New AAN Guideline on Neuroprotection After Cardiac Arrest

Pauline Anderson

May 17, 2017

The American Academy of Neurology (AAN) has published a new guideline on neuroprotective interventions aimed at reducing brain injury among comatose patients following cardiopulmonary resuscitation.

For comatose adult patients, the authors recommend therapeutic hypothermia (TH), or cooling the core body temperature to 32°C to 34°C, for nontraumatic cardiac arrest due to shockable rhythms (ventricular fibrillation [VF] and pulseless ventricular tachycardia [VT]), and targeted temperature management (TTM) to 36°C as an acceptable alternative.

"The brain is the major determinant of functional outcome after a cardiac arrest and restarting the heart," Romergryko G. Geocadin, MD, professor, Departments of Neurology, Anesthesiology-Critical Care Medicine, and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, told Medscape Medical News.

Dr Romergryko G. Geocadin

"After cardiac arrest resuscitation, the vast majority of patients are comatose and the type of recovery that they will have from then on is dependent on the extent of their brain injury. The more you minimize the brain injury, the better their quality of life is going to be."

Mild hypothermia has emerged as a possible therapy to optimize brain health in these patients.

The new guidelines, also endorsed by the Neurocritical Care Society, were published online May 10 in Neurology.

The AAN convened a panel of experts to develop the practice guidelines. The panel examined all data on neuroprotective interventions published from 1966 to 2016, paying particular attention to neurologic endpoints beyond survival.

One of the studies the panel examined compared a core temperature range of 32°C to 34°C to no intervention (so maintaining normal body temperature of 37.5°C) in out-of-hospital cardiac arrest with shockable rhythms and found a significant neurologic advantage for hypothermia (risk difference of 16%; confidence interval [CI], 4% to 27%) at 6 months.

Another study investigated whether the advantage was due to the target temperature (32°C to 34°C) or a slightly lower body temperature plus fever prevention. This study compared hypothermia to attaining a target temperature of 36°C and found the two strategies were similar in terms of neurologic outcome.

Dr Geocadin stressed that there's a "big misconception" that 36°C is a normal body temperature. "It's not; it requires active intervention."

He stressed, however, that "36 degrees was never compared to placebo" in the studies that were examined.

"Personally, my preference would be 32 to 34 degrees because that's really where the science is based in many preclinical studies and the randomized placebo-controlled clinical trials," he said.

Offering resuscitated comatose patients prehospital cooling in addition to subsequent in-hospital cooling does not appear to improve survival or neurologic status, the panel found.

Patients with shockable heart rhythm are generally those who are less ill, the classic example being a 50-year-old man with an undiagnosed heart disorder who suddenly sustains a cardiac arrest while jogging.

In contrast, patients with nonshockable rhythms (asystole and pulseless electrical activity [PEA]) are typically critically ill, possibly septic, and on a ventilator in hospital and "already fighting for their lives," said Dr Geocadin.

Because there are no randomized controlled trials of TH for in-hospital cardiac arrest, only uncontrolled trials, panel members carried out a meta-analysis and found a signal of possible benefit of TH in this setting.

"It's not a clear recommendation for in-hospital cardiac arrest, but we feel that patients may benefit from therapeutic hypothermia even for in-hospital arrest," said Dr Geocadin.

However, added Dr Geocadin, "the studies show that those patients who are less sick and have shockable rhythms are most likely to benefit from therapeutic hypothermia."

The experts determined that TH to 33°C may also be offered in cases of nonshockable rhythms.

Although the cardiac arrests examined included witnessed and unwitnessed cases, "we didn't look at these populations specifically, so we can't make statements" with regard to these situations separately, said Dr Geocadin.

Sepsis and shock are typically included in the in-hospital cardiac arrest recommendations, he noted. "We do not have studies large enough to make specific differentiation" on these conditions, he said. "We also did not specifically look at these subsets of cardiac arrests patients, so it's best not to differentiate."

Optimal Duration?

Although the studies the panel investigated used TH for 12 hours or 24 hours, none actually weighed what was the optimal duration of the intervention, said Dr Geocadin.

The panel examined studies that looked at agents sometimes given to patients with cardiac arrest, including corticosteroids. They found no beneficial outcome for many of these agents and noted possible adverse effects.

"There is no benefit from using corticosteroids, and since they have been shown to have serious side effects, their use in these patients may even cause harm," said Dr Geocadin.

Barbiturates are also sometimes used in this patient population. These drugs suppress brain activity, which is thought to be neuroprotective, but no benefit was noted in the studies.

"Furthermore, these agents can also reduce blood pressure [BP], so their use in patients already with marginal BP could be harmful," said Dr Geocadin.  

There's insufficient evidence for use of nimodipine, selenium, and magnesium sulfate in patients who are comatose after cardiac arrest, they conclude. Lidoflazine, thiopental, and diazepam are likely ineffective in improving survival, the research shows.

Other studies looked at agents in combination with TH, including a pilot study of coenzyme Q10, an over-the-counter supplement. "It seemed to have a signal that patients may have improved survival, but quality of life wasn't improved in combination with therapeutic hypothermia."

Dr Geocadin stressed that the guidelines pertain to nontraumatic as opposed to traumatic cardiac arrest.

"One of the problems with therapeutic hypothermia is that it lessens the ability of the blood to clot, and in cases where patients are bleeding from trauma, they could actually bleed more if they receive therapeutic hypothermia."

Despite growing evidence of the potential for TH to protect the brain in patients with cardiac arrest, the use of this intervention in hospitals across the United States "is still very low," said Dr Geocadin.  Although he doesn't know the exact figure, the estimates are as low as 6% and probably no higher than 50%.

Dr Geocadin urges physicians to approach the family of a comatose patient with cardiac arrest to offer this option to optimize that patient's brain health.

"At the end of the day, the strongest determinant for the quality of life of patients after a cardiac arrest is the brain. The brain is the most sensitive organ to lack of oxygen and lack of blood flow."

He also feels passionate that neurologists, as brain specialists, should be part of the team of doctors caring for patients with cardiac arrest early after resuscitation.

The expert panel also listed areas where additional research is needed. One of the most pressing concerns, said Dr Geocadin, is determining TH characteristics.

"We know that therapeutic hypothermia works, but how can we tweak it to make it the best it can be? Is it fine-tuning the duration, or the timing of rapid administration? Or is it combining it with other approaches?"

Another area that needs study is what exactly is happening to the brain during TH.

"We don't have reliable real-time surrogate measures to determine if the treatment is effective or not on the brain."

The main recommendations from the expert panel include the following:

  • For patients who are comatose after an initial cardiac rhythm of VT or VF, TH (32°C to 34°C for 24 hours) is highly likely to be effective in improving neurologic outcome and survival compared with non-TH (two Class I studies) and should be offered (Level A).

  • For patients who are comatose with an initial cardiac rhythm of VT/VF or asystole/PEA, targeted TTM (36°C for 24 hours followed by 8 hours of rewarming to 37°C and temperature maintenance below 37.5°C until 72 hours) is likely as effective as TH in improving neurologic outcome and survival (one Class I study) and is an acceptable alternative to TH (Level B).

  • For patients who are comatose with an initial rhythm of VF, there is insufficient evidence to support or refute the use of 32°C vs 34°C TH because of lack of statistical precision (Class III studies; Level U).

  • For patients who are comatose in whom the initial rhythm is PEA/asystole, treatment with TH vs non-TH possibly improves functional neurologic outcome and survival at hospital discharge and may be offered (Level C).

For patients who are comatose after cardiac arrest, prehospital cooling as an adjunct to in-hospital cooling is highly likely to be ineffective in further improving neurologic outcome and survival (multiple Class I studies) and should not be offered (Level A).

Guidelines Welcome

In an accompanying editorial, Gregory Kapinos, MD, Department of Neurosurgery, Neurology and Emergency Medicine, and Lance B. Becker, MD, Department of Emergency Medicine, Hofstra Northwell School of Medicine, Hempstead, New York, said most physicians who treat patients with cardiac arrest with TH "will welcome the guidelines."

The guideline authors "deserve praise for being comprehensive and meticulous," Dr Kapinos and Dr Becker write.

Overall, the recommendations suggest that the lower the temperature the better, in contrast to the 2015 American Heart Association (AHA) guidelines, which allow a choice, even a range, between 32°C and 36°C, they said.

The current AAN guidelines could have been more precise for prehospital cooling and should have only recommended against methods proven to be potentially deleterious — for example, 4°C fluid loads or intranasal cooling, according to the editorial.

"It is premature to close the door on all methods of prehospital TH induction."

Although the AAN guidelines are inconclusive about the comparison of different cooling methods and protocol use, "recent data suggest that intravascular cooling is associated with faster, better cooling" compared with traditional techniques, the editorial writers noted.

This, they said, corroborates the clinical experience of many — that it's easier, although maybe counterintuitive, to maintain a patient at 33°C than at 36°C.

Dr Kapinos and Dr Becker said they concur with the AAN experts that "cooling should be harder, better, faster, stronger, in the sense that neurologists should be hardliners who embrace cooling as a default mode for nearly all cardiac arrest survivors, making it harder to exclude patients, while using cooling techniques that are the better ones, starting as quickly as possible after ROSC [return of spontaneous circulation], and that 33°C is stronger than 36°C."

Experts should find TTM methods that are tailored to diverse subgroups, taking into account the arrest rhythm and time to ROSC, and should "steward the cooling dose to cerebral parenchymal metabolic signatures and neuroimaging measures," said the editorial writers.

"We hope that the speed, depth, and length of cooling and re-warming will soon be informed by physiologic processes, trended biomarkers, and EEG [electroencephalography] responses, gathered for goal-directed therapy, culminating in evidence-based individualized precision cooling."

Dr Geocadin has received funding for travel from the AAN, AHA, and the Neuro-critical Care Society; has received honoraria from the AAN, the University of Maryland, and University of California, San Diego; has received funding for research from the National Institutes of Health (NIH); and has served on the editorial boards of Neurocritical Care, Resuscitation, and Seminars in Neurology: Critical Care Practice and Research. Dr Kapinos reports that he is copyright owner of the "Advanced Neurological Life Support" training program, course, and manual, a patent outline deposited at the US Library of Congress; and was trademark owner of "Advanced Neurological Life Support (ANLS)," with intent to use the mark in commerce on or in connection with the identified goods and/or services (12/5/2009), but with subsequent abandon with no use in commerce and has no financial ties to any thermal modulation devices or pharmaceutical companies. Dr Becker reports that he has worked closely with the NIH as a reviewer and grantee, and in a leadership role as the chair of the Myocardial Protection Working Group for the NIH National Heart, Lung, and Blood Institute's sponsored PULSE Conference and PULSE Leadership Group, which is dedicated to support of funding in resuscitation research; served as a member of the Food and Drug Administration (FDA) Device Evaluation panels; and has appeared as an expert presenter before the FDA panels; has institutional grant support from Philips Medical Systems, NIH, Zoll Medical Corp, and Nihon Kohden; has received honoraria and payments for serving on various NIH committees and boards, and Nihon Kohden; holds patents involving hypothermia induction and reperfusion therapies and oxygen consumption measurements; is a longstanding volunteer member of the AHA, which has a financial interest selling training materials worldwide on resuscitation techniques.

Neurology. Published online May 10, 2017. Abstract, Editorial

For more Medscape Neurology news, join us on Facebook and Twitter


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.