Hypothermia for neuroprotection after cardiac arrest: Mechanisms, clinical trials and patient care

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Abstract

Therapeutic hypothermia is a proven part of cardio-cerebral resuscitation after cardiac arrest as it improves neurologic outcomes after hypoxic brain injury. This article reviews the mechanisms of hypothermic neuroprotection, the clinical trials that support its use after cardiac arrest, as well as the impact of hypothermia on patient management and prognosis. In caring for patients suffering hypoxic brain injury after cardiac arrest, the role of the neurologist is no longer limited to prognosis but is now to become actively involved in clinical management which includes the use of therapeutic hypothermia.

Introduction

Cardiovascular disease has remained the number one cause of death in this country for over 100 years, accounting for 1 of every 2.7 deaths [1]. A significant proportion of these deaths present as sudden cardiac arrest [2]. With the advent of Basic and Advanced Life Support training, many more of these cardiac arrest victims are resuscitated and admitted to intensive care units [3]. However, the loss of cerebral perfusion associated with cardiac arrest frequently leads to anoxic brain injury, or ‘post-resuscitation encephalopathy’ [4] and in the vast majority of patients is associated with a grim prognosis [5], [6]. Traditionally, predominance of poor outcome in post-resuscitation patients and the lack of effective therapies for brain injury have led the neurologist to focus on prognostication of functional outcome in these patients. While the classic work by Levy and colleagues in the 1980s [5], [7] provided the basis for prognosis in patients with anoxic brain injury, several subsequent clinical trials provide a much wider substrate to understand recovery, and improve not only the ability to prognosticate but to better define clinical trials in this area. A new emphasis on neuroprotection has led to a paradigm shift toward cardio-cerebral resuscitation [8], which places additional focus on maintaining cerebral perfusion. However, recent data regarding neurologic outcomes after cardiac arrest remains distressing with a neurologically intact survival rate of only 1.4% [9].

After many years of experimental work, two landmark studies recently published provided scientific evidence that hypothermia after out-of-hospital cardiac arrest can have a substantial impact on these dismal survival rates and functional outcomes [10], [11]. The Hypothermia After Cardiac Arrest (HACA) study group showed significant improvement in functional outcome from 39% to 55% with hypothermia [11], and Bernard et al. [10] similarly found an improvement from 26% to 49%. These studies have provided hope for improving outcomes in the multitude of people who suffer from post-resuscitation encephalopathy each year, and have created much interest in induced hypothermia. In fact, the American Heart Association and the International Liaison Committee on Resuscitation (ILCOR) acknowledged the effectiveness of this therapy and recommend that appropriate comatose survivors of cardiac arrest be treated with hypothermia [12], [13]. The advisory statement supporting the use of therapeutic hypothermia by the Advanced Life Support Task Group of ILCOR is supported by the following organizations: Resuscitation Council of South Africa, American Heart Association, European Resuscitation Council, Australian and New Zealand Council on Resuscitation, Japanese Resuscitation Council, Latin American Resuscitation Council and the Heart and Stroke Foundation of Canada.

Based on these recommendations, the use of therapeutic hypothermia has been incorporated in the resuscitation practices in many medical institutions across the United States and the world. In these institutions, consultation and joint management with practicing neurologists is frequently requested for these comatose patients. It is becoming evident that the involvement of the neurologist in the care of these patients is extending beyond prognostication to actual neuroprotective strategies, which at this time focuses on therapeutic hypothermia. This article provides pertinent updates for the neurologist, including the mechanisms of injury and its amelioration by hypothermia, clinical trials, complications of hypothermia, and how hypothermia may impact the role of the neurologist in the care of these patients.

Section snippets

Pathophysiology

The interruption of cerebral blood flow during cardiac arrest causes brain injury at two distinct time points: ischemia and subsequent reperfusion. Phenomenologically, there are three different modes of cell death caused by each phase [14]. Cellular necrosis occurs during ischemia itself, and results in immediate cellular death via membrane breakdown [15]. Delayed neuronal cell death may be caused by events occurring during reperfusion, and are manifest as either apoptosis or autophagocytosis

Clinical trials

The annual rate of out-of-hospital cardiac arrest in the United States is approximately 0.55 per 1000 [52]. Based on the U.S. population, this corresponds to over 163,000 events annually [1]. Of these victims, 77% can expect a poor outcome – either severe neurologic disability or death – at 6 months [6]. Hypothermia has proven to be the only intervention to date that may have a substantial impact on these outcomes. Two clinical studies showed significant neurologic benefits in cardiac arrest

Therapeutic hypothermia methods

The two major studies of hypothermia after cardiac arrest differed in the timing of both the initiation and duration of hypothermia. Therefore, we don't yet know the ideal timing of hypothermia after cardiac arrest, but it does seem logical that rapid initiation would improve outcomes. It is also recognized that more research is needed to determine the optimum target temperature, duration of hypothermia, and rates of cooling and rewarming. The HACA study rewarmed patients passively over 8 h

Adverse effects of hypothermia

Induced hypothermia affects all organ systems, and may potentially put patients at risk for adverse events. Physiologic effects of hypothermia on the cardiovascular system include bradycardia, increased systemic vascular resistance, and an altered EKG [10]. Additionally, hypothermia can interfere with electrolyte balances, including a shift of potassium ion to the intracellular compartment causing a transient hypokalemia, as well as hypophosphatemia [62]. Hypothermia may also cause

Impact on prognosis

Predicting outcomes for survivors of cardiac arrest has long been one of the most difficult tasks asked of the neurologist. In 1985, Levy et al. published a study on outcome prediction in hypoxic–ischemic coma. They found that pupillary reflex, eye opening, and motor response could be used to assess outcome after cardiac arrest. These findings helped define the prognostic methods for cardiac arrest patients not treated with hypothermia. Numerous studies on outcome after cardiac arrest have been

Summary

Hypothermia has a range of neuroprotective effects on the brain injury resulting from cardiac arrest. Two randomized clinical trials have shown that hypothermia improves neurologic outcomes in patients suffering cardiac arrest. The American Heart Association recommends that all adult patients who remain unconscious after cardiac arrest with ventricular fibrillation be cooled to 32 °C to 34 °C for 12 to 24 h [12]. Systemic hypothermia does have effects on nearly every organ system, but short

Acknowledgement

Dr. Geocadin was supported in part by NIH Grants R01-HL071568 and R21-NS42690.

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