors in the hypothermia to 33°C group versus 26% of normothermic patients, among 77 patients with out-of-hospital cardiac arrest due to VT.² The other, a medium-sized randomized controlled multicenter trial was done in 9 European centers by the Hypothermia After Cardiac Arrest (HACA) group wherein among 273 patients with out-of-hospital arrest due to shockable initial rhythms (VF or VT), hypothermia to 34°C led to improved neurologic outcome 55% versus 39% with usual care.³

TH (also called targeted temperature management) had demonstrated a robust benefit with a number needed to treat (NNT) of 6. While these 2 landmark studies focused on out-of-hospital cardiac arrest with VT/VF as initial rhythms, subsequent studies showed likely survival and quality-of-life benefits for victims of cardiac arrest with initial rhythms of asystole or PEA with hypothermia (TH).⁴ While no prospective randomized controlled trial has been undertaken to show the benefit of TH in patients with PEA and asystole,^5,6,7,8 existing studies have also shown that TH is not harmful either. Current recommendations strongly favor cooling all comatose cardiac arrest victims regardless of presenting ECG rhythm in accordance to the International Liaison Committee on Resuscitation (ILCOR) guidelines (American Heart Association [AHA] class I recommendation for out-of-hospital arrest with VT/VF as the initial rhythm, and IIB for those with PEA and asystole as initial rhythm), and the European Resuscitation Council.⁹

This approach was recommended despite arguments by some investigators that the evidence was weak, owing to the risk of bias and small samples.^10,11 Furthermore, its use has been extended to cardiac arrest of other causes and with other presenting rhythms as well as to the in-hospital setting.¹² Although a Cochrane review supports these guidelines,¹³ some investigators have suggested a need for additional trials to confirm or refute the current treatment strategy.^14,15,16 In addition, one trial showed that fever developed in many patients in the standard treatment group.¹⁷ It is therefore unclear whether the reported treatment effect was due to hypothermia or to the prevention of fever, which is associated with a poor outcome.^18,19,20

The subsequent debate has focused on 2 issues. The first issue is whether TH should be extended to patients outside the originally described populations.^21,22,23 It may be reasoned that the potential benefits of temperature management on brain injury due to circulatory arrest would be the same irrespective of the cause of arrest. However, whole body hypothermia influences all organ systems and any potential benefit should be balanced against possible side effects.²⁴ The population of patients with cardiac arrest is heterogeneous, and the potential risks and benefits of temperature intervention may not be the same across subgroups. The second issue is the most beneficial target temperature for therapeutic hypothermia.²⁵ The recommended temperature of 32°C to 34°C has been extrapolated from experiments in animals^26,27; however, similar results have been observed with milder cooling.²⁸

Therapeutic Hypothermia in Nonshockable Cardiac Arrest

There are less robust recommendations with the use of mild TH in cardiac arrest with nonshockable initial rhythm (PEA or asystole). Only few studies have been published to evaluate the potential benefit of therapeutic hypothermia in comatose subjects presenting with nonshockable initial rhythm with conflicting results. The meta-analysis of studies by Kim et al done before 2010 using mild therapeutic hypothermia in survivors of nonshockable cardiac arrest found that TH is associated with reduced in-hospital mortality but no significant neurologic benefit.²⁹ Three retrospective analyses of out-of-hospital nonshockable cardiac arrest found possible improvement of neurologic outcomes using TH.^30,31,32 A large cohort study by Dumas et al found no benefit for therapeutic hypothermia in nonshockable cardiac arrest.³³

It is not clear whether other factors influence the outcome in nonshockable cardiac arrest. It would be logical to think that neurologic injury whether shockable or nonshockable cardiac arrest could have the same mechanism. Adult patients with PEA or asystole cardiac arrest are usually sicker, with ongoing hypoxemia and circulatory shock that often result in bradycardia or hypotension before progressing to pulseless cardiac arrest.³⁴ Additional brain insult may have been incurred during prearrest asphyxia and circulatory shock.

Cooling and Rewarming

The optimal time to initiate TH, the optimal method of cooling, the optimal rate of induction, level and duration of hypothermia, and the optimal rate of rewarming are still unknown. In animal models of cardiac arrest, the benefit of hypothermia declines when it is started more than 15 minutes after Reperfusion.³⁵ Bernard et al^36,37 hypothesized that early initiation of cooling in the field after ROSC would improve both survival and neurologic outcome. Rapid cooling after resuscitation from cardiac arrest with an intravenous infusion of cold saline appears feasible and safe.³⁸ Infusion of cold intravenous fluid is an attractive strategy to achieve early cooling because of its portability, ease in administration, and potential widespread availability in the prehospital setting. However, no benefit was observed among 234 patients resuscitated from prehospital VF and then randomized to early field cooling.³⁹

This large randomized trial⁴⁰ found that prehospital, rapid infusion of up to 2 L of 4°C normal saline did induce mild hypothermia faster than standard care but did not improve survival or neurologic status at discharge after resuscitation from prehospital shockable (VF) or nonshockable (without VF) cardiac arrest. The resuscitation and intervention were performed by paramedics from emergency medical service (EMS) agencies with a high overall rate of resuscitation. The intervention reduced core body temperature by hospital arrival, and patients reached the goal temperature about 1 hour sooner than in the control group. The intervention was associated with significantly increased incidence of rearrest during transport, time in the prehospital setting, pulmonary edema, and early diuretic use in the emergency department (ED). Mortality in the out-of-hospital setting or ED and hospital length of stay did not differ significantly between the treatment groups.

Clinical evidence in humans undergoing intra-arrest therapeutic hypothermia (IATH) is limited, but has been shown to be both safe and feasible, and in one study it showed improvements in ROSC, survival to hospital discharge, and neurologic outcomes.^41,42,43

In the pivotal clinical trials,^2,3 therapeutic hypothermia was achieved with use of noninvasive surface cooling methods by application of ice packs in the Australian trial and with the use cold air mattress covering the entire body in the European trial. Other studies made use of invasive core cooling via intravascular catheters, ice-cold fluid infusion, peritoneal lavage, and use of extracorporeal circulation. Each method has their advantages and disadvantages. It is important however that the chosen method could rapidly induce cooling as well as maintain the target temperature within a narrow range.

Temperature Modulation

After maintaining a TH of 32°C to 34°C for 24 hours, active, controlled rewarming at a rate of 0.25°C to 0.5°C per hour is recommended until a core temperature of 36°C to 37°C is achieved. Upon rewarming, the therapeutic temperature management system should remain in place for a further 48 to 72 hours to ensure normothermia, protecting the brain from the detrimental effects of hyperthermia. Rebound pyrexia is a common phenomenon occurring in about 40% of patients posttherapeutic hypothermia. Only temperatures greater than 38.7°C appear to be associated with worse neurologic outcomes in patients who survive to discharge.⁴⁴ The mechanism for this common presentation of fever after therapeutic hypothermia is not well understood, however several factors are thought to contribute to its presence: altered thermoregulation from damage to thalamic structures, rebound hyperthermia, infection, and proinflammatory states all are likely contributors.

Shivering

Another important consideration when treating with hypothermia is the management and prevention of shivering. Shivering is a centrally mediated thermoregulatory response that normally sets in at 35.5°C, and is usually overcome below 34°C. However, these reference temperatures apply to healthy individuals, and may not be the same in all cardiac arrest patients. The absence of shivering after induction of hypothermia, or spontaneous hypothermia prior to induction of hypothermia has been associated with worse outcomes⁴⁵; it is possible that damage to the hypothalamus impairing thermoregulation may be a marker for more severe injury. On the other hand, the presence of shivering is known to increase body temperature which has been shown to worsen brain injury and negatively impact outcome.⁴⁴

Does It Really Work?

To make things more uncertain, in the largest randomized trial yet published in 2013, Nielsen et al probe further whether TH is effective in cardiac arrest with and without shockable rhythms, if fever is also prevented as standard of care. This study included 939 patients after out-of-hospital cardiac arrest of presumed cardiac cause between 2010 and 2013 in 36 centers in Europe and Australia, regardless of the initial rhythm (80% had a shockable initial rhythm, 12% had asystole, and 8% had PEA). They were randomized to receive targeted temperature management using any cooling method to either 33°C or a near-normal temperature of 36°C, induced as soon as possible, for 28 hours, followed by rewarming, followed by fever-reduction methods for 72 hours postarrest. This trial showed that hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C regardless of initial rhythm. There were no differences between groups in the rate of death (50% with hypothermia, 48% without), or in the composite outcome of poor neurologic outcome or death after 6 months (risk ratios were almost exactly 1). When the analysis was restricted only to the 80% of subjects with shockable cardiac arrest, there was still no benefit from TH: The relative risk for death among the cooled patients was 1.06.

The investigators did not find any harm with a targeted temperature of 33°C as compared with 36°C. However, it is worth recognizing that for all outcomes, none of the point estimates were in the direction of a benefit for the 33°C group. On the basis of these results, decisions about which temperature to target after out-of-hospital cardiac arrest require careful consideration.

There are multiple possible explanations for the absence of benefit from lower temperatures in patients with cardiac arrest.⁴⁶ The population was less select than in previous trials, including patients with shockable rhythms and those with nonshockable rhythms. There has been evolution of intensive care over the past decade, and improvements in patient care may have reduced the potential incremental benefits of a single intervention. In addition, illness severity varies greatly among patients with cardiac arrest, and there may be subgroups of patients who do benefit from induced hypothermia but who were not designated in advance. Particularly if the degree or duration of hypothermia must be adjusted to match the severity of brain injury, the benefits to a subgroup may be missed in a trial of one regimen of hypothermia for all comers.

One interpretation of these results is that they reinforce the importance of controlling temperature, even while they question whether 33°C is the best temperature. For example, many patients in the “normothermia” group of the older trials actually became hyperthermic,^47,48 which is deleterious.^49,50 The exceptional rates of good outcomes in both the 33°C and 36°C groups in the present trial may reflect the active prevention of hyperthermia.

Further investigation is needed to address and define the population of cardiac arrest patients for whom the costly and intensive method of therapeutic hypothermia should be applied to or withheld.

Other Applications

Hypothermia is utilized in the management of severe traumatic brain injury (TBI) to lower cerebral metabolic rate of oxygen (CMRO₂) despite the lack of unequivocal evidence supporting its use. Most single-center studies suggest that induced hypothermia is associated with improved outcome. However, 2 large randomized multicenter studies in adults with severe TBI (National Acute Brain Injury Study: Hypothermia I and II) failed to show benefit,^51,52 and a randomized study of hypothermia in children with TBI suggested harm.⁵³ While mild-to-moderate hypothermia has not been shown to improve outcome, the preponderance of literature suggests it is effective in lowering intracranial pressure (ICP).

In laboratory investigations of traumatic spinal cord injury, no treatment appears as promising as therapeutic hypothermia. The current issue remains translating this putative success into an approved human clinical therapy. The issue began to receive copious public interest after the case of football player whose recovery was widely credited to TH. He was said to be complete (ASIA A) below the clavicles. Of note, he received methylprednisolone infusion in the ambulance as well as IV chilled saline and ice packs to the groin. In the ED, he was hemodynamically stable with a temperature of 36°C. His C3-C4 facet dislocation was operatively reduced about 3 hours after injury. The following day, he was cooled for several days at 33°C, recovering strength about 15 hours postinjury.⁵⁴ Was this the effect of hypothermia, or of the combination of steroids and early open reduction with adjunctive hypothermia? Such is the potential confounding where steroids and other aspects of care have varied in the setting of varied hypothermia protocols. For now, the use of TH after spinal cord injury (SCI) is considered experimental.

A recently published multicenter randomized controlled clinical trial⁵⁵ by Mourvillier et al showed that moderate hypothermia did not improve outcome in patients with severe bacterial meningitis and may even be harmful. After inclusion of 98 comatose patients, the trial was stopped early at the request of the DSMB because of concerns over excess mortality in the hypothermia group (25 of 49 patients [51%]) versus the control group (15 of 49 patients [31%]; relative risk [RR], 1.99; 95% confidence interval [CI], 1.05-3.77; P = 0.04).

The use of therapeutic hypothermia poses some potential risks, and some considerations need to be noted for its possible adverse effects. The clinical trials showed nonsignificant occurrence of adverse events between TH and control groups. Nonetheless, the more common adverse conditions to be vigilant for include pneumonia, sepsis, bleeding, electrolyte abnormalities, cardiac arrhythmias, and dysglycemia.⁵⁶ Establishing treatment protocols of care for induction and maintenance of hypothermia and rewarming, as well as tracking and correction of potential adverse events have enhance the delivery of care and contributed to the success of the TH.