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AAN Practice Guideline
Evidence Supports Therapeutic Hypothermia for Pulseless Comatose Cardiac Arrest Patients after Successful CPR

ARTICLE IN BRIEF

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APPROXIMATELY 320,000 out-of-hospital cardiac arrests in the United States occurred in 2015, according to the American Heart Association, and post-resuscitation outcomes are very poor.

The study author of a new AAN practice guideline on managing brain injury after cardiac arrest said the strongest evidence suggests that medically-induced therapeutic hypothermia can protect the brain and improve survival for out-of-hospital nontraumatic cardiac arrest patients who are comatose after cardiopulmonary resuscitation and where their initial heart rhythm is either pulseless ventricular tachycardia or ventricular fibrillation.

Medically-induced hypothermia can protect the brain and improve survival for out-of-hospital nontraumatic cardiac arrest patients who are comatose after cardiopulmonary resuscitation and where their initial heart rhythm is either pulseless ventricular tachycardia or ventricular fibrillation, according to a new evidence-based guideline from the American Academy of Neurology.

The AAN Guideline Development Subcommittee reviewed 50 years of published studies and found high-quality evidence that emergency department or in-hospital therapeutic hypothermia (TH) and targeted temperature management (TTM) can be neuroprotective for cardiac arrest patients who remain comatose after CPR with return of spontaneous circulation after ventricular tachycardia (VT), ventricular fibrillation (VF), or pulseless electrical activity (PEA)/asystole,

The guideline appeared in the May 10 online issue of Neurology.

There were approximately 320,000 out-of-hospital cardiac arrests in the United States in 2015, according to the American Heart Association, and post-resuscitation outcomes are very poor. Survival rates after hospital discharge range from 6 percent to 9.6 percent for out-of-hospital cardiac arrest and 22.3 percent for in-hospital cardiac arrest, according to data from the Centers for Disease Control and Prevention, and brain damage is a major cause of mortality and disability.

Although the exact neuroprotective mechanisms are unclear, research suggests that core body cooling slows brain metabolism and excitation in brain cells, reduces damage from hypoxemia after reperfusion, stabilizes the blood-brain barrier, and curbs inflammation. Cerebral metabolism falls by 6 percent to 10 percent for each degree that body temperature falls.

Neurology Today asked panel chair Romergryko G. Geocadin, MD, FAAN, professor of neurology in the division of neurosciences critical care at Johns Hopkins University School of Medicine in Baltimore to discuss the panel's findings.

WHY WAS THE REVIEW CONDUCTED?

There is growing interest in acute neuroprotective interventions for patients in acute emergencies like sudden cardiac arrest. Many studies have found TH can improve outcomes in patients who continue to have a pulse (VT and VF), but it may also be beneficial for those without an initial pulse (pulseless electrical activity and asystole) and who remain comatose after successful CPR. We also wanted to review the evidence to discover whether any drugs or nonpharmaceutical techniques might help such patients.

WHAT WERE THE MAIN FINDINGS?

The highest quality of evidence in studies showed TH provided between 16 percent and 46 percent improvement in functional neurological outcomes and 14 percent improvement in six-month survival over normothermia in all but PEA/asystole patients, where functional outcomes were 6 percent better, and a 12 percent survival benefit over normothermia was observed.

The evidence supports hospital-initiated TH for comatose patients where initial cardiac rhythm is either pulseless VT or VF after out-of-hospital cardiac arrest, and we recommend 32-34 degrees Celsius for 24 hours. TH involves reducing core body temperature using various methods, including ice packs, cooling blankets or helmets, endovascular or internal cooling techniques.

WHAT ABOUT TARGETED TEMPERATIVE MANAGEMENT (TTM)?

TTM involves cooling to 36 degrees for 24 hours, followed by slow rewarming to 37 degrees over eight hours and maintainance of normothermia for 72 hours. We found that TTM is an acceptable alternative to TH, and the data also suggest that both can be potentially beneficial for patients with an initial rhythm of PEA/asystole. That said, studies with the highest level of evidence (Class I) showed TH to be highly effective in improving survival and neurological outcomes where initial cardiac rhythm is either pulseless VT or VF, and possibly for those who are comatose with an initial rhythm of PEA/asystole. In PEA/asystole patients, TTM may be an acceptable alternative, but differences in trial designs reduced the quality of this evidence.

WHAT SHOULD CLINICIANS KNOW ABOUT TTM?

Practitioners should know that 36 degrees is therapeutic, but only if actively maintained at that temperature. If the temperature rises to 37 degrees or higher, it is no longer effective, but many emergency physicians appear to be unaware that 36 degrees is an acceptable therapeutic target. As we move forward, perhaps using a combination of interventions will one day yield even better results.

DO ANY OTHER INTERVENTIONS HELP?

We looked at specific drugs and other techniques, and how they performed in head-to-head comparison trials against placebo. These studies assessed the use of xenon gas inhalation, nimodipine, lidoflazine, selenium, thiopental, magnesium plus diazepam, and corticosteroids. We found no evidence to make any recommendations on these drugs. While many of these have shown promise in animal studies, there was insufficient data to indicate that any of them might improve survival or neurologic outcomes. The same was true for non-pharmaceutical interventions like administering oxygen immediately after resuscitation or providing patients with high-volume hemofiltration. One pilot study showed some improvement in survival with coenzyme Q10, but no benefits for functional outcomes.

WERE THERE ANY UNEXPECTED FINDINGS?

That none of these agents yielded any benefits was unexpected, as was our finding that pre-hospital cooling is ineffective. Pre-hospital cooling is undertaken prior to the admission of the patient to the hospital. The hope of the investigators was that early intervention would provide additional benefit to patients. But we are not sure why studies on pre-hospital cooling did not show any benefit. We did not find an added benefit of pre-hospital cooling with infusion of chilled saline. Other pre-hospital cooling methods, while still preliminary, also did not provide added benefit to TH/TTM.

HOW CAN NEUROLOGISTS PLAY A BIGGER ROLE?

For many years, the focus of neurologists with patients after successful CPR has been on prognostication and withdrawal of life-sustaining therapies.This guideline encourages proactive involvement by neurologists by focusing on preventing brain injury and improving survival. Previous research has indicated that very little could be done to help such patients, but now we have concrete evidence that brain injury can be reduced or prevented.

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DR. ROMERGRYKO G. GEOCADIN: “This guideline encourages proactive involvement by neurologists by focusing on preventing brain injury and improving survival. Previous research has indicated that very little could be done to help such patients, but now we have concrete evidence that brain injury can be reduced or prevented.”

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SUMMARY: RESPONSE TO TH IN PATIENTS WITH VT/VF AS THE INITIAL CARDIAC RHYTHM AFTER RETURN OF SPONTANEOUS CIRCULATION

In emergency departments, neurologists' acute involvement typically centers on strokes, seizures, and traumatic brain injury, but not so much with cardiac arrest. This is what we hope to change with this guideline.

WHAT ARE THE MOST IMPORTANT RESEARCH NEEDS?

Among the many areas that require more research are studies on the role of TH for patients with PEA/asystole, as well as the best methods for inducing and maintaining TH, the ideal rate of cooling, the optimal target temperature range, and rewarming temperatures. So far, no method has established superiority. We also need more research on the TH/TTM treatment window. Cooling within two to four hours, and even six hours after successful CPR, have the most supportive data, but some studies have reported effectiveness after even longer periods.

In most of the studies, effective TH and TTM temperatures range between 32 and 34 degrees, maintained for 24 hours, with gradual managed rewarming. The question is whether treatment might improve with longer periods of cooling. We need to fully understand if any drugs or techniques can mimic TH or TTM, and whether it will be wise to use them.

We also need further studies on supplementing TH protocols using approaches like extracorporeal membrane oxygenation and pharmacologic agents.

Another needed research area is the potential impact of multiple brain-related complications such as seizures, status epilepticus, myoclonus, and cerebral edema in patients treated with TH or TTM. There was too little research to offer recommendations on their impact on prognostics or quality of life. Also, few studies specifically addressed the impact of withdrawing life-support on outcomes.

Finally, neuroscientists need to become more involved because there are a lot of research questions that remain. For example, many of these patients experience seizures before or after cooling, and we do not yet know the best approach for dealing with them. Also, almost all of these patients are in a coma after CPR, and we need to know if there are ways to improve recovery after coma. Myoclonus, status epilepticus, and cerebral edema are common, as is depression, which sometimes occurs years after CPR. Unfortunately, we are still at a loss how best to reduce or treat these conditions.

LINK UP FOR MORE INFORMATION:

• Geocadin RG, Wijdicks EF, Armstrong MJ, et al Practice guideline summary: Reducing brain injury following cardiopulmonary resuscitation. Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology http://neurology.org/lookup/doi/10.1212/WNL.0000000000003966. Neurology 2017; Epub 2017 May 10.
    • Neumar RW, Shuster M, Callaway CW, et al 2015 AHA Guidelines for CPR and EEC. American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care http://circ.ahajournals.org/content/132/18_suppl_2. Circulation 2015;132:S313–S314.
      • Callaway CW, Donnino MW, Geocadin RG, et al. Part 8: Post-cardiac arrest care: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care http://circ.ahajournals.org/content/132/18_suppl_2/S465. Circulation 2015;132 (18 Suppl 2):S465–482.
      • Neumar RW, Nolan JP, Adrie C, et al Post-cardiac arrest syndrome: Epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation http://circ.ahajournals.org/node/57334.short. Circulation 2008;118(23):2452–2483.