Why Rapid Cooling Might Be the Key

The Future of Therapeutic Hypothermia for Stroke

David M. Warmflash, MD

Disclosures

May 22, 2020

Last year, researchers at Yale made the news when they revitalized the brains of 32 pigs by cooling them down. That is, they revived certain biological functions in the brains of 32 pigs 4 hours after their death.

The idea that clinicians can provide neuroprotection to the brain by lowering a patient's body temperature has been percolating in modern medicine since the late 1940s, and even back to antiquity. Today, therapeutic hypothermia through various surface and whole-body cooling methods is used to help manage ischemic conditions of the brain, including cerebral ischemia due to cardiac arrest and hypoxic-ischemic encephalopathy. But many cooling techniques come with drawbacks, like heart block, infection, electrolyte disturbances, and bleeding diathesis.

The Yale team was able to avoid these complications by using a novel nasopharyngeal catheter system that circulates a chilled, oxygenated blood supplement. They found that over the course of a 6-hour treatment, a number of cerebral functions — including spontaneous synaptic activity, cerebrovascular dilatation, glial inflammatory responses, and active metabolism — were restored in the pig brains. Translating this research into humans will surely take a while, but the results come at a time when many researchers and clinicians are reviving interest in hypothermic therapy for brain traumas and stroke.

Following initial enthusiasm around hypothermia for cerebroprotection during heart surgery, by the 1960s, support for the technique had, shall we say, cooled. This was due in part to advances in technology for cardiopulmonary bypass. But beginning in the early 2000s, attitudes began changing. "Over the past 15 years, institutions have gradually adopted the use of therapeutic hypothermia for cardiac arrest patients in the emergency department setting," notes John Ma, MD, professor and chair in the Department of Emergency Medicine at Oregon Health Sciences University.

Supporting the practice is the HYPERION study, published this past October. The study authors found that therapeutic hypothermia of 33° C for 24 hours after cardiac arrest with nonshockable rhythm produced favorable neurologic outcomes compared with targeted normothermia. Although no difference in survival itself was seen, the results stand to improve the perception of therapeutic hypothermia as a viable treatment for managing stroke and perhaps other conditions of the brain.

"Based on my own inbox, I can state that [HYPERION] has definitely stimulated renewed interest in therapeutic hypothermia for stroke," notes Patrick Lyden, MD, of the Department of Neurology at Cedars-Sinai Medical Center, who directed the Intravascular Cooling in the Treatment of Stroke 2 (ICTuS-2) trial but was not involved in HYPERION. Published in 2016, this study combined hypothermia via intravascular cooling with tPA treatment for stroke. The trial was ended early, partly because intra-arterial neurothrombectomy had earned approval, and also due to the realization that new technology could enable better cooling, and so a future trial would probably produce better results. "Nonshockable patients have always been a question mark and the [HYPERION] trial was well done, and the results impressive," says Lyden.

A Israeli retrospective study of 92 patients, published in the early weeks of 2020, found therapeutic benefit with hypothermia after out-of-hospital cardiac arrest (OHCA). Therapeutic hypothermia improved neurologic outcomes and 1-year survival in post–ventricular fibrillation patients. Patients under 65 who were nonshockable — or post-asystole — also received a modest neurologic benefit from therapeutic cooling. Another retrospective OHCA study from this year found therapeutic hypothermia to be associated with improvement both in survival and Glasgow Coma Scale score.

Weighing the Evidence

Yet, not all of the data are supportive. 2013's targeted temperature management (TTM) study failed to show a significant difference in outcomes between temperature management at 33° C versus 36° C following cardiac arrest. And other recent research, including a new meta-analysis of 12 therapeutic hypothermia trials in acute ischemic stroke patients, found no overall benefit of the treatment, along with an increased incidence of complications. The study only included research published up until June 2019, however, and thus excludes the HYPERION study.

Mohammed A. Almekhlafi, MD, MSc, senior author on the paper and assistant professor of clinical neurosciences, radiology, and community health sciences at the Cumming School of Medicine at the University of Calgary, reasons that hypothermia simply needs to be more anatomically focused and induced more quickly. "Neuroprotection has eluded clinical application despite over 1000 experimental candidate therapies. Therapeutic hypothermia is by far the most potent of these therapies that is yet to be successfully translated [in stroke]," he says. Almekhlafi explains that given the many adverse events associated with cooling therapy, technologies like that employed by the Yale team in pigs, and those that selectively cool target organs, will have the highest likelihood of success in clinical studies.

"Some clinicians simply believe that cooling doesn't work, that the biology of the human brain is so much different than that of animals," says critical care physician Thomas Kreck, MD, alluding to findings from the TTM trial and other negative studies. "But I see it as a great failing of the medical device community that we have not more aggressively pursued the benefits of brain cooling. Kreck is the co-founder of NeuroSave, a medical device startup that is developing ultrarapid brain cooling to treat stroke. He believes that technological factors are the main reason why some trials have not lived up to the potential demonstrated in animal and in vitro studies.

Larger human trials are likely to steer the fate of therapeutic hypothermia in stroke management. However, Kreck, Lyden, and others in the field are motivated by encouraging data in preclinical models of neurologic injury. Whereas research has elucidated a plethora of pathways, mediators, and potential intervention points related to damage from strokes, trauma, and cerebral edema, hypothermia is the only measure that can intervene in all pathways at once. Furthermore, the advent of endovascular stroke treatment means that an increasing number of stroke patients will be instrumented anyway, strengthening the rationale for endovascular cooling, which, together with pharmacologic measures (meperidine, buspirone) and surface blankets to fool the body into thinking it's warm, enable more rapid induction of hypothermia compared with surface cooling.

Lyden points out that in his own ICTuS-2 trial, some patients took 4, 8, or even 12 hours to reach target temperature, but that this must change. "I strongly believe the next trial should use ultrafast cooling to get patients to target within 20 minutes," Lyden says.

A Chilly Future

Following the release of the HYPERION study results came an announcement about an upcoming clinical trial on cooling that will involve 1800 patients and up to 50 medical centers. A National Institutes of Health–funded project with $30 million coming from the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke, the trial is gearing up to hone in on the optimal duration of rapid cooling at 33° C in post–cardiac arrest settings.

More insight also comes from a preclinical study that Lyden and colleagues published online in 2018, demonstrating varying effects of hypothermia on brain cells and the blood-brain barrier. The findings reveal that, if maintained too long, hypothermia actually begins to inhibit the neuroprotective effect that astrocytes exhibit on the brain. This has direct implications in regard to the ICTuS-2 trial, which not only was plagued by delays in reaching target temperature but also featured cooling for 24 hours and rewarming over an 8-hour period. The long hypothermia and rewarming periods were expected to be helpful prior to the trial, but given what the study reveals about astrocytes, in addition to reaching target temperature of 33° C within 20 minutes, Lyden wants the next trial to maintain target temperature for only 2 hours and then warm to 35° C or 37° C.

Another means of improving hypothermia outcomes might be identifying patients for whom it's most appropriate. The authors of a study published last month looked at ECG data from patients with accidental and therapeutic hypothermia, and found that the corrected QT interval (QTc) might be useful as a biomarker for predicting who is at risk for hypothermia-induced arrhythmias, a potential complication of cooling. Confirmation of this finding could make QTc useful as a tool for personalizing the temperature and duration of therapeutic hypothermia to individual patients.

Clinical use of hypothermia is such a small field that virtually everyone knowledgeable enough to comment in an article such as this typically has some involvement in the research. But according to Lyden, we have the technology to administer effective endovascular cooling. Kreck believes that we can do even better with new devices that are on the horizon, especially those that cool more rapidly and do so from the head, thereby enabling a lower brain temperature while keeping core body temperature in the mild hypothermia range.

"Over a half-century of animal experiments definitively demonstrate that temporarily reducing brain temperature can prevent injured brain cells from dying after cardiac arrest and stroke," notes Kreck, adding that data in humans are now mounting.

Perhaps sometime soon, as research provides more clarity and new technologies emerge, an old technique will enjoy a new infancy. Perhaps therapeutic hypothermia will one day be standard of care in stroke management.

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