The results of trial, presented online today at Critical Care Reviews Trial Results Meeting, titled ”The Targeted Hypothermia Versus Targeted Normothermia After Out-of-hospital Cardiac Arrest (TTM2)” which is also part of the upcoming June issue of The New England Journal of Medicine (https://www.nejm.org/doi/full/10.1056/NEJMoa2100591). TTM2 trial was an international, multicenter, randomized trial in which target temperature management initiated at the ICU with a target temperature of 33 °C after out-of-hospital cardiac arrest was compared with a strategy to maintain normothermia and active treatment of fever (≥ 37.8°C). Participants (1 900 patients) were randomized within 3 hours of return of spontaneous circulation with the intervention period lasting 40 hours in both groups. The primary outcome was all-cause mortality at 180 days after randomization and the main secondary neurological outcome was poor functional outcome at 180 days after arrest.

The pragmatic trial with cooling initiated at a late stage, after admission to the ICU, did not demonstrate any significant difference in mortality rates or intact neurological survival between the two strategies of targeted temperature management (33°C vs. early treatment of fever) and therefore cast doubt on the results of earlier trials that evaluated induced hypothermia in this population. This suggest that the value of temperature management in previous trials, although performed in different study populations, may have been an effect of avoidance of fever.

One key issue is the potential benefit of early cooling initiated during cardiopulmonary resuscitation (CPR). Nielsen et al. permitted a time to initiate cooling within 3 hours from return of spontaneous circulation (ROSC). We suggest that this time window, in line with experimental trials and clinical experience of accidental hypothermia, may be crucial to influence outcome. Studies have shown that the severity of neuronal lesions is dependent on the delay in initiation of cooling after reperfusion.[1] 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 good neurologic outcome in patients with out-of-hospital cardiac arrest, particularly if it applied less than 20 minutes after arrest[2] In patients with initial shockable rhythm ( VF/VT patients ), the difference in CPC 1-2 was 50.9% versus 29.8%, (p=0.003), and in the proportion with complete recovery CPC 1 (patients with complete neurological recovery) was 47.4% versus 21.1% (p=0.008). Thus, we should consider whether the benefit of this strategy with delayed onset of cooling may have attenuated the effect of hypothermia in this trial.

The effect of early cooling in patients with VF/VT was recently established in a pooled analysis in Critical Care Medicine of two randomized controlled trials (PRINCE and PRINCESS). 2020 American Heart Association’s guidelines has updated and strongly advised to implement early cooling and advanced TTM (”target temperature management”) systems following cardiac arrest.

This finding by Nielsen and collaborators also contradicts the recent understanding of the benefits of this form of therapy published by the same journal (The New England Journal of Medicine) in Dec 2019^[3]. The Therapeutic Hypothermia after Cardiac Arrest in Nonshockable Rhythm (HYPERION) trial showed that among patients with coma who had been resuscitated from cardiac arrest with non-shockable rhythm, moderate therapeutic hypothermia at 33°C compared with targeted normothermia (37 °C) led to a significantly higher percentage of patients who survived with a favorable neurologic outcome at day 90 (P = 0.04).

The studied patients had higher percentage of bystander-initiated CPR (80%) than in previous clinical trials (49 to 58%).[4][5] Thus, whether such results could be widely applied to communities with a longer time to resuscitation remains to be clarified. In prolonged cardiac arrest, we do not expect that a reduction of neurologic metabolism by hypothermia will have a real effect on already damaged structures.

We should not conclude, on the basis of this trial, that hypothermia is simply an anti-hyperthermic strategy. Not all cardiac arrests are equal in terms of the time to return of spontaneous circulation. A recent study presented during the American College of Cardiology 2021 Annual Scientific Session clearly shows the importance of the optimal prehospital care, including the ability to have a bystander perform chest compressions at the scene of the arrest, and the ability to rapidly, safely and effectively cool the patient’s brain by Rhinochill^®. Furthermore, early cooling of the brain during CPR and during transport of the patient to a dedicated cardiac center may serve as a bridge to reduce brain injury when treatment with ECMO is to be considered.

                      CEO Martin Waleij comments

The TTM2 study is large and well conducted but has several potential limitations, where the time to cooling is the most problematic and much less attention has been spent on the significance of the early-stage cooling on the outcomes due to the limitation of current practice. Therapeutic Hypothermia brought a great deal of benefits to numerous patients during the past decade particularly once it applied earlier to the shockable rhythm patients as shown by PRINCESS trial. Further analysis to identify the subgroups of patients who can benefit most from this form of therapy deem necessary. This trial added 37.5°C in addition to 33°C and 36°C for clinician to choose for SCA patients to implement high quality TTM.

Our solution the BrainCell concept will target, the problem with limitations of previous products in the treatments chain of cardiac arrest patients, as well as expanding the concept into neurology. By the integration of RhinoChill^® and BrainCool^™, BrainCell enables health-care personnel to easily and effectively and most importantly immediately initiate cooling of the brain immediately after the SCA (RhinoChill^®). The BrainCell ensures long-term cooling during multiple days (BrainCool™), completing the chain of treatment.

Following first TTM trial back in 2013 (Nielsen et al NEJM 2013 369;2197[6]), some physicians and health systems stopped routinely using hypothermia in patients or adopting a 36°C as target temperature, however, follow-up observational studies reported low compliance with target temperature 36°C, higher rates of fever, and a trend towards clinical worsening in patient outcomes.^[7] and even increased in mortality [8]

About the publication

See Protocol off TTM2in here for more info (https://clinicaltrials.gov/ct2/show/NCT02908308)

Although the rewarming rate is considered a delicate phase in TTM, the optimal rate of rewarming is still a knowledge gap in TTM field and further research may help elucidate this, and at least 1 trial is ongoing (NCT02555254) (Impact of Speed Of Rewarming After Cardiac Arrest and Therapeutic Hypothermia (ISOCRATE). https://clinicaltrials.gov/ct2/show/NCT02555254

BrainCool continue their mission that all cardiac arrest patients should be cooled at the earliest opportunity in a hospital or at field emergency setting with the aim and objective to improve survival and neurological recovery.

Our solution the BrainCell concept will target, the problem with limitations of previous products in the treatments chain of cardiac arrest patients, as well as expanding the concept into neurology.  

By the integration of RhinoChill^® and BrainCool^™, BrainCell enables health-care personnel to easily and effectively and most importantly immediately initiate cooling of the brain immediately after the SCA (RhinoChill^®). The BrainCell ensures long-term cooling during multiple days (BrainCool), completing the chain of treatment.”

This disclosure contains information that BrainCool is obliged to make public pursuant to the EU Market Abuse Regulation (EU nr 596/2014). The information was submitted for publication, through the agency of the contact person, on  2021-06-17 01:38 CET.

For more information

Martin Waleij – CEO                                                               
+46 – 733 -93 70 76                                                                                          
E-mail: martin.waleij@braincool.se                       

About BrainCool AB (publ)

BrainCool AB (publ) is an innovative medical device company that develops, markets, and sells leading medical cooling systems for indications and areas with significant medical benefits within the healthcare sector. The company focuses on two business segments, Brain Cooling and Oncology. BrainCool AB (publ) is based in Lund, Sweden, and its share is listed on Spotlight Stock Market.