Effect of Trans-Nasal Evaporative Intra-arrest Cooling on Functional Neurologic Outcome in Out-of-Hospital Cardiac Arrest: The PRINCESS Randomized Clinical Trial

Abstract

Importance: Therapeutic hypothermia may increase survival with good neurologic outcome after cardiac arrest. Trans-nasal evaporative cooling is a method used to induce cooling, primarily of the brain, during cardiopulmonary resuscitation (ie, intra-arrest).

Objective: To determine whether prehospital trans-nasal evaporative intra-arrest cooling improves survival with good neurologic outcome compared with cooling initiated after hospital arrival.

Design, setting, and participants: The PRINCESS trial was an investigator-initiated, randomized, clinical, international multicenter study with blinded assessment of the outcome, performed by emergency medical services in 7 European countries from July 2010 to January 2018, with final follow-up on April 29, 2018. In total, 677 patients with bystander-witnessed out-of-hospital cardiac arrest were enrolled.

Interventions: Patients were randomly assigned to receive trans-nasal evaporative intra-arrest cooling (n = 343) or standard care (n = 334). Patients admitted to the hospital in both groups received systemic therapeutic hypothermia at 32°C to 34°C for 24 hours.

Main outcomes and measures: The primary outcome was survival with good neurologic outcome, defined as Cerebral Performance Category (CPC) 1-2, at 90 days. Secondary outcomes were survival at 90 days and time to reach core body temperature less than 34°C.

Results: Among the 677 randomized patients (median age, 65 years; 172 [25%] women), 671 completed the trial. Median time to core temperature less than 34°C was 105 minutes in the intervention group vs 182 minutes in the control group (P < .001). The number of patients with CPC 1-2 at 90 days was 56 of 337 (16.6%) in the intervention cooling group vs 45 of 334 (13.5%) in the control group (difference, 3.1% [95% CI, -2.3% to 8.5%]; relative risk [RR], 1.23 [95% CI, 0.86-1.72]; P = .25). In the intervention group, 60 of 337 patients (17.8%) were alive at 90 days vs 52 of 334 (15.6%) in the control group (difference, 2.2% [95% CI, -3.4% to 7.9%]; RR, 1.14 [95% CI, 0.81-1.57]; P = .44). 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 similar between groups.

Conclusions and relevance: Among patients with out-of-hospital cardiac arrest, trans-nasal evaporative intra-arrest cooling compared with usual care did not result in a statistically significant improvement in survival with good neurologic outcome at 90 days.

Trial registration: ClinicalTrials.gov Identifier: NCT01400373.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Nordberg reported grants from Swedish Heart-Lung Foundation and the Laerdal Foundation and nonfinancial support from BrainCool AB during the conduct of the study. Dr Taccone reported personal fees from BARD outside the submitted work. Dr Truhlar reported nonfinancial support from the Karolinska Institute during the conduct of the study. Dr Goldstein reported personal fees from Boehringer Ingelheim and AstraZeneca outside the submitted work. Dr Svensson reported grants from the Swedish Heart and Lung foundation during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. Flow of Patients in a Study of the Effect of Trans-Nasal Intra-arrest Cooling on Neurologic Outcome in Out-of-Hospital Cardiac Arrest

Patients screened but not included were not counted. DNAR indicates do-not-attempt resuscitation.

Figure 2.. Patients With Cerebral Performance Category (CPC) 1-2 90 Days After Cardiac Arrest

EMS indicates emergency medical service.

Figure 3.. Distribution of Cerebral Performance Category (CPC) Scale Scores 90 Days After Cardiac Arrest