November 17, 2013

DALLAS, TX — Therapeutic hypothermia in resuscitated out-of-hospital cardiac arrest gets favorable reviews in the guidelines, but they acknowledge the thin evidence supporting a benefit. And there are plenty of details that still need thrashing out, such as the optimal target temperature and ideal time to start lowering body temperature.

Those two questions were explored in a pair of large randomized trials published today in conjunction with their presentation here at the American Heart Association (AHA) 2013 Scientific Sessions [1,2].

One saw comparable survival and neurologic outcomes at six months in patients randomized to one of two hypothermia target temperatures, 33°C and 36°C, which were maintained for up to 36 hours as a hedge against fever. The findings question conventional target temperatures, which hover around 33°C, in that the lower target didn't lead to better outcomes than one scarcely below normal body temperature.

On the other hand, outcomes were notably favorable in both groups, leading the authors to speculate whether temporary measures for preventing body temperatures from rising much above normal might protect patients after resuscitated cardiac arrest.

In the other trial, initiation of therapeutic hypothermia in the field by paramedics, achieved rapidly by cold saline infusion, shortened the time to target temperature by an hour but failed to alter survival or neurologic outcomes compared with standard management. Patients receiving the early intervention also rearrested more often and had more transient pulmonary edema.

Not Just Hypothermia: Temperature Management

Dr Niklas Nielsen

About half of patients in the >900-patient trial comparing two target temperatures died or had poor neurologic outcomes after six months, report the authors, led by Dr Niklas Nielsen (Helsingborg Hospital and Lund University, Sweden). The study, called Target Temperature Management 33oC versus 36oC after Cardiac Arrest (TTM), is published online today in the New England Journal of Medicine in conjunction with Nielsen's scheduled formal presentation of the trial.

"It is worth recognizing that for all outcomes, none of the point estimates were in the direction of a benefit for the 33°C group," they write, apparently hinting at a signal of possible harm from the lower target temperature. Nielsen et al therefore propose that "decisions about which temperature to target after out-of-hospital cardiac arrest require careful consideration."

Elaborating for heartwire , Nielsen said the signal "could be a random finding, but it really should make us consider the appropriateness of current practice. It's a cohort of patients with a median age of 64, so a lot of elderly people, a lot of comorbidities, and it might be dangerous to do something [hypothermia to 33°C] that's very unphysiological."

Still, outcomes for both groups in the current trial appear better than results in the control group of at least one of the studies[3] on which the current proclivity for therapeutic hypothermia is based, according to the group. The populations differ, and "prehospital and critical care management has changed during the past decade," they point out.

"Nevertheless, it is important to acknowledge that there may be clinically relevant benefit of controlling the body temperature at 36°C, instead of allowing fever to develop in patients who have been resuscitated after cardiac arrest."

Interviewed, Dr Maaret Castrén (Karolinska Institutet, Stockholm, Sweden) said one of the study's messages is that temperature management in these patients seems protective. "We have seen in smaller studies . . . that the patients get a fever after the hypothermia period [has ended]. So how long do you have to cool?" It remains unanswered, she said, whether cooling should be performed during the whole period fever could emerge.

Nielsen noted that "we have no conclusive evidence that treating fever in these patients is beneficial. We think so," but that's based on observational evidence. "We really don't know if fever is a cause of injury or just an effect of injury."

An accompanying editorial from Drs Jon C Rittenberger and Clifton W Callaway (University of Pittsburgh, PA) sided with the positive message about fever control[4]. "One interpretation of these results is that they reinforce the importance of controlling temperature, even while they question whether 33°C is the best temperature."

Indeed, they write, "The exceptional rates of good outcomes in both the 33°C and 36°C groups in the present trial may reflect the active prevention of hyperthermia. Whatever the mechanisms, it seems clear that we should not regress to a pre-2002 style of care that does not manage temperature at all."

Three Degrees of Separation

As published, the TTM trial randomized 950 adults who were unconscious on admission to 36 centers in Europe and Australia after out-of-hospital cardiac arrest to receive targeted body-temperature management with internal temperature goals of either 33°C or 36°C. To be eligible, patients must have had >20 consecutive minutes of spontaneous circulation after resuscitation; arrests that were unwitnessed could not have asystole as the initial rhythm.

The analysis covered 473 patients in the 33°C group and 466 in the 36°C group, who made up the modified intention-to-treat population.

Measures to achieve hypothermia were instituted on randomization by intravascular cooling catheter in 24% and surface cooling systems in 76% at the discretion of each site, for a total time of 36 hours. Providers delivering the therapy weren't blinded to treatment assignment, but almost everyone else involved in the study was blinded, including the authors, they write.

Life-sustaining therapy was withdrawn in 132 patients and 115 patients in the 33°C and 36°C groups, respectively, for reasons that included multiorgan failure, brain death, and "ethical concerns." Neurologic criteria for guiding treatment-withdrawal decisions were prespecified.

Indeed, "One of the greatest innovations in this trial is adoption of a protocol for withdrawal of life-sustaining treatment," according to Rittenberger and Callaway. "Almost all prior studies" of care after cardiac arrest are "tainted" by the subjectivity of decisions to withdraw life-sustaining treatment "because of perceived poor neurologic prognosis."

The primary end point was death from any cause through the conclusion of the trial, specified as 180 days after the last patient's enrollment. Survival at the end of the trial was 50% in the low-temperature group and 48% in the higher-temperature group (hazard ratio 1.06, 95% CI 0.89–1.28; p=0.51).

At 180 days after randomization, 54% and 52%, respectively, had died or had poor neurologic function according to the Cerebral Performance Category (CPC) scale, for a risk ratio (RR) of 1.02 (95% CI 0.88-1.16, p=0.78).

The findings were similar using the modified Rankin scale in place of the CPC and after adjustment for confounders. And they were statistically similar across prespecified subgroups including by age, sex, time from arrest to return of spontaneous circulation, shockable vs nonshockable initial rhythm, whether patient was in shock at admission, and size of the treating center.

The risk of serious adverse events (excluding death) trended higher in the 33°C group (RR 1.03, 95% CI 1.00–1.08; p=0.086). Hypokalemia was significantly more prevalent at the lower temperature (p=0.02), and there were trends for pneumonia and cooling-catheter insertion-site bleeding. The risk of intracranial bleeding trended lower for the 33°C group.

According to the editorial, "Perhaps the most important message to take from this trial is that modern, aggressive care that includes attention to temperature works, making survival more likely than death when a patient is hospitalized after [cardiopulmonary resuscitation] CPR."

Is Earlier, Faster Hypothermia Better?

Dr Francis Kim

In the test of a prehospital regimen for achieving hypothermia in patients unconscious after resuscitated cardiac arrest, core body temperature fell by about 1.25°C in patients randomized to receive up to 2 L of 4°C saline solution while in transit to the hospital, compared with patients managed according to standard protocols.

Entry criteria required patients to be unconscious but allowed those with or without ventricular fibrillation; importantly, therapeutic hypothermia was instituted in the hospital in nearly all patients in both groups who were in VF, report Dr Francis Kim (University of Washington, Seattle) and colleagues.

Of patients getting in-hospital therapeutic hypothermia, achieved using surface or intravascular cooling systems, those who had received cold saline prehospital achieved the target temperature of <34°C an hour sooner than those who had received standard prehospital care.

The study, with >1300 patients, is published today in the Journal of the American Medical Association to coincide with its presentation at the AHA sessions.

Primary survival and neurologic outcomes at discharge were not significantly different between the two groups.

Survival and Neurologic Outcomes at Hospital Discharge (Primary End Points)*

End points VF, Prehospital hypothermia, n=292 (%) VF, Standard prehospital care, n=291 (%) No VF, Prehospital hypothermia, n=396 (%) VF, Standard prehospital care, n=380 (%)
Survival to discharge 67.2 64.3 19.2 16.3
Full neurologic recovery 42.8 49.8 9.1 8.9
Mild neurologic impairment 14.7 12.0 5.3 4.5

*All differences between intervention and control are nonsignificant

The current study, write Kim et al, doesn't support "routine use of cold saline following return to spontaneous circulation among patients resuscitated from prehospital cardiac arrest." The group speculates that the institution of a cooling protocol during resuscitation, rather than afterward, might lead to better results.

In an interview, Kim noted that some emergency-response agencies have started to use cold fluid infusions to kick-start induction of hypothermia in the field.

"I think our study, since it was so large and was powered to examine this question, really answers the question definitively. Prehospital cooling using cold fluid is really not effective if your goal is to improve survival and neurologic outcomes. Whether other cooling techniques are going to be beneficial [for prehospital use], those questions also need to be examined."

The TTM trial was supported by the Swedish Heart-Lung Foundation and other noncommercial sources listed in the text. Nielsen reports no conflicts of interest; disclosures for the coauthors are listed on the website. Rittenberger reports he has nothing to disclose; Callaway reports he has no conflicts of interest involving the editorial. Kim had no conflicts of interest; disclosures for the coauthors are listed in the paper. The prehospital therapeutic hypothermia study was supported by the National Heart, Lung, and Blood Institute and the Medic One Foundation.

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