Two Trials Look at Therapeutic Hypothermia in Out-of-Hospital Cardiac Arrest Patients

DALLAS, TX—The use of pre-hospital therapeutic hypothermia does not affect survival or neurologic status in cardiac arrest patients. If the therapy is used in-hospital, the precise temperature to which the body is cooled has minimal implications, according to 2 trials presented November 17, 2013, at the annual American Heart Association Scientific Sessions.

Questioning Pre-hospital Cooling

Francis Kim, MD, of the University of Washington, Seattle (Seattle, WA), and colleagues randomized 1,359 patients resuscitated after cardiac arrest (42.9% with ventricular fibrillation [VF]) to standard care with (n = 688) or without (n = 671) prehospital cooling by infusing up to 2L of 4°C normal saline as soon as possible following return of spontaneous circulation. Patients were treated by paramedics in Seattle, WA, between December 15, 2007, and December 7, 2012. Mostly all patients resuscitated from VF and admitted to the hospital received cooling regardless of their randomization.

The study was simultaneously published in the Journal of the American Medical Association.

The intervention decreased mean core temperature by 1.20°C (95% CI -1.33°C to -1.07°C) and 1.30°C (95%CI -1.40°C to -1.20°C) in patients with and without VF, respectively, by hospital arrival and reduced the time to achieve a temperature of less than 34°C by about 1 hour compared with the control group.

Nevertheless, rates of survival to hospital discharge and neurologic status denoting full recovery or mild impairment were similar between the study and control groups regardless of VF status (table 1).

Table 1. Survival and Neurologic Status


(n = 688)

No Cooling
(n = 671)

P Value

Survival to Hospital Discharge




Neurologic Status of Full Recovery or Mild Impairment




The rate of deaths in the field were similar between the intervention and control groups (1.3% vs. 1.6%; P = 0.61). Those who underwent cooling experienced more rearrest in the field than controls (26% vs. 21%; P = 0.008), as well as increased diuretic use and pulmonary edema on first chest X-ray.

Although cold normal saline reduced core temperature by hospital arrival, “prehospital cooling does not add benefit to hospital-initiated cooling,” Dr. Kim said. “The study findings do not support routine initiation of hypothermia using cold fluid in the prehospital setting.”

Discussant Maaret Castrén, MD, PhD, of the Karolinska Institute (Stockholm, Sweden), congratulated the researchers on completing such a large study in the EMS setting.

However, she said, results on the quality of the CPR and the variation in temperature were missing. In addition, Dr. Castrén listed factors that influence survival that were not included, such as identification by dispatcher and in-hospital post-resuscitation care.

Exact Temperature Does Not Matter

For the TTM (Targeted Temperature Management) trial, researchers led by Niklas Nielsen, MD, PhD, of Helsingborg Hospital (Helsingborg, Sweden), randomized 950 unconscious patients after out-of-hospital cardiac arrest to cooling to either 33°C (n = 473) or 36°C (n = 466). Patients were treated at 36 hospitals in 10 countries from 2010 to 2013. Temperature was managed with an intravascular cooling catheter in 24% of patients and with a surface cooling system in 76% of patients in both groups. The study was simultaneously published in the New England Journal of Medicine.

Kaplan Meier curves showed no difference in mortality between the study groups after 180 days. Neurological function was also similar between the groups; however, serious adverse events trended higher in the 33°C group (table 2).

Table 2. Clinical Outcomes at 180 Days


TTM 33°C
(n = 473)

TTM 36°C
(n = 466)

RR (95% CI)

P Value




1.06a (0.89-1.28)


Neurological Function (mRS)



1.01 (0.89-1.14)


Serious Adverse Events



1.03 (1.00-1.08)


a HR

Results were maintained in pre-defined subgroup analyses.

Discussing the trial, Benjamin S. Abella, MD, MPhil, of the University of Pennsylvania (Philadelphia, PA), said focus should be on patients with moderate post-arrest injury going forward because those with severe or mild/no injury will have poor or good outcomes, respectively, with any targeted temperature management. For those with moderate post-arrest injury, the level of TTM, whether 33°C or 36°C, can still potentially affect outcome, he said.

Several knowledge gaps remain, according to Dr. Abella, to determine the proper “dosage” of therapy:

  • Duration of post-arrest TTM
  • Depth of post-arrest TTM for select patients
  • Optimal injury measurement post-arrest
  • Pharmacologic adjuncts to TTM
  • Early vs. late post-arrest cardiac cath

Dr. Abella said he struggles with deciding how he might change his practice going forward. “I fear that if we uniformly apply 36 degrees for our patients, we may be excluding benefit for some of our patients,” he commented.

In an accompanying editorial, Jon C. Rittenberger, MD, and Clifton W. Callaway, MD, PhD, of the University of Pittsburgh (Pittsburgh, PA), write that “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 CPR.”

Future studies, they say, “can continue to refine protocols, define subgroups that benefit from individual therapies, and clarify how to best adjust temperature or other interventions to each patient’s illness.”

1. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;Epub ahead of print. 

2. 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;Epub ahead of print. 

3. Rittenberger JC, Callaway CW. Temperature management and modern post-cardiac arrest care. N Engl J Med. 2013;Epub ahead of print.

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  • TTM was funded by the Swedish Heart-Lung Foundation. 
  • Drs. Kim and Nielsen report no relevant conflicts of interest. 
  • Dr. Castrén reports serving on the board of the Falck Foundation and receiving research support from Benechill. 
  • Dr. Abella reports receiving research grants from Medtronic and Philips and honoraria from HeartSine, Stryker, and Velomedix.