No significant improvement in survival with good neurological outcome
For out-of-hospital cardiac arrest, a novel hypothermia method at the scene of collapse failed to significantly improve survival while preserving neurological function at 90 days, the investigator-initiated PRINCESS trial found.
In the randomized study of over 600 patients, 16.6% of those who received intra-arrest trans-nasal evaporative cooling remained alive and with good neurological outcomes at 90 days, compared with 13.5% of those given usual in-hospital care (3.1% difference, 95% CI -2.3% to 8.5%, P=0.25), according to Per Nordberg, MD, PhD, of Karolinska Institute in Sweden, and colleagues.
Overall, 17.8% of patients who received the intervention remained alive at 90 days versus 15.6% for the usual care group (2.2% difference, 95% CI -3.4% to 7.9%, P
=0.44), the group reported in JAMA.
Noting that assessments of primarily in-hospital therapeutic hypothermia have had varied results, Nordberg and colleagues suggested several reasons for the lack of difference between the intervention and control groups.
"The cooling intervention might not have been effective enough to lower temperature during CPR to mitigate brain injuries secondary to the ischemia and reperfusion process," they wrote. "The start of cooling might have been too late to provide the benefit seen in experimental models in which such cooling was immediately applied."
Median time to core temperature less than 34°C was 105 minutes in the intervention group versus 182 minutes in the control group (P<0.001). Mean temperature at hospital arrival was 1.2°C lower in the intervention group (P<0.001). All patients received hypothermia at 32°C to 34°C for 24 hours upon hospital admission.
PRINCESS (Prehospital Resuscitation Intranasal Cooling Effectiveness Survival Study) included 677 patients with witnessed out-of-hospital cardiac arrest. Across seven European countries from July 2010 to January 2018, patients (median age 65, 25% women) were randomly assigned to receive trans-nasal evaporative intra-arrest cooling performed by emergency medical services (n=343) or standard care (n=334). In all, 671 completed the trial. Outcome assessors were blinded to treatment.
Predefined subgroup analyses noted that rapid cooling was associated with higher rates of good neurological outcome -- defined as Cerebral Performance Category (CPC) 1-2 -- at 90 days in patients with initially shockable rhythms (8.9% difference, 95% CI -2.0% to 19.7%) and in the per-protocol analysis that was restricted to all randomized patients with adherence to the intervention (3.6% difference, 95% CI -1.9% to 9.1%), although the confidence intervals for these differences each included a null effect.
In a post-hoc analysis, 14.8% of the intervention group achieved a CPC 1 score, indicating complete neurologic recovery without any sequelae versus 10.5% of controls (4.4% difference, 95% CI 95% CI -0.7% to 9.4%), though again the confidence interval included a null effect.
In the subgroup of patients with initially shockable rhythms, CPC 1 was noted in 32.6% of the intra-arrest cooling group compared with 20% of those who received usual care (12.6% difference, 95% CI 2.3%-22.9%), the group noted.
"Patients with out-of-hospital cardiac arrest with initial rhythm of ventricular fibrillation have the strongest recommendation for temperature management in current guidelines," the authors wrote. "The explorative findings in this subgroup of patients may be of importance to define the study population for future hypothermia trials."
Infusions of cold fluids administered intra-arrest or soon after the return of spontaneous circulation (ROSC) are effective, but appear to carry significant hemodynamic adverse effects, they explained.
"In particular, adverse effects have been observed in patients with ventricular fibrillation as first rhythm, where intra-arrest infusion of cold fluid decreased the rate of patients achieving ROSC. Based on these findings, prehospital cooling using rapid infusion of cold intravenous fluid is not recommended," they wrote.
Minor nosebleed was the most common device-related adverse event, reported in 45 of 337 patients (13%) in the intervention group. The adverse event rate within 7 days was otherwise similar between groups.
"The PRINCESS trial adds to the narrative about translating hypothermia for brain injury after cardiac arrest and other hypoxia from the laboratory to clinical practice," commented Karen Hirsch, MD, of Stanford University in Palo Alto, California, and Clifton Callaway, MD, PhD, of the University of Pittsburgh, in an accompanying editorial. "Truly protective hypothermia will require aggressive and novel techniques, such as trans-nasal evaporative cooling, to actually achieve hypothermia within minutes during CPR, the time window during which preclinical studies suggest hypothermia might prevent brain injury and provide meaningful, sustained improvements in neurologic recovery."
The editorialists noted that it "may be more accurate to conclude that this trial shows 'an uncertain 3% effect,' leaving open the possibility for future trials to test with increased confidence whether any true benefit exists," but added that the results do not support adoption of this type of cooling for out-of-hospital cardiac arrest.
Limitations noted by the authors include that care providers were not blinded to treatment, potential bias due to the failure to include many eligible patients with cardiac arrest, and the possibility that the study was underpowered.
The study was supported by grants from the Swedish Heart-Lung Foundation and the Laerdal Foundation. The cooling devices were provided by BrainCool AB.
Nordberg reported non-financial support from BrainCool AB during the study. Co-authors disclosed relationships with BARD, Boehringer Ingelheim, and AstraZeneca.
Hirsch has received fees from Qool Therapeutics, a company developing new ways of delivering hypothermia. Callaway reported no conflicts of interest.
Source Reference: Nordberg P, et al "Effect of trans-nasal evaporative intra-arrest cooling on functional neurologic outcome in out-of-hospital cardiac arrest: The PRINCESS randomized clinical trial" JAMA 2019;321(17):1677-1685.
Source Reference: Hirsch KG, Callaway CW "Translating protective hypothermia during cardiac arrest into clinical practice" JAMA 2019;321(17):1673-1675.
Read the original article on Medpage Today: Pre-Hospital Hypothermia After Cardiac Arrest Falls Short