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May - 2019


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

P Nordberg, FS Taccone, A Truhlar, et al JAMA, 2019, 321(17):1677-1685


There is probably a diverse range of opinions about therapeutic cooling after OHCA, from don’t believe in it, to advocating temperature management in a target from 32-36C for 24 to 72-hours. In addition, there is the question of pre-hospital cooling, and the technique used for cooling.


This RCT of 677 patients with OHCA examines the efficacy of intra-arrest trans-nasal cooling for adults with bystander witnessed OHCA. The possible benefits of intra-nasal evaporative cooling are avoidance of the volume and hemodynamic effects of cold saline, and the ability to be rapidly used in-arrest, with preferential cooling of the brain. 

Patients randomised to cooling received a mixture of air or oxygen and a liquid coolant (perfluorohexane) via nasal catheters. As coolant evaporates it absorbs heat from surrounding tissue and rapidly cools the nasal cavity to about 2C. The method

was developed primarily to cool the brain because it takes advantage of the nasal pathways (ie, the conchal folds and turbinates) that provide a highly vascular and large, diffuse surface area that is in close proximity to the cerebral circulation. If ROSC occurred cooling was continued until hospital arrival. 

Patients randomised to standard care received no cooling. All patients followed post-resuscitation guidelines including TTM.

What did they find;

  • patients were similar at baseline
  • In terms of temperature management
    • Median time to cooling in the treatment group was 19 mins from collapse
    • Temp at ED arrival was 34.8C vs 35.7C
    • Time to target temp was 105 minutes in intervention group and 182 minutes in control group
  • Primary outcome: 
    • 90-day survival with CPC 1-2 16.6% vs 13.5% (RR 1.23, 95% CI 0.86-1.72, p=0.25)
    • 90-day survival in subgroup with shockable rhythm, with CPC 1-2 (good recovery or moderate disability) 34.8% vs 25.9% (RR 1.28, 95% CI 0.90-1.72, p=0.11)
  • Secondary outcomes
    • No difference overall survival
    • No difference of distribution of CPC category for all-comers 
    • In shockable rhythm subgroup only difference was CPC 1 was 32.6% intervention vs 20% control RR 1.54 (95% CI 1.06-2.06)
    • No difference in adverse events  

Overall pre-hospital trans-nasal evaporative intra-arrest cooling did not result in an improvement in survival with good neurologic outcome for adult patients with OHCA. The subgroup analysis of patients with shockable rhythm revealed an area of further interest, ie incense in good recovery (CPC 1) in intervention vs control group. The authors note the intervention may have been too late, ie time to cooling was 105 minutes, after CPR. This was due to cooling being placed in secondary EMS vehicle.



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.


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