Therapeutic hypothermia following out-of-hospital cardiac arrest

Another study questioning therapeutic hypothermia has been published following the recent publication of two research studies which resulting in several organisations, including the European Resuscitation Council and ILCOR to issue statements on targeted temperature management.

© Gary Wilson/ Pre-hospital Research Forum

© Gary Wilson/ Pre-hospital Research Forum

Comparative Effectiveness of Therapeutic Hypothermia After Out-of-Hospital Cardiac Arrest: Insight from a Large Data Registry

Therapeutic Hypothermia and Temperature Management. Online Ahead of Print: December 28, 2013

This study was undertaken by the authors to determine the effectiveness of therapeutic hypothermia (TH) after out-of-hospital cardiac arrest (OHCA) among a large cohort of adults in the Cardiac Arrest Registry to Enhance Survival (CARES), with an emphasis on subgroups with a non-shockable first documented rhythm.

All adult index events at participating sites from November 2010 to December 2013 were study eligible. All patient data elements were provided with summary statistics calculated for all patients with and without TH. For multivariate adjustment, a multilevel (i.e., hierarchical), mixed-effects logistic regression (MLR) model was used with hospitals treated as random effects. Propensity score matching (PSM) on both shockable and non-shockable patients was done as a sensitivity analysis. After predefined exclusions, our final sample size was 6369 records for analysis: shockable=2992 (47.0%); asystole=1657 (26.0%); pulseless electrical activity=1249 (19.6%); other unspecified non-shockable=471 (7.4%). Unadjusted differences in neurological status at hospital discharge with and without TH were similar (p=0.295).

After multivariate adjustment, TH had either no association with good neurological status at hospital discharge or that TH was actually associated with worse neurological outcome, particularly in patients with a non-shockable first documented rhythm (i.e., for NS patients, MLR odds ratio for TH=1.444; 95% CI [1.039, 2.006] p=0.029, and OR=1.017, p=0.927 via PSM).

Highlighting the limitations, the authors concluded that when TH is indiscriminately provided to a large population of OHCA survivors with a non-shockable first documented rhythm, evidence for its effectiveness is diminished. The authors suggest more uniform and rigid guidelines for the application of TH.

This was published only a month after the European Resuscitation Council issued a statement ( on target temperature management following two studies into the treatment of patients with ROSC after out-of-hospital cardiac arrest (OHCA) arise from these studies, questioning whether:

1. Should ice-cold intravenous fluid continue to be used for inducing hypothermia prehospital?
2. Should the target temperature be 32-34 °C or 36 °C for the management of comatose cardiac arrest survivors with ROSC?

Shortly after the European Resuscitation Council (ERC) released the statement, International Liaison Committee on Resuscitation (ILCOR)  published an advisory statement to guide clinicians on the use of temperature management in post cardiac arrest patients (

According to ILCOR: “A key message from this study is that targeted temperature management (TTM) remains an important component of the post resuscitation care of the unconscious cardiac arrest patient and that similar results were obtained when either 33ºC or 36ºC were selected as target temperature.”

With regard to choosing that temperature to cool your patients, the following advice was issued: ” Pending formal consensus on the optimal temperature, we suggest that clinicians provide post-resuscitation care based on the current treatment recommendations” and “We accept that some clinicians may make a local decision to use a target temperature of 36°C pending this further guidance”. Further formal discussions are being undertaken by ILCOR regarding future decisions on targeted temperature management.

Below are details on the original two studies which sparked the release of the advisory statements:

Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest found no difference in survival when lowering cardiac arrest patients’ temperature to 33 °C vs. 36 °C. [N Engl J Med 2013; 369:2197-2206 December 5, 2013]

Unconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. The authors objective was to compare two target temperatures, both intended to prevent fever.

In an international trial, the authors randomly assigned 950 unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33°C or 36°C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale.

In total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33°C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36°C group (225 of 466 patients) (hazard ratio with a temperature of 33°C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P=0.51). At the 180-day follow-up, 54% of the patients in the 33°C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36°C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P=0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P=0.87). The results of analyses adjusted for known prognostic factors were similar.

In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C.

Effect of Prehospital Induction of Mild Hypothermia on Survival and Neurological Status Among Adults With Cardiac Arrest: A Randomized Clinical Trial was the second study which resulted in the statement. (JAMA. 2014;311(1):45-52.)

Objective To determine whether prehospital cooling improves outcomes after resuscitation from cardiac arrest in patients with ventricular fibrillation (VF) and without VF.

Design, Setting, and Participants A randomised clinical trial that assigned adults with prehospital cardiac arrest to standard care with or without prehospital cooling, accomplished by infusing up to 2 L of 4°C normal saline as soon as possible following return of spontaneous circulation. Adults in King County, Washington, with prehospital cardiac arrest and resuscitated by paramedics were eligible and 1359 patients (583 with VF and 776 without VF) were randomized between December 15, 2007, and December 7, 2012. Patient follow-up was completed by May 1, 2013. Nearly all of the patients resuscitated from VF and admitted to the hospital received hospital cooling regardless of their randomisation.

Main Outcomes and Measures The primary outcomes were survival to hospital discharge and neurological status at discharge.

Results The intervention decreased mean core temperature by 1.20°C  in patients with VF and by 1.30°C  in patients without VF 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. However, survival to hospital discharge was similar among the intervention and control groups among patients with VF (62.7% vs 64.3%) and among patients without VF (19.2% vs 16.3%). The intervention was also not associated with improved neurological status of full recovery or mild impairment at discharge for either patients with VF (57.5% of cases had full recovery or mild impairment vs 61.9% or those without VF (14.4% of cases vs 13.4% of controls). Overall, the intervention group experienced rearrest in the field more than the control group (26%  vs 21% ), as well as increased diuretic use and pulmonary oedema on first chest x-ray, which resolved within 24 hours after admission.

Conclusion and Relevance Although use of prehospital cooling reduced core temperature by hospital arrival and reduced the time to reach a temperature of 34°C, it did not improve survival or neurological status among patients resuscitated from prehospital VF or those without VF.