PRINCESS: Prehospital Cooling Not Linked to Better Survival After OHCA

November 20, 2018

CHICAGO — Prehospital cooling during resuscitation after out-of-hospital cardiac arrest (OHCA) is safe to use but is not significantly effective in increasing cognitively-intact survival, new research suggests.

In the phase 2, randomized Prehospital Resuscitation Intranasal Cooling Effectiveness Survival Study (PRINCESS), patients who received intra-arrest therapeutic hypothermia that was initiated in the field with a transnasal evaporative cooling (TNEC) device (Rhinochill, Benechill) during resuscitation were compared with patients who received standard of care, which included therapeutic hypothermia after hospital admission. All patients also received systemic cooling at the intensive care unit.

The PRINCESS trial, which involved more than 600 patients from seven European countries, did not meet its primary end point of between-group differences in "survival with good neurologic outcome," defined as a Cerebral Performance Category (CPC) score of 1 or 2 at 90 days. There were also no significant differences in the subgroup of patients who had ventricular fibrillation (VF).

However, prehospital TNEC was significantly associated with the secondary outcomes of decreased time to target temperature for the full group and complete neurologic recovery in those with VF.

"As guidelines are stated at the moment, you should not cool the patient outside of the hospital," principal investigator Per Nordberg, MD, PhD, Center for Resuscitation Science, Karolinska Institute, Stockholm, told attendees during a late-breaking science session here at the American Heart Association Scientific Sessions 2018.

"But we proved that early cooling is safe to do with this method when you don't bring volume to the heart," Nordberg later told | Medscape Cardiology. "We believe in cooling the brain to reduce injury in cardiac arrest," he added.

Official discussant Christopher B. Granger, MD, Duke University School of Medicine, Durham, North Carolina, agreed that the trial "confirmed" that patients can be safely and rapidly cooled early and during an OHCA, "but we still do not know if this has meaningful improvement in clinical outcome," he said.


Nordberg said during his presentation that it is known that "hypothermia protects the brain after cardiac arrest, and animal data have consistently shown" that the earlier this is done, the better the outcome.

"However, most clinical trials are based on cooling started at the hospital, in intensive care units, where you have to wait several hours sometimes before cooling is started," he added.

Also, "when early/prehospital cooling has been assessed, the method used has been cooling with cold fluids, which we have seen is bad for patients" because it is not hemodynamically safe, noted Nordberg.

In the noninvasive TNEC method, a catheter is inserted into the nasal cavity, where it delivers a spray mixture of oxygen and coolant.

"It cools very rapidly the surrounding tissue and also the blood circulation going to the brain," Nordberg explained. "You can apply it wherever you are. In this trial, it was at the scene of the arrest but you can also start it at the ER, at the cath lab, or at x-ray. It delivers continuous cooling and, maybe most important, it doesn't give a volume load to the heart."

The researchers previously conducted the 182-patient-strong Pre-Resuscitation Intra-Nasal Cooling Effectiveness (PRINCE) trial, with key results presented at the 2009 AHA Scientific Sessions. PRINCE showed that the Rhinochill system device, which was housed in a 25-pound backpack and allowed therapeutic hypothermia to be instituted in the field, was both feasible and safe for use in cardiac arrest patients.

Although it wasn't powered to assess for clinical outcomes, the trial showed some indication of improved survival and neurologically intact survival in the intervention group.

Survival Focus

On the basis of the PRINCE findings, which were published in Circulation in 2010, PRINCESS was created with a focus on survival.

This study involved 677 patients 18 to 79 years of age (mean age, 65 years; 75% men) who experienced a bystander-witnessed OHCA between 2010 and 2018. Of these participants, 60% received bystander CPR and 40% had VF.

Exclusion criteria included an emergency medical services (EMS) response longer than 15 minutes and a return of spontaneous circulation (ROSC) prior to randomization.

In the study, the EMS initiated CPR at a mean of 9 minutes, an airway was established within 14 minutes, and patient randomization occurred at 17 minutes at the scene of the arrest.

All of the participants were assigned to receive either prehospital cooling with the TNEC device (n = 343) or standard care (n = 334). The median time from collapse to intra-arrest cooling was 19 minutes.

Neurologically intact survival was defined as a CPC score of 1 (good cerebral performance; little to no deficit) or 2 (moderate cerebral disability; capable of independent activities of daily life) 3 months after the cardiac arrest.

Results and Trends

Time to target temperature (<34oC) was significantly shorter in the prehospital cooling group than in the standard care group (mean, 101 vs 182 minutes; < .001).

However, neurologically intact survival at 90 days was not significantly different between the two treatment groups overall (16.6% vs 13.5%; P = .26) or in those with VF (34.8% vs 25.9%; P = .11).

"These are the most important [data] of the trial," said Nordberg. Although there was no statistical difference in the whole population, "there was a signal in those with ventricular fibrillation, maybe the most important subgroup of patients, toward a benefit in the primary outcome."

Complete neurologic recovery did not differ significantly between prehospital cooling and standard care in the full study population (14.8% vs 10.5%; P = .09), although it did in those with VF (32.6% vs 20%; P = .02).

At 90 days, 50 of 60 patients with a CPC of 1 in the intervention group and 35 of 52 with a CPC of 1 in the control group were alive.

The most common device-related adverse events in the intervention group were minor nosebleed (14%), transient white nose tip (6%), and prolonged nosebleed (1%).

Vasopressor requirement within 7 days was experienced by 76% of the intervention group and 70% of the control group. Other complications within 7 days included cardiogenic shock in 22% and 24% of the groups, respectively, pulmonary edema in 5% and 13%, and VF in 2% and 4%.

"We showed that transnasal evaporative cooling in out-of-hospital cardiac arrest is hemodynamically safe, which I think is an important message. And we've shown that cooling patients outside the hospital is possible with this new method," Nordberg said.

"One of the Largest Trials"

"I want to congratulate Per and his collaborators on an excellent job in one of the largest randomized trials ever done in cardiac arrest," said Granger, who was not involved with the research.

He told attendees that before the PRINCESS trial, therapeutic hypothermia had shown "moderate evidence for improving survival" on the basis of one medium-sized randomized controlled trial (n = 275) and one small trial with controlled allocation (n = 77).

In addition, Kim et al assessed 1359 patients and found that prehospital cooling with 2 L of 4oC saline immediately after achieving an ROSC had no benefit on neurologic outcome, including among its subgroup of patients with VF, compared with hospital cooling (JAMA. 2014;311:45-52). There were also more safety issues, including more reports of rearrest and heart failure.

"What the PRINCESS trial asked that we didn't know before was: If rapid cooling is started very early, such as before or immediately after ROSC, does that improve good neurologic outcome?" However, the study didn't really answer that question, Granger said.

"The strengths of PRINCESS were that it was a large trial in a very challenging setting; it studied an important question; it was a successful experiment of testing early rapid cooling; and it showed that this approach is feasible and safe," he said.

However, it also had "limited power to detect modest but important benefits in outcome even with this, for the field, large randomized trial of cardiac arrest," Granger said.

"With the primary outcome not significantly reduced, the subgroup analyses may not be reliable, particularly since the findings diverged from Kim in the ventricular fibrillation subgroup," he said.

Granger later reiterated to| Medscape Cardiology that PRINCESS was a "very high-quality" and important study.

"It showed that it is possible to cool patients safely and rapidly and reliably with this interesting device that can be inserted into the nose during the cardiac arrest, and there was a suggestion that there might be benefit, but it was not enough of a suggestion to change care," he summarized.

That said, "I'd be supportive if there was interest and willingness and funding to do another trial in this setting focusing on patients with VF arrest. I think that would be worthwhile," Granger concluded.

The study was funded by the Karolinska Institute. The cooling devices were provided by the manufacturer at not cost. Nordberg reports having received research grants from the Swedish Heart and Lung Foundation. Granger reports having done research and consulting for Medtronic, which makes devices used after a cardiac arrest.

American Heart Association (AHA) Scientific Sessions 2018: Abstract 18598. Presented November 11, 2018.

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