Prehospital Intranasal Cooling After Cardiac Arrest Feasible, May Improve Survival

Susan Jeffrey

November 16, 2009

November 16, 2009 (Orlando, Florida) — Use of a new device that allows therapeutic hypothermia to be instituted in the field has been shown to be feasible and safe for patients in cardiac arrest.

Target brain temperature was reached 3 hours in advance of those patients in whom cooling was begun in the hospital using a portable system that cools the brain via nasal prongs, similar to those devices used to deliver oxygen. Although the study was not powered to assess clinical outcomes, researchers saw some indication of improved survival and neurologically intact survival in patients in whom hypothermia was instituted before hospital arrival, particularly in the subgroup of patients in whom cardiopulmonary resuscitation (CPR) was begun within 10 minutes of the arrest.

Results of the Pre-Resuscitation Intra-Nasal Cooling Effectiveness (PRINCE) trial, funded by BeneChill Inc, the manufacturer of the RhinoChill system, were presented here at the American Heart Association 2009 Scientific Sessions.

"We can conclude that the PRINCE trial, the first randomized intra-arrest cooling study, showed that intranasal cooling using RhinoChill is feasible and safe during arrest," Maaret Castrén, MD, professor of emergency medicine at Karolinska Institute in Stockholm, Norway, concluded.

Dr. Maaret Castrén

"Even if the study was not powered for outcome, we can cautiously say that survival and neurologically intact survival to discharge was significantly higher when CPR was initiated within 10 minutes," she said.

Transnasal Access

It is now well established that therapeutic hypothermia provides a survival benefit for patients in cardiac arrest. Two randomized trials were published in 2002 in the same issue of the New England Journal of Medicine, both showing improved outcomes with hypothermia in patients resuscitated after cardiac arrest (N Engl J Med. 2002;346:549–556, 557–563).

In those trials, cooling was begun in-hospital between 30 minutes and 2 hours after the collapse, Dr. Castrén noted. The PRINCE trial was an attempt to begin therapeutic hypothermia outside the hospital during CPR, using a transnasal system that introduces a mixture of volatile coolant and oxygen into the nasal passages directly under the large vessels of the brain.

Dr. Denise Barbut

The evaporation of the gas cools the nasal cavity quickly to approximately 2°C, and from there, the cold is transmitted to the brain. Eventually the rest of the body also cools, but it is the brain that is the target, said Denise Barbut, MD, a neurologist and president and chief executive officer of BeneChill Inc. "The brain cannot get too cold," she said. "The colder it is, the better off it is, as long as it doesn't actually freeze. The body can't go below a certain temperature before complications arise, so cooling the brain fast and early is critically important."

The device is portable, housed in a backpack weighing approximately 25 pounds, and has intranasal catheters that deliver the coolant directly into the nasal cavity. No electricity is required. "It's very simple and easy to use," said coauthor Per Nordberg, MD, also from the Karolinska Institute. "You apply it within a minute, and it takes 30 to 60 seconds to start cooling."

Dr. Per Nordberg

The current study was a safety and feasibility trial of use of the system by first responders during CPR. A total of 200 patients who experienced a witnessed cardiac arrest with CPR begun within 20 minutes were randomly assigned to prehospital transnasal cooling or standard Advanced Cardiac Life Support (ACLS) care. Cooling was begun as soon as was considered feasible without interfering with ACLS protocols, the investigators noted. Patients in both groups underwent therapeutic hypothermia once they arrived at the hospital. All arrests were included, regardless of the initial rhythm.

Of 200 randomized patients, 18 were eventually excluded from the analysis, often because they were later found to have do not resuscitate orders or other exclusion criteria, Dr. Castrén noted, leaving 83 in the intranasal cooling group and 99 in the standard care group.

The target tympanic temperature of 34°C, used as an approximation of brain temperature, was reached 3 hours earlier in the group receiving prehospital cooling, and the target core body temperature was reached 2 hours earlier.

Adverse events were minor, she said, with nasal discoloration being the most common.

PRINCE Trial: Adverse Events With Intranasal Cooling vs No Intranasal Cooling

Device-Related Events Intranasal Cooling, No. (%) (n = 83) No Intranasal Cooling, No. (%) (n = 99)
Nasal discoloration 13 (15.6) 0 (0)
Epistaxis 3 (3.6) 0 (0)
Perioral bleeding 1 (1.2) 0 (0)
Periorbital emphysema 1 (1.2) 0 (0)
Serious adverse events unrelated to device in admitted patients (sepsis, AMI, additional cardiac arrest) 6/30 (20) 14/42 (33.3)

AMI = acute myocardial infarction; PRINCE = Pre-Resuscitation Intra-Nasal Cooling Effectiveness

Although the study was not powered to look at efficacy, 31.1% of the standard care patients admitted to the hospital survived vs 46.7% of those receiving intranasal cooling (P = .15), not a statistically significant difference.

When they looked at survival to discharge in the 75% of patients who received CPR within 10 minutes of collapse, the investigators saw a significant increase from 29.4% in the standard group to 59.1% in the intranasal cooling group (P = .028).

Of those patients with ventricular fibrillation, survival to discharge was not significantly different at 47.6% in the standard care group vs 62.5% in the cooled group.

Finally, the neurologically intact survival rate was 21.4% with standard care vs 36.7% in those treated with intranasal cooling (P = .15). Again, significant benefit from cooling was seen in the subgroup who received CPR within 10 minutes of arrest, with the neurologically intact survival rate increasing from 17.6% with standard care to 45.5% with intranasal cooling (P = .025).

Limitations of the study are that no data were collected on CPR quality, Dr. Castrén pointed out, and there was no standardized postresuscitation protocol. Now that the device has been shown to be safe and feasible, future studies will introduce the cooling device earlier in the resuscitation protocol, she added.

The device is already approved in Europe but has not yet been commercialized because the evidence to support its use was not available before this study, Dr. Barbut noted. The system should be available in Europe by the first quarter of 2010, and they plan in the future to approach the Food and Drug Administration about possible approval here.

Promising Data

Dr. Michael Sayre

Asked for comment on these findings, Michael R. Sayre, MD, from Ohio State University Medical Center in Columbus, called the findings promising but cautioned that the results will require replication before they can be generalized.

"Cardiac arrest is extremely common," he told Medscape Neurology. "Approximately 200,000 Americans have a cardiac arrest every year outside the hospital, and today, less than 20,000 of those survive, so if these results are confirmed in other settings, this could be really important."

The study included patients with all rhythms at baseline, he noted, which is important, because when introducing a technology such as this, it is critical to ensure that it is safe in all kinds of patients. Dr. Sayre said he looks forward to further data on the efficacy of the device.

The study was funded by BeneChill Inc. Dr. Barbut is president and chairman of BeneChill Inc.

American Heart Association 2009 Scientific Sessions: Abstract 13. Presented November 15, 2009.


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