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

Per Nordberg, F. Taccone, A. Truhlar, S. Forsberg, J. Hollenberg, M. Jonsson, J. Cuny, P. Goldstein, N Vermeersch, A Higuet, F. Jimenes, F. Ortiz, Julia Williams, D Desruelles, J Creteur, E. Dillenback, C Busche, Hans-Jorg Busch, M. Ringh, D. KonradJ Peterson, Jean-Louis Vincent, Leif Svensson

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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.

Original languageEnglish
Pages (from-to)1677 - 1685
Number of pages9
JournalJournal of the American Medical Association (JAMA)
Issue number17
Publication statusPublished - 7 May 2019


  • Aged
  • Brain/physiopathology
  • Brain Injuries/etiology
  • Cardiopulmonary Resuscitation/methods
  • Emergency Medical Services
  • Epistaxis/etiology
  • Female
  • Humans
  • Hypothermia, Induced/adverse effects
  • Male
  • Middle Aged
  • Out-of-Hospital Cardiac Arrest/complications
  • Sample Size
  • Single-Blind Method
  • Survival Rate
  • Time-to-Treatment
  • Treatment Outcome


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