ARTICLE IN BRIEF
A new study found that contrary to conventional belief, pre-hospital hypothermia had no effect on the rate of survival to hospital discharge or on neurologic outcome among surviving cardiac arrest patients, either among patients with ventricular fibrillation (VF) or non-VF arrest.
Contrary to expectation, prehospital cooling does not improve neurologic outcomes or survival after cardiac arrest, and increases the risk of re-arrest and pulmonary edema, according to a study published online Nov. 17, 2013, in the Journal of the American Medical Association (JAMA). These results, combined with another recent study that found cooling to 33° C no better than cooling to 36° C, “question the entire practice as to whether hypothermia is beneficial in cardiac arrest,” according to one expert not involved in the trial, or instead whether simply avoiding fever should be the major goal.
The JAMA study, led by Francis Kim, MD, associate professor of medicine at the University of Washington and Harborview Medical Center in Seattle, could hardly have been more definitive. Over a five-year period, Dr. Kim randomized 1359 patients with cardiac arrest to either standard care or prehospital cooling with up to 2 liters of 4°C intravenous normal saline, begun by emergency responders on the way to the hospital, as soon as spontaneous circulation returned. This represented about 40 percent of all patients with cardiac arrest in the Seattle area during that time; the remainder could not be resuscitated.
On average, patients were cooled by about 1.2° C by the time of their arrival at the hospital, usually within half an hour after arrest, and the intervention reduced the time to achieve target cooling of 34° C by about an hour. However, it had no effect on the rate of survival to hospital discharge or on neurologic outcome among surviving patients, either among patients with ventricular fibrillation (VF) or non-VF arrest.
“Obviously, this was disappointing to us,” Dr. Kim said, since it had been widely assumed that the earlier cooling could be started, the better. Many centers across the country have instituted field cooling for cardiac arrest patients, he said, based on that assumption. But Dr. Kim's results echo those from a smaller trial published in the journal Circulation in 2010, which indicated no benefit from prehospital cooling with Ringer's solution.
However, the results from Dr. Kim's trial were not simply that field cooling offered no advantage to patients. Instead, those patients randomized to prehospital cooling experienced re-arrest on the way to the hospital more often — 26 percent versus 21 percent — as well as increased pulmonary edema and use of diuretics. The reasons for this increased morbidity are not clear, but animal models suggest that intravenous cooling may be linked to decreased coronary artery perfusion pressure, compared with surface cooling. Blood gas pH and partial pressure of oxygen are also reduced, potentially worsening outcomes.
“The results of this randomized study,” in conjunction with the 2010 study, “do not support the routine use of cold saline following return of spontaneous resuscitation among patients resuscitated from prehospital cardiac arrest,” Dr. Kim concluded.
Yet another study, just published in the Dec. 5 New England Journal of Medicine, further casts into doubt conventional wisdom and current practice, said Alejandro Rabinstein, MD, professor of neurology and director of the Neuroscience Intensive Care Unit at the Mayo Clinic in Rochester, MN. That study, from a group in Sweden, showed no benefit of cooling to 33° C versus 36° C.
“The two trials put together question the entire practice as to whether hypothermia is beneficial in cardiac arrest, or whether what we should be doing from the very beginning is avoiding hyperthermia, even in a mild degree,” Dr. Rabinstein noted. “The question now is whether the target really should be 33° C, or whether instead it would be just as beneficial to just keep patients at 36° C, essentially at normal body temperature, but not let them become hyperthermic. The whole field is now in a mode of reflection.”
Stephan A. Mayer, MD, professor of neurology and director of the Neurological Intensive Care Unit at Columbia University Medical Center, described the pair of papers as “earth-shattering” for the field. “They are forcing us to re-examine what we thought was going on” when inducing hypothermia.
Dr. Mayer pointed out that the past decade has witnessed a “hypothermia revolution” within the field of intensive care, which has undeniably improved outcomes, and to an astonishing degree. Prior to the widespread use of hypothermia, survival at discharge for cardiac arrest was about 1 percent; it's now 40 percent for those with VF, and almost 20 percent in those with non-VF arrest.
As a result of that revolution, “a growing group of neurologists are becoming actively integrated into the acute resuscitation of patients with cardiac arrest, becoming integral members of multidisciplinary teams, focused on bringing these people back from the dead, beginning in the emergency room,” Dr. Mayer said. “We are trying to push the field.”
The New England Journal of Medicine study “has now challenged our notion of the benefit of cooling per se. It may be more the fever prevention that is making the difference. So hospitals are now confronted by the question of whether to cool to 33° C, or make the target 36° C. Both are reasonable. So all the medical centers are on their own.”
“The Kim study [in JAMA] shatters another assumption, which is even more interesting,” Dr. Mayer said. “As neurologists, our model life-threatening disease is stroke, and we all believe that time equals brain, and that if anything is beneficial to the brain, the sooner you can get to that intervention, the better. But what we may be dealing with here is actually better conceptualized as a reperfusion injury in progress.”
In this view, the damage from cardiac arrest may evolve over many hours to several days after the initial ischemia. “If that's the case, then it may be that shaving down one hour isn't really going to matter,” Dr. Mayer said, since hypothermia would be providing its benefits in the many hours after arriving at the hospital, not the relatively few minutes before.
As for how to treat the emergency patient, Dr. Mayer is firm: “I think everyone with cardiac arrest should get very aggressive, high-quality resuscitation, and begin active therapeutic temperature management to a target of 33° C to 36° C in the hospital. I think that is now our standard of care.”
But this may not be the last word. Dr. Rabinstein noted that the new trials “are going to re-energize the field from a research standpoint. We had settled on a practice paradigm that has now been questioned. And that will necessarily call for more investigation.”
•. Kim F, Nichol G, Maynard C, et al. Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: A randomized clinical trial. JAMA. 2013; E-pub 2013 Nov 17.
•. Bernard SA, Smith K, Cameron P, et al. for the Rapid Infusion of Cold Hartmanns (RICH) Investigators. Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: A randomized controlled trial. Circulation. 2010; 122:(7):737–742. E-pub 2010 Aug 2.
•. Nielsen N, Wetterslev J, Cronberg T, et al. for the TTM Trial Investigators. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013; 369:(23):2197–2206. E-pub 2013 Nov 17.