Jun 272017

Will "therapeutic" hypothermia someday need to be renamed?

After a rush of optimism surrounding small trials showing large benefits from hypothermia to 33° after out-of-hospital cardiac arrest, hospitals and intensivists flocked to provide hypothermia to all victims of cardiac arrest (in- or out-of-hospital).

When the much more powerful TTM trial showed no benefit of deep cooling to 33° as compared to simple fever prevention (maintenance of core temperature at 36°), many centers changed practice to fever prevention, reflecting the new evidence. Others argued the TTM trialists simply didn't cool fast enough and continued to deeply cool all cardiac arrest patients to 33° regardless of cardiac arrest type or where it occurred.

An observational study in JAMA suggests that for hospitalized patients suffering cardiac arrest, that approach could be misguided.

In the largest study to date evaluating targeted temperature management after in-hospital cardiac arrest, the use of intentional hypothermia was associated with poorer survival rates and worse neurologic outcomes than usual care. The study used Get With the Guidelines-Resuscitation registry data on 1,568 patients treated with hypothermia among 26,183 patients with in-hospital cardiac arrest between 2002-2014.

Using propensity matching, induced hypothermia was associated with a relative 12% reduction survival to hospital discharge, as compared with usual care (27.4% versus 29.2%, P=0.01). Neurologic disability at one year was also higher in the hypothermia patients (20.5% vs 17%, P<0.001).

Patients with shockable rhythms (ventricular fibrillation or ventricular tachycardia) who got hypothermia had worse outcomes than patients with shockable rhythms who did not get hypothermia. Extending observational follow-up to one year, no survival benefit was seen among the hypothermia patients.

One in five of the patients who received hypothermia were over-cooled below 32°, reflecting the challenges and possible perils of intentional hypothermia.

As with any observational study, the possibility of confounding by selection bias is significant and impossible to eliminate. Physicians may have tended to provide hypothermia to sicker patients or those with longer cardiac arrests, for example. Propensity matching can reduce such confounding, but whether residual effects remain in the analysis is impossible to ascertain.

In this study, investigators lacked data on comatose status, patient-level temperature curves or protocol adherence. These gaps allow plenty of room to argue that patients may not have been cooled fast enough or long enough, or that some unmeasured bias obscured a real benefit of hypothermia.

The authors were undeterred by such doubts, arguing "[c]urrent use of therapeutic hypothermia for in-hospital cardiac arrest may warrant reconsideration."

Patients experiencing cardiac arrest in the hospital are a very different population than those experiencing arrest outside the hospital: sicker, often with abnormal heart rhythms well before the arrest. They receive CPR sooner on average than patients outside the hospital, perhaps with less anoxic brain injury, so any benefit of hypothermia (if one exists) may not accrue.

There is virtually no evidence to support the use of hypothermia after in-hospital cardiac arrest. There are no randomized trials of hypothermia for in-hospital cardiac arrest, and the very few observational studies are too small or flawed to draw any conclusions.

Lead author Paul S. Chan, MD, Saint Luke's Mid America Heart Institute, Kansas City, Missouri, told the media:

There is a critical need to conduct a randomized controlled trial of hypothermia in in-hospital cardiac arrest and not just assume because it is beneficial for some out-of-hospital cardiac patients then we can extrapolate to other groups. In the meantime I would not recommend it be used for in-hospital cardiac arrest patients.

Dr. Chan says "... [hypothermia] is beneficial for some out-of-hospital cardiac patients ..." But according to the largest trial to date (TTM), induced hypothermia was not beneficial even in out-of-hospital cardiac arrest, compared to fever prevention. Shouldn't someone first prove that hypothermia below 36° helps at all after cardiac arrest -- in or out of the hospital?

Read more:

Association Between Therapeutic Hypothermia and Survival After In-Hospital Cardiac Arrest.  JAMA. 2016;316(13):1375-1382. doi:10.1001/jama.2016.14380

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Is hypothermia harmful after in-hospital cardiac arrest?