A new publication in Circulation Journal, https://pubmed.ncbi.nlm.nih.gov/34261843/, with statistically significant results on patients whose collapse to return of spontaneous circulation (ROSC) interval was delayed over 18 min after shockable out-of-hospital cardiac arrest (OHCA) with in-hospital rapid cooling by intravenous ice-cold fluids.
The study was an analysis of collected data from 248 comatose survivors with ROSC who were treated with therapeutic hypothermia (34°C for 12-72 h) after witnessed shockable OHCA in Japan. A scientific presentation from Japan, investigating difference in applying rapid cooling from the ER versus standard treatment at the ICU (rapid cooling by intravenous ice-cold fluids vs. standard cooling) is showing strong results for earlier cooling. The primary endpoint was favourable neurological outcome (Cerebral Performance Category of 1 or 2) at 30 days after OHCA. Furthermore, the clinical study design divided the patients into 2 groups by the median collapse-to-ROSC interval (18 min).
The results of the clinical trial shows that in the longer collapse-to-ROSC interval group, over 18 minutes favourable neurological outcome was significant higher in the rapid cooling group than in the standard cooling group (60.7% vs. 33.3%, P<0.01) and the adjusted odds ratio after rapid cooling was 3.069 (95% confidence interval 1.423-6.616, P=0.004).
Sc manager Mohammad Fazel, PhD, PEng comments:
This scientific publication, by the research groups in Japan, clearly shows the association of the neurological outcome with the collapse-to-ROSC interval in the targeted temperature management (TTM) space. In general, there is no established consensus on the relationship of the duration from collapse to the beginning of TTM, from ROSC to the beginning of TTM or from the beginning of TTM to the achievement of target temperature. However, recent clinical evidence published May 2019 in JAMA from PRINCESS trial showed that the intra-arrest therapeutic hypothermia, initiated in the field with trans nasal evaporative cooling (with RhinoChill), compared to standard care would provide benefits in survival with significantly improved neurologic outcome in OHCA patients with initial shockable rhythm, particularly if it applied less than 20 minutes after arrest. The study by this group, Matsuzaki et al, also suggest that the time window between collapse to ROSC may be crucial to influence neurological outcome to manifest the potential benefit of early cooling. The authors conclude that "Rapid cooling after hospital arrival improved neurologically intact survival in comatose survivors whose collapse-to-ROSC interval was delayed more than 18 min after shockable OHCA."
Comparison of the by stander CPR in the study population
Furthermore, the studied patients had similar percentage of bystander-initiated cardiopulmonary resuscitation (CPR) (~50%) with the first two positive randomized human evidence emerged in 2002 (49%) (HACA and Bernard Trials) [,] ; and much lower compared to the study population in the TTM2 trial (82%). The TTM2 trial compared TTM at 33°C to TTM at 37°C in patients resuscitated from cardiac arrest and found no difference in neurologic outcome or mortality. However, the majority of the patients in TTM2 trial were recruited in countries with a high rate of bystander CPR. Thus, whether such results could be widely applied to communities with a longer time to resuscitation remains to be clarified. Retrospective studies indicate that patients with a short cardiac arrest time (as it is in case of bystander CPR) and, thus, only minor brain damage might not benefit from mild hypothermia as the beneficial effect of mild hypothermia increases with cumulative time of circulatory standstill. For instance, in Germany, the rate of bystander-CPR is about 40% (in US this value is about 33%), and consequently more severe brain damage in OHCA patients is expected in these regions.
Thus, TTM may offer a great deal of benefits to these patients. Even Though theTTM2 trial is incredibly well performed study, the results only reflected for the study population they included, under their study conditions and are not for the patients and conditions at most US hospitals and Germany. Compared to the most recent data in US, TTM2 has two times more of the numbers of witnessed arrest and bystander CPR and almost three times more of shockable rhythms. All of these parameters are well-established to track with post-arrest injury.
Safety concerns and adverse events using Prehospital infusion of ice-cold fluids
Prehospital infusion of ice-cold fluids has been reported to cause recurrent cardiac arrest or in-hospital pulmonary edema in many cases, and current guidelines do not recommend prehospital induction of therapeutic hypothermia with ice-cold fluids. Authors of this study also reported that in some patients with a favorable neurological outcome, the core temperature, once it was successfully lowered by approximately 1°C by infusion of cold fluids, increased again when the patient entered the intensive care unit, because undergoing coronary angiography or PCI takes time in primary care.
CEO Martin Waleij comments
It is apparent that there is a time window for delivering therapeutic TTM treatment. This study provides good evidence for in-hospital rapid induction of cooling with the BrainCell concept for shockable OHCA, indicating the shorter Time to door to target, the better outcome. The BrainCool vision and strategy is by applying intra arrest cooling (that is cooling during cardiac arrest before ROSC) we will be able to further enhance this promising results.
 Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557-63.
 The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549-56.