Intensive Care Med 2004;30:757–769

Induced hypothermia can be used to protect the brain from post-ischemic and traumatic neurological injury. Potential clinical applications and the available evidence are discussed in a separate paper. This review focuses on the practical aspects of cooling and physiological changes induced by hypothermia, as well as the potential side effects that may develop. These side effects can be serious and, if not properly dealt with, may negate some or all of hypothermia’s potential benefits. However, many of these side effects can be prevented or modified by high-quality intensive care treatment, which should include careful monitoring of fluid balance, tight control of metabolic aspects such as glucose and electrolyte levels, prevention of infectious complications and various other interventions. The speed and duration of cooling and rate of rewarming are key factors in determining whether hypothermia will be effective; however, the risk of side effects also increases with longer duration. Realizing hypothermia’s full therapeutic potential will therefore require meticulous attention to the prevention and/or early treatment of side effects, as well as a basic knowledge and understanding of the underlying physiological and pathophysiological mechanisms. These and other, related issues are dealt with in this review.

Crit Care Med – published ahead of print

To evaluate whether implementation of a therapeutic hypothermia protocol on arrival in a community hospital improved survival and neurologic outcomes in patients initially found to have ventricular fibrillation, pulseless electrical activity, or asystole, and then successfully resuscitated from out-of-hospital cardiac arrest.

Design
A retrospective study of patients who presented after implementation of a therapeutic hypothermia protocol compared with those who presented before the protocol was implemented.

Setting
Harborview Medical Center, Seattle, WA.

Patients
A total of 491 consecutive adults with out-of-hospital, nontraumatic cardiac arrest who presented between January 1, 2000 and December 31, 2004.

Interventions
An active cooling therapeutic hypothermia protocol, using ice packs, cooling blankets, or cooling pads to achieve a temperature of 32^oC to 34^oC was initiated on November 18, 2002 for unconscious patients resuscitated from cardiac arrest.

Measurements and main results
Demographics and outcomes were obtained from medical records and an emergency medical database. The primary outcomes were survival and favorable neurologic outcome at discharge associated with the therapeutic hypothermia protocol. An adjusted analysis was performed, using a multivariate regression. During the therapeutic hypothermia period, 204 patients were brought to the emergency department; of these 204 patients, 132 (65%) ultimately achieved temperatures of <34^oC. Of the 72 patients who did not achieve goal temperatures: 40 (20%) died in the emergency department or shortly after being admitted to the hospital, 15 (7%) regained consciousness, four (2%) had contraindications, 13 (6%) had temperature increase or did not have documented use of the therapeutic hypothermia protocol. In the prior period, none of the 287 patients received active cooling. Patients admitted in the therapeutic hypothermia period had a mean esophageal temperature of 34.1^oC during the first 12 hrs compared with 35.2^oC in the pretherapeutic hypothermia period (p < 0.01). Survival to hospital discharge improved in the therapeutic hypothermia period in patients with an initial rhythm of ventricular fibrillation (odds ratio = 1.88, 95% confidence interval = 1.03-3.45), however not in patients with nonventricular fibrillation (odds ratio = 1.17, 95% confidence interval = 0.66-2.05). In adjusted analysis, ventricular fibrillation patients during the therapeutic hypothermia period trended toward improved survival (odds ratio = 1.71, 95% confidence interval = 0.85-3.46) and had favorable neurologic outcome (odds ratio = 2.62, 95% confidence interval = 1.1-6.27) compared with the earlier period. This benefit was not observed in patients whose initial rhythm was pulseless electrical activity or asystole.

Conclusions
The therapeutic hypothermia period was associated with a significant improvement in neurologic outcomes in patients whose initial rhythm was ventricular fibrillation, but not in patients with other rhythms.

Cochr Database of Systematic Reviews, 2009;4

Good neurologic outcome after cardiac arrest is hard to achieve. Interventions during the resuscitation phase and treatment within the first hours after the event are critical. Experimental evidence suggests that therapeutic hypothermia is beneficial, and a number of clinical studies on this subject have been published.

Crit Care Med 2009;37:403-409

To evaluate the effects of therapeutic hypothermia (HT) of 33°C after cardiac arrest (CA) on cardiac arrhythmias, heart rate variability (HRV), and their prognostic value.

Design
Prospective, comparative substudy of a randomized controlled trial of mild HT after out-of-hospital CA, the European Hypothermia After Cardiac Arrest study.

Setting
Intensive care unit of a tertiary referral hospital (Helsinki University Hospital).

Patients
Seventy consecutive adult patients resuscitated from out-of-hospital ventricular fibrillation were randomly assigned either to therapeutic HT of 33°C or normothermia.

Interventions
Patients randomized to HT were cooled with an external cooling device for 24 hours and then allowed to rewarm slowly during 12 hours. In the normothermia group, the core temperature was kept <38°C by antipyretics and physical means. All patients received standard intensive care for at least 2 days.

Measurements and main results
Twenty-four hour ambulatory electrocardiography recordings were performed at 0-24 hours, at 24-48 hours, and at 14 days. The clinical outcome was assessed at 6 months after CA. The occurrence of premature ventricular beats was increased in the HT-treated group during the first two recordings, with no difference in the number of ventricular tachycardia or ventricular fibrillation episodes. All HRV values were significantly higher during the HT (p < 0.01), but no differences were observed 2 weeks later. In multivariate analysis, only shorter delay to restoration of spontaneous circulation (p = 0.009) and the sd of individual normal-to-normal intervals >100 msec of the 24-48-hour recording in the HT group (p = 0.018) predicted good outcome.

Conclusions
The use of therapeutic HT of 33°C for 24 hours after CA was not associated with an increase in clinically significant arrhythmias. Preserved 24 to 48-hour HRV may be a predictor of favorable outcome in patients with CA treated with HT.

Critical Care 2006, 10:167

Pneumonia (hospital-acquired and community-acquired) is commonly encountered in intensive care. Several papers recently published on this subject have shed more light on different aspects of this important topic. Hypothermia has been shown to improve post-arrest outcome, but how often do we use it? And finally, several papers have recently appeared in the journals related to the admission of the elderly to the critical care area and their outcome.

Critical Care Medicine 2006;34:1865-1873

We sought to evaluate current physician use of therapeutic hypothermia after cardiac arrest, to ascertain reasons for nonadoption of this treatment, and to determine current cooling techniques employed.

Design
Web-based survey.

Setting
International physician cohort in the United States, UK, and Finland.

Subjects
Physicians (MD or DO) caring for resuscitated cardiac arrest patients.

Interventions
An anonymous Web-based survey was distributed to physicians identified through United States-based critical care, cardiology, and emergency medicine directories and critical care networks in the UK and Finland. Recipients were queried regarding use of postresuscitation therapeutic hypothermia.

Measurements and Main Results
Of the final 13,272 surveys actually distributed to physicians, 2,248 (17%) were completed. Most respondents were attending physicians (82%) at teaching hospitals (76%) who practiced critical care (35%), cardiology (20%), or emergency medicine (22%). Of all replies, 74% of United States respondents and 64% of non-United States respondents had never used therapeutic hypothermia. United States emergency medicine physician adoption of cooling was significantly less than that of United States intensivists (16% vs. 34%, p < .05). The most often cited reasons for nonuse by respondents were "not enough data," "not part of Advanced Cardiac Life Support guidelines," and "too technically difficult to use." Factors associated with increased use included non-United States residence, critical care specialty, and larger hospital size.

Conclusions
Physician utilization of cooling after cardiac arrest remains low. For improved adoption of therapeutic hypothermia, our data suggest that development of better cooling methodology and recent incorporation into resuscitation guidelines may improve use.

N Engl J Med 2002;346:557-63.

Background
Cardiac arrest outside the hospital is common and has a poor outcome. Studies in laboratory animals suggest that hypothermia induced shortly after the restoration of spontaneous circulation may improve neurologic outcome, but there have been no conclusive studies in humans. In a randomized, controlled trial, we compared the effects of moderate hypothermia and normothermia in patients who remained unconscious after resuscitation from out– of-hospital cardiac arrest.

Methods
The study subjects were 77 patients who were randomly assigned to treatment with hypothermia (with the core body temperature reduced to 33 deg C within 2 hours after the return of spontaneous circulation and maintained at that temperature for 12 hours) or normothermia. The primary outcome measure was survival to hospital discharge with sufficiently good neurologic function to be discharged to home or to a rehabilitation facility.

Results
The demographic characteristics of the patients were similar in the hypothermia and normothermia groups. Twenty-one of the 43 patients treated with hypothermia (49 percent) survived and had a good outcome – that is, they were discharged home or to a rehabilitation facility – as compared with 9 of the 34 treated with normothermia (26 percent, P=0.046). After adjustment for base-line differences in age and time from collapse to the return of spontaneous circulation, the odds ratio for a good outcome with hypothermia as compared with normothermia was 5.25 (95 percent confidence interval, 1.47 to 18.76; P=0.011). Hypothermia was associated with a lower cardiac index, higher systemic vascular resistance, and hyperglycemia. There was no difference in the frequency of adverse events.

Conclusions
Our preliminary observations suggest that treatment with moderate hypothermia appears to improve outcomes in patients with coma after resuscitation from out-of-hospital cardiac arrest.

N Engl J Med 2002;346:549-56

Background
Cardiac arrest with widespread cerebral ischemia frequently leads to severe neurologic impairment. We studied whether mild systemic hypothermia increases the rate of neurologic recovery after resuscitation from cardiac arrest due to ventricular fibrillation.

Methods
In this multicenter trial with blinded assessment of the outcome, patients who had been resuscitated after cardiac arrest due to ventricular fibrillation were randomly assigned to undergo therapeutic hypothermia (target temperature, 32 deg C to 34 deg C, measured in the bladder) over a period of 24 hours or to receive standard treatment with normothermia. The primary end point was a favorable neurologic outcome within six months after cardiac arrest; secondary end points were mortality within six months and the rate of complications within seven days.

Results
Seventy-five of the 136 patients in the hypothermia group for whom data were available (55 percent) had a favorable neurologic outcome (cerebral– performance category, 1 [good recovery] or 2 [moderate disability]), as compared with 54 of 137 (39 percent) in the normothermia group (risk ratio, 1.40; 95 percent confidence interval, 1.08 to 1.81). Mortality at six months was 41 percent in the hypothermia group (56 of 137 patients died), as compared with 55 percent in the normothermia group (76 of 138 patients; risk ratio, 0.74; 95 percent confidence interval, 0.58 to 0.95). The complication rate did not differ significantly between the two groups.

Conclusions
In patients who have been successfully resuscitated after cardiac arrest due to ventricular fibrillation, therapeutic mild hypothermia increased the rate of a favorable neurologic outcome and reduced mortality.

N Engl J Med 2002;346:546

For decades, cooling the body below the normal physiologic temperature has been used as a therapeutic tool. Hypothermia is used most often during cardiac surgery with cardiopulmonary bypass, as a means of protecting the brain from ischemic injury. Hypothermia is also used during some neurosurgical procedures and is being investigated as a treatment for ischemic stroke and traumatic brain injury. In this issue of the Journal, two groups of investigators report on the use of therapeutic hypothermia to prevent neurologic injury in comatose survivors of cardiac arrest.

More than 350,000 Americans die as a result of sudden cardiac arrest every year (approximately 1,000 people every day). About 10-30% of long-term survivors have permanent brain damage as a result of global brain ischemia. Recently, hypothermia has been shown to make a difference. In 2002, two randomized, controlled, clinical trials demonstrated significantly improved outcomes in patients treated with hypothermia (surface cooling) after cardiac arrest. Patients were cooled to 32-34°C for 12 to 24 hrs. Last year the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation (ILCOR) recommended cooling for unconscious patients after out-of-hospital cardiac arrest from ventricular fibrillation.

Crit Care Med 2004;32:897-899

The use of mild hypothermia for the treatment of neurologic injury after resuscitation from out-of-hospital cardiac arrest has now been endorsed by the International Liaison Committee on Resuscitation on the basis of supportive evidence from two prospective, randomized, controlled clinical trials. Patients who remain unconscious after resuscitation from cardiac arrest (where the initial cardiac rhythm is ventricular fibrillation) should now receive 12-24 hrs of hypothermia (33°C) as part of their routine care in the intensive care unit.