RICH and PRINCE Probe Prehospital Therapeutic Hypothermia After Cardiac Arrest

Reed Miller

August 09, 2010

August 9, 2010 (Melbourne, Australia) Two studies published last week are shedding light on the possibilities and limitations of prehospital "brain cooling" after cardiac arrest. In the Rapid Infusion of Cold Hartmann's (RICH) study, paramedic cooling with a rapid infusion of a large volume of ice-cold intravenous fluid (Hartmann's solution) after resuscitation did not appear to improve the outcomes of cardiac arrest patients with ventricular fibrillation more than waiting until the patient reaches the hospital to begin cooling. In the second study, the Pre-Resuscitation Intranasal Cooling Effectiveness (PRINCE) trial, investigators showed significant reductions in time required to achieve therapeutic levels of cooling, using coolant gases and oxygen given directly into the nasal passages.

Both studies were published online in the August 2, 2010 issue of Circulation.

Previous studies have suggested that therapeutic hypothermia can improve outcomes in patients who suffer out-of-hospital cardiac arrests, but the question of whether prehospital cooling further boosts outcomes is not clear, RICH researchers Dr Stephen Bernard (Ambulance Victoria, Melbourne, Australia) and colleagues explain.

Bernard and colleagues randomized 234 adults who had been resuscitated from out-of-hospital cardiac arrest with an initial cardiac rhythm of ventricular fibrillation to either prehospital cooling with a rapid infusion of a high volume of ice-cold lactated saline solution or to cooling only after hospital admission.

In the paramedic-cooled group, 47.5% patients had a favorable outcome at hospital discharge, compared with 52.6% in the hospital-cooled group (risk ratio, 0.90; 95% confidence interval, 0.70 to 1.17; p=0.43). There were no significant differences in secondary end points. In all, 20.3% of patients in the paramedic-cooled group were discharged home at the end of their hospital stay, compared with 29.3% of the hospital-cooled group; 27.1% and 23.3%, respectively, were discharged to rehabilitation; and 52.5% and 46.6%, respectively, died in the hospital.

The mean decrease in core temperature for the paramedic-cooled group was 0.8 °C (p=0.01). Paramedic-cooled patients were supposed to receive 2000 mL of fluid, but they only received a median of 1900 mL before they reached the hospital; only about half of these patients received the full allotment of ice-cold fluid because of the relatively short transport time to the hospital. As a result, there was a smaller decrease in the mean temperature of paramedic-cooled patients and a smaller temperature difference between the groups upon hospital arrival than the researchers anticipated.

"The major difference between our study and the several previous studies comparing paramedic cooling and hospital cooling is that our study was much larger and powered to detect a significant difference," Bernard told heartwire . "It is surprising and disappointing that we did not find a clinical benefit with earlier cooling. . . . This was probably due to the transient modest difference in temperatures between the two groups."

In an accompanying editorial [2], Dr Lance Becker (University of Pennsylvania, Philadelphia) notes that "the study of Bernard et al highlights that in-ambulance intravenous saline cannot be the end of hypothermia but is merely the beginning of a 24-hour therapy that must be vigilantly maintained." He suggests that significant cooling power appears to be lost as the ice-cold saline travels through a length of intravenous tubing and, although the patients cool down during transport, they begin to warm up as soon as they reach the hospital.

"From this study, we can see some drawbacks to cooling that are specific to the use of intravenous saline, including the following: volume loading, decreased coronary perfusion pressure, lack of cooling power, need for refrigeration in the ambulance, and requirement of an intravenous device," Becker argues. "The study highlights the challenges of clinical cooling studies but is not able to answer the important question about the need for earlier cooling. It also suggests that ice-cold saline may not be an ideal human coolant for in-ambulance cooling and even less so for intra-arrest cooling, in which coronary perfusion pressure is more of an issue than in the post-resuscitation setting."

None of the patients infused with cold fluid in the study developed pulmonary edema or recurrent cardiac arrest en route to the hospital, something many cardiologists worry about. "Hopefully, our data will reassure them that this is a simple, inexpensive technique to initiate therapeutic hypothermia in a postarrest setting," Bernard explained.

Laboratory studies suggest an infusion of ice-cold fluid during resuscitation--as opposed to afterward--could lead to earlier cerebral cooling and thereby improve outcomes, although clinical studies of this approach completed so far have been too small to show that it improves outcomes; Bernard said that his group will launch a trial of this approach within the next few weeks in Melbourne.

Will Cooler Heads Prevail?

Also published online August 2, 2010 in Circulation is the PRINCE study, by Dr Maaret Castrén (Karolinksa Institute, Stockholm, Sweden) and colleagues, which uses the RhinoChill system. The study was sponsored by the device manufacturer BeneChill (San Diego CA). RhinoChill delivers volatile coolant gases and oxygen directly into the nasal passages under the large vessels of the brain.

As reported by heartwire , Castrén presented results from the 200-patient PRINCE trial at the American Heart Association annual meeting in Orlando in November 2009. Study coauthor Dr Per Nordberg (Karolinska Institute) told heartwire that the differences in numbers and percentages in the published study are very small, compared with the abstract presented, and did not affect the overall major outcomes.

In the study, patients suffering a cardiac arrest were treated within 20 minutes, either with intra-arrest cooling using a RhinoChill device (n=96) or with standard care (n=104); both groups underwent cooling after hospital arrival. Time to reach the target temperature of 34 °C was significantly shorter in the treatment group for tympanic temperature (102 vs 282 minutes, p=0.03); a similar reduction in core temperature did not reach statistical significance (155 vs 284 minutes, p=0.13).

There were 18 device-related adverse events: one case of periorbital emphysema, three cases of epistaxis, one perioral bleed, and 13 nasal discolorations.

The study was not adequately powered to detect changes in secondary outcomes: no significant differences were seen in rates of return of spontaneous circulation, overall survival rates, or in the percentage of patients surviving neurologically intact to discharge.

Nordberg told heartwire that his group has also seen encouraging data suggesting that the RhinoChill process has a beneficial effect on myocardial function, and that animal studies have shown that transnasal evaporative cooling increases coronary perfusion pressure while improving resuscitation rates and left ventricular ejection fraction. These effects will be studied in a predefined subgroup analysis in the ongoing PRINCE trial, he said.

"In the PRINCE study, we have shown that this method of cooling can safely be performed during an arrest, without derailing the resuscitation effort, and is relatively easy to implement. Furthermore, we have shown that target tympanic and core temperatures are achieved several hours earlier than with standard hospital-based cooling," Nordberg said. "To achieve widespread clinical use of RhinoChill, the promising outcomes that are reported need to be repeated in a larger study to determine the extent of the added outcome benefit over hospital-based cooling alone."

Nordberg said that his group has just started the next trial with the RhinoChill technology, which will randomize cardiac arrest patients to either standard treatment with cooling upon arrival at the ICU or to early prehospital cooling with RhinoChill; unlike the previous study, this one will be powered to detect differences in total survival.

Commenting on the PRINCE study in his editorial, Becker suggests that the transnasal approach overcomes many of the challenges inherent in the transvenous fluid approach to induced hypothermia. "A strength of this approach appears to be its relative noninvasiveness and ease of administration," he writes. "It may prove an ideal device for the emergency medical services setting."

Bernard told heartwire that he finds these preliminary data on RhinoChill to be compelling, but he believes that, at least until more clinical data are available, "many clinicians will be anxious about the effects of literally freezing the skull base in patients, and puzzled as to how that cools the rest of the brain." He speculated that the RhinoChill technology might also be relatively expensive.

Where Are the American Studies?

In his editorial, Becker notes that all of the major randomized trials of therapeutic cooling have been done outside the US (three in Europe and two in Australia) on "meager" budgets. "The void in US clinical studies on cooling should disquiet us all. The problem deserves serious attention because it represents a failure of our medical research community to prioritize and advance research on a fairly low-cost, technologically simple technique that could save thousands of lives in a short time."

The challenges to conducting these trials in the United States include constraints imposed by regulatory agencies, difficulties of obtaining informed consent, patient confidentiality issues, funding, and market forces, Becker concludes.

"It is time that we acknowledge and openly discuss the fact that the cumulative effect of these realities has been to create an unforgiving barrier to clinical trials of therapeutic hypothermia in the United States."

The RICH study was funded by grants from the Australian National Health and Medical Research Council and the National Heart Foundation of Australia. The PRINCE study is supported by BeneChill, and Dr Denise Barbut, the founder and chair of BeneChill, participated in the study design, data analysis, and writing of the manuscript. Becker is the director of the Center for Resuscitation Science at the University of Pennsylvania and has received research support to the university from the National Institutes of Health, Phillips Medical Systems, Laerdal Medical, Cardiac Science, BeneChill Inc, Zoll Medical Corp, Abbott Point of Care, and the Medtronic Foundation. He has previously served as a consultant to Philips Medical Systems and Gaymar Industries, and currently is a paid consultant to the National Institutes of Health for the Data Safety Monitoring Board and Protocol Review Committee of the Resuscitation Outcomes Consortium.

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