Temperature Management in Adult Cardiac Arrest: Advanced Life Support Systematic Review

The statement "Whether subpopulations of cardiac arrest patients may benefit from targeting hypothermia at 32-34oC remains uncertain. " feels too weak a statement, as it essentially discards a very well performed positive multicenter trial (Hyperion), and newer severity of illness data (Callaway, 2020; Nishikimi, 2021). I would recommend "RCT and cohort data exist suggesting a potential role for targeting hypothermia at 32-34oC to improve neurologic outcome in selected subpopopulations" - this seems to be more appropriately inclusive of all clinical scientific evidence available to date – as I’m not sure it’s fair to say that TTM2 directly overturned Hyperion since the populations included were so different.

The statement "We suggest actively preventing fever by targeting a temperature ≤ 37.5 for those patients who remain comatose after ROSC from cardiac arrest (weak recommendation, low certainty evidence)." without any mention to a range of temperature, i.e. 32-37.5 could be misinterpreted from the point of view of science communication. The comparison of temperature in TTM2 between 33°C and ≥37.8°C found no difference in death at 6 months. For this reason from my perspective it could be more appropriate in term of "good communication of science" to suggest the two options of temperature and not a generic terms preventing fever by targeting ≤ 37.5. This could deeply affect the good practice in real world and the risk could be to abandon completely the Targeted Temperature Management. The patient in the post cardiac arrest needs a TTM between 33-34°C or actively preventing fever by targeting a temperature ≤ 37.5. The risk is to abandon alone the patiet with an uncontrolled temperature and with risk of severe brain injury. A more correct and adherent to the scientific evidence statement would be, similarly to the 2015-2020 one: We suggest target temperature management actively targeting a temperature between 33-37.5 °C for those patients who remain comatose after ROSC from cardiac arrest (weak recommendation, low certainty evidence).

The recommendations do not specifically address 32-34 in a clear way other than they are incorporated into the the < 37.5 statement and that some may benefit. It seems to be very vague and does address 32-34 but instead steps around it a bit. The justifications have more information about what people thought about 32-34. This may have been the intention, but it would be nice to see the TF mention 32-34 in the treatment recommendations in some way that highlights what seems like a shift

The first proposal should be: “We recommend targeted température management aiming at core temperature <37.5’C for those …”. We are talking about still active therapy in most of patients. I understand the Level of evidence could be low (despite TTM2), but the way the statement is Made is misleading “We suggest …” - What is the alternative? Doing nothing ? This has not been studied and should be better clarified that abandoning all form of TTM is not an option (unless you want to point out which populations have never been studied …)

Please be carefull to interprete the TTM2 for all other communities beyond the Europe. In the low income countries and limited resources. CA patient usually have long no flow time and low flow time (not 25 m but 30 -40). No mobile defibrillator. No standard CPR. I personally think that it really work (33 degree) with my patients who suffer, obviously severly injured brain. Quan Nguyen PhD MD, Bachmai hospital Hanoi Vietnam

Suggest replacing the word "comatose" for a more descriptive term of the neurologic status of patients included in TTM trials akin to AHA guidelines ("not following commands" or GCS motor subscore <6) as there are a subset of patients that are unconscious but not fulfilling criteria for comatose (only reflexes) in stricto sensu. The taskforce acknowledge the different terms, but it is unclear why comatose was used. AHA I agree with other comments pertaining to the relative shy language on the degree of temperature modulation for all cardiac arrest (particularly given the point-estimates for the meta-analysis with random-effects), which is likely stemming from TTM2 trial results that is not applicable to a broad patient population. For instance, IHCA and nonshockable Hyperion is the best evidence we have (despite being only Fr and having an unfavorable fragility index), and a consideration for addressing different populations according to the level of evidence would be welcomed. I am concerned about "Comatose patients with mild hypothermia after ROSC should not be actively warmed to achieve normothermia (good practice statement)". We do not know if slow active rewarming (as done in trials) is better or worse than uncontrolled passive rewarming. Rather than taking a stance on the mode of rewarming, an alternative approach is to recommend that if targeting higher temperatures than current core temperature, rewarming should be no faster than 0.25C/h. Unfortunately, approach to shivering was not included as PICOST but remains an important knowledge gap and integral to any TTM regardless of target temperature. Would be potentially helpful to outline as such and be addressed in future iterations.

Section of Recommendation in Conclusions: 1. The proposed statement regarding the active prevention of fever less than or equal to 37.5°C may be limited as only roughly half of the patients in the normothermic group used temperature management devices in the TTM 2 study (Dankiewicz 2021, 2283). As such, ALS TFMs phrased this as a suggestion. Despite this, we are seriously concerned that even more physicians will abandon temperature management than after the previous TTM shock in 2013. This could further worsen the neurological outcomes of ROSC patients around the world. Consensus and treatment recommendations should be scientific, and any recommendation statements that might include the possibility of worsening patient outcomes should be cautiously delivered or even reconsidered. Another concern regarding this statement is that it can be read as just controlling the body temperature to less than or equal to 37.5°C after ROSC, which means that it could be applicable even when the body temperature varies, for example, between 35 and 37.5°C. It is thus necessary to include a statement limiting the body temperature variations after ROSC for at least 48 h. Alternatively, we suggest target temperature management that actively targets a temperature between 33 and 37.5°C in comatose patients after ROSC using temperature management devices. 2. We strongly suggest that the following phrase be added after the sentence, “Whether subpopulations of cardiac arrest patients may benefit from targeting hypothermia at 32-34 oC remains uncertain”: “and further research using high-quality targeted hypothermia for selected subpopulations based on the severity of brain injury would help elucidate this issue.” Section of Justification in Conclusions: In addition to the discussion by ALS TFMs described in the Justification and evidence of the decision framework highlights, we note the following: 1. There is a huge variation in reported survival outcomes and other core elements of the current Utstein-style recommendations for OHCA across nations and regions (Kiguchi 2020, 39), as reported by ILCOR. Only two RCTs of targeted hypothermia were not effective in improving the neurological outcomes of brain injury in ROSC patients in TTM (Nielsen 2013, 2197) and TTM2 (Dankiewicz 2021, 2283) studies. As such, assuming that this would happen in patients with completely different backgrounds and severity must be done with caution. 2. Recent registry studies revealed that targeted hypothermia was associated with better neurological outcomes in stratified cardiac arrest patients depending on concurrent diseases and their severity (Callaway 2020, e208215; Nishikimi 2021, e741). 3. It is crucial to differentiate the levels of severity of brain damage after ROSC, as there may be uncharacteristic heterogeneity in the patient population. 3. Basic research has demonstrated that the brain-protective effect of hypothermia is canceled when the time required to achieve the target temperature exceeds 4 h (Che 2011, 1423). In the TTM/TTM2 studies, it took over 8 h from cardiac arrest through randomization to reach the target body temperature, and it is, therefore, unsurprising that there were no significant differences. In addition, there were large temperature fluctuations during the maintenance period, which should not happen in high-quality TTM, and which may lead to an increase in complications. Therefore, recommendation statements related to actively preventing fever because of the possibility of worsening patient outcomes should be delivered very cautiously or even reconsidered. Japan Resuscitation Council President, Hiroshi Nonogi, MD, PhD

The general statement for fever prevention seems too broad and the subgroup statement seems too weak. Given that conventional '1-variable-at-a-time' subgroup analysis was used in the majority of these studies, usually based on relatively arbitrary cutoffs to dichotomize continuous variables, and that evaluating effect modification with an proper heterogeneity of treatment effect analysis has not yet been performed by the TTM team (which I understand is planned), a blanket statement suggesting fever prevention for all comatose patients seems premature. At a minimum, please consider qualifying the first recommendation on fever prevention to the population that is driving the strength of the evidence (ie presumed cardiac cause, sustained ROSC, definitively managed within 3-4 hours of ROSC, etc.), particularly due to the large number of patients screened versus enrolled in the majority of the studies.

#Regarding Statement: “We suggest actively preventing fever by targeting a temperature ≤ 37.5 for those patients who remain comatose after ROSC from cardiac arrest (weak recommendation, low certainty evidence).” I congratulate the authors for incorporating new science in such short time frame from publication of a seminal study. My main concern with this statement is that TTM aiming 32-34C is not explicitly addressed. Are the authors suggesting that TTM 32-34C should not be done? Or perhaps the authors suggest that the 37.5C goal is preferred over the 32-34C goal. If this is the intent of this statement, I think that clearly spelling things out would help readers incorporate this recommendation in their practice. If the authors are not sure yet and there was not consensus, incorporating explicit guidance on TTM 32-34C would help readers interpret these recommendations in the post-TTM2 context. This is the key question practitioners are trying to address after TTM2 results. Guidance on this topic is one of the main reasons practitioners are going to refer to these ILCOR recommendations, so having that spelled out would be very helpful.

I am no expert, but there is a lot of data coming from different groups all over the world (RCTs, observational data, animal data) that show that hypothermia around 33°C has a strong benefit. In the current proposal 32°C-34°C is not even mentioned as if data other than coming from the TTM trials do not exist. The two TTM trials (coming from one group) showed that under certain circumstances (short cardiac arrest, long time until the therapy is started) 33°C may not be beneficial – but what about all the other RCTs coming from different groups that show that it works?

I am concerned about the downgrading of the HACA and Bernard trials to hypothesis generating pilot trials when discussing TTM1 and TTM2 resulting in a way that knowledge seems to be drawn only from the two TTM trials. The way of study conduct has certainly changed over the last 20 years, but still there are differences between the early trials showing outcome differences and the later not showing them. In contrast to cancelling all previous recommendations and abandoning hypothermia, ILCOR should implement a task force responsible to investigate the potential reasons for such differences in outcome betwenn the earlier and the later trials. It might not only be the way of study designs, but maybe other important deifferences might explain differences such asconcomittant medications (earlier studies without, TTMs with propofol), neurological prognostication (which has not been validated until now), speed and precision of cooling (when it takes more than 7 hours on average in both TTM trials to get to 33°C, have these trials really investigated hypothermia?). If ILCOR likes to adopt the wording from TTM2, the recommendations regarding fever prevention instead of hypothermia may include the remark "...in patient in whome hypothermia cannot be rapidly achieved".

According to legend, after being forced to recant his claims that the Earth moves around the Sun, Galilleo Gallilei said ‘E pur si muove.’ This is roughly taken to mean that despite his recantation, the Church's proclamations to the contrary, or any other conviction or doctrine of men, the Earth does, in fact, move (around the Sun and not vice versa.) https://en.wikipedia.org/wiki/And_yet_it_mov s Disclosure I am principal investigator of a randomized trial of hypothermia in patients with ST-elevation myocardial infarction. The trial is sponsored by ZOLL Circulation (San Jose, CA), which manufactures and markets devices for intravascular temperature management (IVTM). Overview I congratulate the members of the International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support (ALS) Task Force on their timely synthesis of the effectiveness of induced hypothermia (IH) or targeted temperature management (TTM) in patients resuscitated from cardiac arrest (CA). However, I encourage the members of the ALS task force to go a bit further in their analysis of prior trials of TTM after CA. A useful method for doing so when a trial fails to detect a difference in the primary outcome was previously published.(1) Below I use this method as a framework for my comments on the lack of benefit of TTM in patients with cardiac arrest reported in the TTM2 trial. Note that I have shortened and reordered this framework a bit to make the critique more coherent. I ask that the members of the ALS task force consider my critique below before they conclude whether based on the totality of evidence available it is plausible that hypothermia is or is not beneficial in patients resuscitated from cardiac arrest. Is There A Strong Biologic Rationale That Favors Treatment? Multiple studies in small and large animal models of cardiac arrest demonstrate that hypothermia to 34C or less is better than normothermia.(2-14) As well, multiple studies in small and large animal models of cardiac arrest demonstrate that rapid hypothermia is better than delayed hypothermia.(5, 8, 15, 16) In humans resuscitated from CA, briefer time from restoration of spontaneous circulation (ROSC) to target temperature is associated with significantly reduced likelihood of death or neurologic impairment.(17) The impact of this work has been limited in part by an error in the table of the article that is acknowledged by the authors but has not been corrected in the publication (Table 1). Note that other studies in humans have failed to detect this relationship. But these latter studies evaluated patients with a prolonged downtime who were unlikely to benefit from the intervention, or did not rapidly achieve target temperature, or lacked power to detect a small but important association between treatment time intervals and outcome. Collectively these data demonstrate that there is a strong biologic rationale that favor treatment with rapid induction and maintenance of hypothermia to reduce morbidity and mortality after resuscitation from CA. Is There Some Indication of Potential Benefit? A key difference among trials of IH or TTM in patients resuscitated from CA is time to target temperature. Holzer and Sterz reported time from ROSC vs. core temperature (Figure 1):(18) in the intervention group, this was approximately 8 h to 34C. Generally, subsequent trials have reported time from randomization to target temperature rather than time from ROSC. But there is large variation in the time from ROSC to target temperature as estimated from the primary results of each trial (Table 2). Note that the TTM2 investigators stated in their methods paper that ‘rapid cooling in the hypothermia group will be achieved by means of cold fluids and cooling devices.’(19) A key exclusion criterion in the TTM2 trial was if more than 180 minutes had passed from ROSC to screening of eligibility for enrollment. In their primary report of the results of TTM2,(20) the investigators emphasize the time from randomization rather than ROSC to target temperature. Despite their stated goal of applying rapid cooling, they reported a similar time to target temperature in TTM2 as they achieved in the original TTM.(21) A leader of the TTM2 trial has stated that patients enrolled in the trial were cooled as fast as is feasible using contemporary medical devices.https://web.archive.org/web/*/https://twitter.com/DogICUma/status/1405348094594621444 But the recent TTM24vs48 trial(22) achieved briefer time to target temperature than that achieved in TTM2: (281 [IQR, 217-360] minutes in the 48 h group vs. 320 [IQR 241-410] minutes in the 24 h group [P = .01]. Importantly the mean core temperature did not achieve the intended target temperatures in the intervention group in neither TTM nor TTM2 (i.e., mean core temperature did not cross 34C). Collectively, these data suggest that the relative benefit of IH was attenuated as compared to the control group in the TTM2 trial because the intervention was neither delivered as intended nor as quickly as feasible. The planned primary outcome of TTM2 was all-cause mortality at six months.(20) Other outcomes were assessed at 30 days, 6 months, and 24 months after randomization. Although there was no significant difference in mortality between the intervention and control group at six months, it appears that the intervention was associated with increased early mortality as the survival curves have wider separation around 30 days but come together after that (Figure 2). A plausible interpretation of this is that hypothermia as implemented in the TTM2 trial was associated with increased early mortality. In the TTM2 trial, hypothermia was initiated with chilled intravenous saline in the TTM2 trial.(19, 23) In an animal model of CA, intra-arrest chilled intravenous saline was associated with reduced coronary perfusion pressure (CPP).(24) It is well known that greater CPP is associated with greater likelihood of resuscitation.(25) In humans resuscitated from CA, chilled intravenous saline to initiate hypothermia was associated with no survival benefit and possible increased adverse events.(26, 27) Collectively, these data suggest that the use of chilled intravenous saline to initiate TTM could have contributed to the apparent increased early mortality in the intervention group as compared to the control group in the TTM2 trial. Was The Treatment Regimen Appropriate? The majority of patients who were enrolled in the TTM2 had hypothermia induced and maintained with surface cooling methods (SCM) as opposed to intravascular temperature management (IVTM). But SCM cools at slower rates than IVTM.(28) Multiple systematic reviews show that use of SCM is associated with worse outcomes than IVTM.(29, 30) Collectively, these data suggest that it is plausible that use of SCM rather than IVTM attenuated differences between the intervention and control group in the TTM2 trial. Limited information is available about the quality of post-resuscitation care that was provided to patients enrolled in the TTM2 trial. During the TTM2 trial, ‘general intensive care management [was] according to standard practice at participating hospitals.’(19) A leader of the TTM2 trial has stated that all patients received good concurrent care because they were enrolled at sites that have collaborated with the TTM investigators for years.(Personal Communication, N Nielsen, Jun 23, 2021) But 33% of patients who participated in TTM2 were enrolled at sites that did not participate in the original TTM trial. Importantly, a retrospective analysis of observational data previously demonstrated that the quality of post-resuscitation care including but not limited to how TTM is initiated and maintained is associated with outcome after resuscitation from CA.(31) Below I explain why the quality of concurrent care is relevant to interpretation of the TTM2 trial. The intervention group received significantly more propofol than the control group in the TTM2 trial: median (interquartile range) 8,768 (3,683, 13,365) mg vs. 7,744 (3,183, 12,595) mg [p value not stated].(20) Propofol is commonly used as an anesthetic and sedative agent in emergency departments and intensive care wards because of its rapid onset and weaning. But it has dose-dependent effects on mitochondria. At low doses, it reduces reactive oxygen species.(32) At higher doses, it reduces adenosine triphosphate (ATP) synthesis.(32-36) The latter seems likely to be undesirable in patients who have recently been deprived of oxygen and have intracellular energy depletion such as after resuscitation from CA. But coronary artery bypass grafting is also associated with deprivation of oxygen and intracellular energy depletion.(37, 38) In a systematic review of multiple randomized trials in patients undergoing coronary artery bypass grafting (n=13 trials, n=696 patients), the use of propofol was associated with increased myocardial injury as compared to use of sevoflurane.(39) In another randomized trial in patients undergoing coronary artery bypass grafting (n=39), use of propofol blocked cardioprotection by remote ischemic conditioning.(40) Note that the two landmark trials that demonstrated that hypothermia improved outcomes as compared to normothermia were both conducted before propofol was available for clinical use.(18, 41) Collectively, these data suggest that it is plausible that frequent use of propofol attenuated the relative benefit of hypothermia as compared to normothermia in the TTM2 trial. Overall, 38% of patients enrolled in TTM2 underwent PCI.(20) Evidence-based practice guidelines strongly recommend administration of a P2Y12 as early as possible or time of PCI.(42) This can include clopidogrel, prasugrel or ticagrelor. It seems plausible that the majority of patients who underwent PCI in the TTM2 trial received clopidogrel as 99% of patients were enrolled at sites located outside the United States, and health care costs are more constrained outside rather than inside the US . But clopidogrel is a prodrug that must be both absorbed and metabolized before having biological activity. Thus, clopidogrel is associated with delayed inhibition of platelet reactivity in patients undergoing induced hypothermia.(43-45) The clinical important of this delay was demonstrated in a randomized trial of intraperitoneal hypothermia in patients with STEMI undergoing PCI.(46) According to the trial protocol, all patients received clopidogrel prior to PCI. There was a significant increased rate of acute stent thrombosis in the intervention group as compared to the control group. The investigators attributed this adverse event to use of clopidogrel. Collectively, these data suggest that it is plausible that frequent use of clopidogrel in the setting of PCI in the TTM2 trial could have been associated with acute stent thrombosis, and thereby contributed to the apparent increased early mortality observed in the intervention group in the TTM2 trial. Overall, 16% of patients enrolled in the TTM2 trial received an implantable cardioverter defibrillator (ICD) during follow-up. Evidence-based practice guidelines strongly recommend implantation of ICDs in survivors of ventricular fibrillation as it is associated with a significant and important mortality benefit.(47) In contrast to the low rate of ICD use in the TTM2 trial, 42% of a national US sample of patients admitted after resuscitation from out of hospital CA in 2002/2003 underwent ICD insertion.(48) Thus, it seems plausible that underuse of ICDs in the TTM2 trial reduced overall survival and attenuated differences in outcome between the control and intervention group. Do Secondary Outcomes Elicit Reveal Positive Findings? The TTM2 trial reported a significant increase in the rate of bradycardia requiring pacing in the intervention group as compared to the control group.(20) It is unclear whether investigators were given specific guidance on when pacing was required in the TTM2 trial protocol.(19) Bradycardia is commonly observed during application of hypothermia. But such bradycardia is associated with increased cardiac output due to increased stroke volume.(49) The TTM investigators and others previously reported that the presence of early bradycardia is associated with improved survival and neurologic outcome after CA.(50, 51) Collectively, these data suggest that the clinical significance of the increased rate of bradycardia requiring pacing reported in the TTM2 is incompletely defined. Can Alternative Analyses Help? Multiple alternative analyses of TTM2 trial data could help better elucidate the effect hypothermia versus normothermia in patients resuscitated from CA. The TTM2 investigators noted that a limitation of the trial was a potential heterogeneous intervention effect, depending on the mode of cooling, and hence different speeds of cooling used at different enrolling sites.(19, 23) An analysis that stratified results by enrolling site could yield insight into the clinical heterogeneity of the effect of hypothermia versus normothermia. There are multiple factors that could have modified the effect of hypothermia as compared to normothermia in the TTM2 trial, as outlined above. An analysis that adjusted for or restricted to optimal method of IH/TTM (e.g., IVTM) as well as receipt of good concurrent care (e.g., type of P2Y12 inhibitor; sedation without propofol; insertion of an ICD) would inform consideration of whether hypothermia does or does not improve outcomes in patients resuscitated from cardiac arrest. However, such an analysis would likely lack power to detect a difference in outcomes as it appears from reports to date that a minority of patients received such care. Until the results of alternative analyses become available, it seems premature to place too much credence on the results of the TTM2 trial. Does More Positive External Evidence Exist? Evidence external to that of the TTM2 trial suggests that hypothermia improves outcomes as compared to normothermia. The HYPERION trial demonstrated that in patients with a first-recorded rhythm that is non-shockable, 10.2% of patients in the hypothermia group were alive with a CPC score of 1 or 2 at 90 days, as compared to 5.7% in the normothermia group (difference, 4.5 percentage points; 95% confidence interval [CI], 0.1 to 8.9; P = 0.04).(52) As well, there was no significant difference in adverse events between the hypothermia and normothermia group. When the original TTM trial was published post-resuscitation practices changed at many hospitals to favor use of a target temperature of 36C as opposed to 33C. Several large multicenter before-after studies conducted outside the US have demonstrated that this change in practice was independently associated with increased mortality.(53, 54) Multiple retrospective analyses of multicenter observational data from the US demonstrate that there is a significant relationship between the duration of ischemia and the effect of hypothermia in patients resuscitated from CA.(55, 56) It seems implausible that if is truly no benefit to hypothermia in patients resuscitated from cardiac arrest, such a dose-response relationship exists between greater hypothermia and better outcomes. Collectively, these data suggest that it is plausible that, notwithstanding the results of the TTM2 trial as well as a systematic review of trials completed to data, hypothermia improves outcomes compared to normothermia in patients resuscitated from cardiac arrest. Summary There are multiple plausible explanations why hypothermia as compared to normothermia did not improve neurologic outcome in the TTM2 trial. The large sample size of TTM2 dilutes the benefit of hypothermia observed in prior trials when pooled together in a systematic review. The results of the TTM2 trial lack face validity as compared to the strong biologic rationale in favor of hypothermia. The TTM2 investigators did not implement the intervention as intended, implemented it in a manner that disfavored hypothermia versus normothermia, and appear to have not consistently provided good concurrent care. There is abundant positive external evidence which suggests that hypothermia is beneficial compared to normothermia in patients resuscitated from CA. In summary, despite the proclamations of the TTM2 investigators to the contrary, in fact hypothermia compared to normothermia likely improves outcomes in patients resuscitated from CA when delivered with optimal methods and good concurrent care. Figure 1: Temperature vs. Time from Restoration of Spontaneous Circulation in HACA Trial(18) Figure 2: Survival with Hypothermia versus Normothermia Over Time in TTM2 Trial(20) Table 1: Predictors of Death or Neurologic Impairment Six Months After Cardiac Arrest(17) Factor Odds Ratio (95% CI) P Value Age, per additional year 1.04 (1.005, 1.08) 0.02 Time to ROSC, per additional minute 1.06 (1.01, 1.12) 0.01 Time to Temp. Target, per additional min. 1.005 (1.002, 1.009) 0.006 First rhythm non-shockable 13.8 (3.4, 56.1) <0.001 Arterial Blood pH, per unit increase 0.009 (0.001, 0.38) 0.04 Data corrected from original publication Table 2: Characteristics of Randomized Trials of Hypothermia vs. Normothermia in Patients Resuscitated From Cardiac Arrest Population Treatment Group Treatment Method Temperature Target, °C Estimated Time from Onset of Arrest to Target Temperature, mins. Favorable Neurologic Outcome, % P Value Bernard(41) Unconscious adults Resuscitated from Out of Hospital VF Normothermia (n=34) n/a n/a 261 0.046 Hypothermia (n=43) Cold Packs 33°C ~270 491 HACA(18) Unconscious adults Resuscitated from Witnessed Out of Hospital VF or Pulseless VT Normothermia (n=138) n/a n/a 392 0.009 Hypothermia (n=137) Cooling Tent 32-34°C ~420 552 TTM(21) Unconscious adults Resuscitated from Out of Hospital VF, Pulseless Electrical Activity (PEA) or Witnessed Asystole Mild Hypothermia (n=466) 76% Surface; 24% IVTM 36°C n/a 483 0.51 Moderate Hypothermia (n=473) 76% Surface; 24% IVTM 33°C >660 473 Hyperion(52) Unconscious adults Resuscitated from PEA or Asystole of Any Cause Mild Hypothermia (n=297) 81% Surface; 15% IVTM 37°C n/a 54 0.04 Moderate Hypothermia (n=284) 89% Surface; 15% IVTM 33°C ~710 104 TTM2(20) Unconscious adults Resuscitated from Out of Hospital CA of Presumed Cardiac or Unknown Cause Hypothermia (n=931) 69% Surface; 31% IVTM 36°C n/a 455 Not Stated Normothermia (n=930) 70% Surface; 30% IVTM 33°C ~550 45 5 1Primary outcome was good neurologic outcome, defined as discharge home or to a rehabilitation facility 2Primary outcome was favorable neurologic outcome within six months, defined as a Pittsburgh cerebral-performance category of 1 (good recovery) or 2 (moderate disability) on a five- category scale 3Primary outcome was mortality at end of study follow up. 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Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial. JAMA. 2017;318(4):341-50. 23. Jakobsen JC, Dankiewicz J, Lange T, Cronberg T, Lilja G, Levin H, et al. Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest: a statistical analysis plan. Trials. 2020;21(1):831. 24. Yannopoulos D, Zviman M, Castro V, Kolandaivelu A, Ranjan R, Wilson RF, et al. Intra-cardiopulmonary resuscitation hypothermia with and without volume loading in an ischemic model of cardiac arrest. Circulation. 2009;120(14):1426-35. 25. Paradis NA, Martin GB, Rivers EP, Goetting MG, Appleton TJ, Feingold M, et al. Coronary perfusion pressure and the return of spontaneous circulation in human cardiopulmonary resuscitation. JAMA. 1990;263(8):1106-13. 26. Kim F, Nichol G, Maynard C, Hallstrom A, Kudenchuk PJ, Rea T, et al. Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial. JAMA. 2014;311(1):45-52. 27. Bernard SA, Smith K, Cameron P, Masci K, Taylor DM, Cooper DJ, et al. Induction of prehospital therapeutic hypothermia after resuscitation from nonventricular fibrillation cardiac arrest*. Crit Care Med. 2012;40(3):747-53. 28. Sonder P, Janssens GN, Beishuizen A, Henry CL, Rittenberger JC, Callaway CW, et al. Efficacy of different cooling technologies for therapeutic temperature management: A prospective intervention study. Resuscitation. 2018;124:14-20. 29. Bartlett ES, Valenzuela T, Idris A, Deye N, Glover G, Gillies MA, et al. Systematic review and meta-analysis of intravascular temperature management vs. surface cooling in comatose patients resuscitated from cardiac arrest. Resuscitation. 2020;146:82-95. 30. Calabro L, Bougouin W, Cariou A, De Fazio C, Skrifvars M, Soreide E, et al. Effect of different methods of cooling for targeted temperature management on outcome after cardiac arrest: a systematic review and meta-analysis. Crit Care. 2019;23(1):285. 31. Stub D, Schmicker RH, Anderson ML, Callaway CW, Daya MR, Sayre MR, et al. Association between hospital post-resuscitative performance and clinical outcomes after out-of-hospital cardiac arrest. Resuscitation. 2015;92:45-52. 32. Branca D, Vincenti E, Scutari G. Influence of the anesthetic 2,6-diisopropylphenol (propofol) on isolated rat heart mitochondria. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 1995;110(1):41-5. 33. Branca D, Roberti MS, Vincenti E, Scutari G. Uncoupling effect of the general anesthetic 2,6-diisopropylphenol in isolated rat liver mitochondria. Arch Biochem Biophys. 1991;290(2):517-21. 34. Branca D, Roberti MS, Lorenzin P, Vincenti E, Scutari G. Influence of the anesthetic 2,6-diisopropylphenol on the oxidative phosphorylation of isolated rat liver mitochondria. Biochem Pharmacol. 1991;42(1):87-90. 35. Sztark F, Ichas F, Ouhabi R, Dabadie P, Mazat JP. Effects of the anaesthetic propofol on the calcium-induced permeability transition of rat heart mitochondria: direct pore inhibition and shift of the gating potential. FEBS Lett. 1995;368(1):101-4. 36. Rigoulet M, Devin A, Averet N, Vandais B, Guerin B. Mechanisms of inhibition and uncoupling of respiration in isolated rat liver mitochondria by the general anesthetic 2,6-diisopropylphenol. Eur J Biochem. 1996;241(1):280-5. 37. Madathil RJ, Hira RS, Stoeckl M, Sterz F, Elrod JB, Nichol G. Ischemia reperfusion injury as a modifiable therapeutic target for cardioprotection or neuroprotection in patients undergoing cardiopulmonary resuscitation. Resuscitation. 2016;105:85-91. 38. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007;357(11):1121-35. 39. Yao YT, Li LH. Sevoflurane versus propofol for myocardial protection in patients undergoing coronary artery bypass grafting surgery: a meta-analysis of randomized controlled trials. Chin Med Sci J. 2009;24(3):133-41. 40. Kottenberg E, Thielmann M, Bergmann L, Heine T, Jakob H, Heusch G, et al. Protection by remote ischemic preconditioning during coronary artery bypass graft surgery with isoflurane but not propofol - a clinical trial. Acta Anaesthesiol Scand. 2012;56(1):30-8. 41. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557-63. 42. O'Gara PT, Kushner FG, Ascheim DD, Casey DE, Jr., Chung MK, de Lemos JA, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(4):e362-425. 43. Bjelland TW, Hjertner O, Klepstad P, Kaisen K, Dale O, Haugen BO. Antiplatelet effect of clopidogrel is reduced in patients treated with therapeutic hypothermia after cardiac arrest. Resuscitation. 2010;81(12):1627-31. 44. Bednar F, Kroupa J, Ondrakova M, Osmancik P, Kopa M, Motovska Z. Antiplatelet efficacy of P2Y12 inhibitors (prasugrel, ticagrelor, clopidogrel) in patients treated with mild therapeutic hypothermia after cardiac arrest due to acute myocardial infarction. J Thromb Thrombolysis. 2016;41(4):549-55. 45. Steblovnik K, Blinc A, Mijovski MB, Fister M, Mikuz U, Noc M. Ticagrelor Versus Clopidogrel in Comatose Survivors of Out-of-Hospital Cardiac Arrest Undergoing Percutaneous Coronary Intervention and Hypothermia: A Randomized Study. Circulation. 2016;134(25):2128-30. 46. Nichol G, Strickland W, Shavelle D, Maehara A, Ben-Yehuda O, Genereux P, et al. Prospective, multicenter, randomized, controlled pilot trial of peritoneal hypothermia in patients with ST-segment- elevation myocardial infarction. Circ Cardiovasc Interv. 2015;8(3):e001965. 47. Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2018;138(13):e210-e71. 48. Birnie DH, Sambell C, Johansen H, Williams K, Lemery R, Green MS, et al. Use of implantable cardioverter defibrillators in Canadian and US survivors of out-of-hospital cardiac arrest. CMAJ. 2007;177(1):41-6. 49. Forkmann M, Kolschmann S, Holzhauser L, Ibrahim K, Guenther M, Christoph M, et al. Target temperature management of 33 degrees C exerts beneficial haemodynamic effects after out-of-hospital cardiac arrest. Acta Cardiol. 2015;70(4):451-9. 50. Thomsen JH, Nielsen N, Hassager C, Wanscher M, Pehrson S, Kober L, et al. Bradycardia During Targeted Temperature Management: An Early Marker of Lower Mortality and Favorable Neurologic Outcome in Comatose Out-of-Hospital Cardiac Arrest Patients. Crit Care Med. 2016;44(2):308-18. 51. Staer-Jensen H, Sunde K, Olasveengen TM, Jacobsen D, Draegni T, Nakstad ER, et al. Bradycardia during therapeutic hypothermia is associated with good neurologic outcome in comatose survivors of out-of-hospital cardiac arrest. Crit Care Med. 2014;42(11):2401-8. 52. Lascarrou JB, Merdji H, Le Gouge A, Colin G, Grillet G, Girardie P, et al. Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm. N Engl J Med. 2019;381(24):2327-37. 53. Salter R, Bailey M, Bellomo R, Eastwood G, Goodwin A, Nielsen N, et al. Changes in Temperature Management of Cardiac Arrest Patients Following Publication of the Target Temperature Management Trial. Crit Care Med. 2018;46(11):1722-30. 54. Nolan JP, Orzechowska I, Harrison DA, Soar J, Perkins GD, Shankar-Hari M. Changes in temperature management and outcome after out-of-hospital cardiac arrest in United Kingdom intensive care units following publication of the targeted temperature management trial. Resuscitation. 2021;162:304-11. 55. Sawyer KN, Humbert A, Leroux BG, Nichol G, Kudenchuk PJ, Daya MR, et al. Relationship Between Duration of Targeted Temperature Management, Ischemic Interval, and Good Functional Outcome From Out-of-Hospital Cardiac Arrest. Crit Care Med. 2020;48(3):370-7. 56. Reynolds JC, Grunau BE, Rittenberger JC, Sawyer KN, Kurz MC, Callaway CW. Association Between Duration of Resuscitation and Favorable Outcome After Out-of-Hospital Cardiac Arrest: Implications for Prolonging or Terminating Resuscitation. Circulation. 2016;134(25):2084-94. According to legend, after being forced to recant his claims that the Earth moves around the Sun, Galilleo Gallilei said ‘E pur si muove.’ This is roughly taken to mean that despite his recantation, the Church's proclamations to the contrary, or any other conviction or doctrine of men, the Earth does, in fact, move (around the Sun and not vice versa.) https://en.wikipedia.org/wiki/And_yet_it_mov s Disclosure I am principal investigator of a randomized trial of hypothermia in patients with ST-elevation myocardial infarction. The trial is sponsored by ZOLL Circulation (San Jose, CA), which manufactures and markets devices for intravascular temperature management (IVTM). Overview I congratulate the members of the International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support (ALS) Task Force on their timely synthesis of the effectiveness of induced hypothermia (IH) or targeted temperature management (TTM) in patients resuscitated from cardiac arrest (CA). However, I encourage the members of the ALS task force to go a bit further in their analysis of prior trials of TTM after CA. A useful method for doing so when a trial fails to detect a difference in the primary outcome was previously published.(1) Below I use this method as a framework for my comments on the lack of benefit of TTM in patients with cardiac arrest reported in the TTM2 trial. Note that I have shortened and reordered this framework a bit to make the critique more coherent. I ask that the members of the ALS task force consider my critique below before they conclude whether based on the totality of evidence available it is plausible that hypothermia is or is not beneficial in patients resuscitated from cardiac arrest. Is There A Strong Biologic Rationale That Favors Treatment? Multiple studies in small and large animal models of cardiac arrest demonstrate that hypothermia to 34C or less is better than normothermia.(2-14) As well, multiple studies in small and large animal models of cardiac arrest demonstrate that rapid hypothermia is better than delayed hypothermia.(5, 8, 15, 16) In humans resuscitated from CA, briefer time from restoration of spontaneous circulation (ROSC) to target temperature is associated with significantly reduced likelihood of death or neurologic impairment.(17) The impact of this work has been limited in part by an error in the table of the article that is acknowledged by the authors but has not been corrected in the publication (Table 1). Note that other studies in humans have failed to detect this relationship. But these latter studies evaluated patients with a prolonged downtime who were unlikely to benefit from the intervention, or did not rapidly achieve target temperature, or lacked power to detect a small but important association between treatment time intervals and outcome. Collectively these data demonstrate that there is a strong biologic rationale that favor treatment with rapid induction and maintenance of hypothermia to reduce morbidity and mortality after resuscitation from CA. Is There Some Indication of Potential Benefit? A key difference among trials of IH or TTM in patients resuscitated from CA is time to target temperature. Holzer and Sterz reported time from ROSC vs. core temperature (Figure 1):(18) in the intervention group, this was approximately 8 h to 34C. Generally, subsequent trials have reported time from randomization to target temperature rather than time from ROSC. But there is large variation in the time from ROSC to target temperature as estimated from the primary results of each trial (Table 2). Note that the TTM2 investigators stated in their methods paper that ‘rapid cooling in the hypothermia group will be achieved by means of cold fluids and cooling devices.’(19) A key exclusion criterion in the TTM2 trial was if more than 180 minutes had passed from ROSC to screening of eligibility for enrollment. In their primary report of the results of TTM2,(20) the investigators emphasize the time from randomization rather than ROSC to target temperature. Despite their stated goal of applying rapid cooling, they reported a similar time to target temperature in TTM2 as they achieved in the original TTM.(21) A leader of the TTM2 trial has stated that patients enrolled in the trial were cooled as fast as is feasible using contemporary medical devices.https://web.archive.org/web/*/https://twitter.com/DogICUma/status/1405348094594621444 But the recent TTM24vs48 trial(22) achieved briefer time to target temperature than that achieved in TTM2: (281 [IQR, 217-360] minutes in the 48 h group vs. 320 [IQR 241-410] minutes in the 24 h group [P = .01]. Importantly the mean core temperature did not achieve the intended target temperatures in the intervention group in neither TTM nor TTM2 (i.e., mean core temperature did not cross 34C). Collectively, these data suggest that the relative benefit of IH was attenuated as compared to the control group in the TTM2 trial because the intervention was neither delivered as intended nor as quickly as feasible. The planned primary outcome of TTM2 was all-cause mortality at six months.(20) Other outcomes were assessed at 30 days, 6 months, and 24 months after randomization. Although there was no significant difference in mortality between the intervention and control group at six months, it appears that the intervention was associated with increased early mortality as the survival curves have wider separation around 30 days but come together after that (Figure 2). A plausible interpretation of this is that hypothermia as implemented in the TTM2 trial was associated with increased early mortality. In the TTM2 trial, hypothermia was initiated with chilled intravenous saline in the TTM2 trial.(19, 23) In an animal model of CA, intra-arrest chilled intravenous saline was associated with reduced coronary perfusion pressure (CPP).(24) It is well known that greater CPP is associated with greater likelihood of resuscitation.(25) In humans resuscitated from CA, chilled intravenous saline to initiate hypothermia was associated with no survival benefit and possible increased adverse events.(26, 27) Collectively, these data suggest that the use of chilled intravenous saline to initiate TTM could have contributed to the apparent increased early mortality in the intervention group as compared to the control group in the TTM2 trial. Was The Treatment Regimen Appropriate? The majority of patients who were enrolled in the TTM2 had hypothermia induced and maintained with surface cooling methods (SCM) as opposed to intravascular temperature management (IVTM). But SCM cools at slower rates than IVTM.(28) Multiple systematic reviews show that use of SCM is associated with worse outcomes than IVTM.(29, 30) Collectively, these data suggest that it is plausible that use of SCM rather than IVTM attenuated differences between the intervention and control group in the TTM2 trial. Limited information is available about the quality of post-resuscitation care that was provided to patients enrolled in the TTM2 trial. During the TTM2 trial, ‘general intensive care management [was] according to standard practice at participating hospitals.’(19) A leader of the TTM2 trial has stated that all patients received good concurrent care because they were enrolled at sites that have collaborated with the TTM investigators for years.(Personal Communication, N Nielsen, Jun 23, 2021) But 33% of patients who participated in TTM2 were enrolled at sites that did not participate in the original TTM trial. Importantly, a retrospective analysis of observational data previously demonstrated that the quality of post-resuscitation care including but not limited to how TTM is initiated and maintained is associated with outcome after resuscitation from CA.(31) Below I explain why the quality of concurrent care is relevant to interpretation of the TTM2 trial. The intervention group received significantly more propofol than the control group in the TTM2 trial: median (interquartile range) 8,768 (3,683, 13,365) mg vs. 7,744 (3,183, 12,595) mg [p value not stated].(20) Propofol is commonly used as an anesthetic and sedative agent in emergency departments and intensive care wards because of its rapid onset and weaning. But it has dose-dependent effects on mitochondria. At low doses, it reduces reactive oxygen species.(32) At higher doses, it reduces adenosine triphosphate (ATP) synthesis.(32-36) The latter seems likely to be undesirable in patients who have recently been deprived of oxygen and have intracellular energy depletion such as after resuscitation from CA. But coronary artery bypass grafting is also associated with deprivation of oxygen and intracellular energy depletion.(37, 38) In a systematic review of multiple randomized trials in patients undergoing coronary artery bypass grafting (n=13 trials, n=696 patients), the use of propofol was associated with increased myocardial injury as compared to use of sevoflurane.(39) In another randomized trial in patients undergoing coronary artery bypass grafting (n=39), use of propofol blocked cardioprotection by remote ischemic conditioning.(40) Note that the two landmark trials that demonstrated that hypothermia improved outcomes as compared to normothermia were both conducted before propofol was available for clinical use.(18, 41) Collectively, these data suggest that it is plausible that frequent use of propofol attenuated the relative benefit of hypothermia as compared to normothermia in the TTM2 trial. Overall, 38% of patients enrolled in TTM2 underwent PCI.(20) Evidence-based practice guidelines strongly recommend administration of a P2Y12 as early as possible or time of PCI.(42) This can include clopidogrel, prasugrel or ticagrelor. It seems plausible that the majority of patients who underwent PCI in the TTM2 trial received clopidogrel as 99% of patients were enrolled at sites located outside the United States, and health care costs are more constrained outside rather than inside the US . But clopidogrel is a prodrug that must be both absorbed and metabolized before having biological activity. Thus, clopidogrel is associated with delayed inhibition of platelet reactivity in patients undergoing induced hypothermia.(43-45) The clinical important of this delay was demonstrated in a randomized trial of intraperitoneal hypothermia in patients with STEMI undergoing PCI.(46) According to the trial protocol, all patients received clopidogrel prior to PCI. There was a significant increased rate of acute stent thrombosis in the intervention group as compared to the control group. The investigators attributed this adverse event to use of clopidogrel. Collectively, these data suggest that it is plausible that frequent use of clopidogrel in the setting of PCI in the TTM2 trial could have been associated with acute stent thrombosis, and thereby contributed to the apparent increased early mortality observed in the intervention group in the TTM2 trial. Overall, 16% of patients enrolled in the TTM2 trial received an implantable cardioverter defibrillator (ICD) during follow-up. Evidence-based practice guidelines strongly recommend implantation of ICDs in survivors of ventricular fibrillation as it is associated with a significant and important mortality benefit.(47) In contrast to the low rate of ICD use in the TTM2 trial, 42% of a national US sample of patients admitted after resuscitation from out of hospital CA in 2002/2003 underwent ICD insertion.(48) Thus, it seems plausible that underuse of ICDs in the TTM2 trial reduced overall survival and attenuated differences in outcome between the control and intervention group. Do Secondary Outcomes Elicit Reveal Positive Findings? The TTM2 trial reported a significant increase in the rate of bradycardia requiring pacing in the intervention group as compared to the control group.(20) It is unclear whether investigators were given specific guidance on when pacing was required in the TTM2 trial protocol.(19) Bradycardia is commonly observed during application of hypothermia. But such bradycardia is associated with increased cardiac output due to increased stroke volume.(49) The TTM investigators and others previously reported that the presence of early bradycardia is associated with improved survival and neurologic outcome after CA.(50, 51) Collectively, these data suggest that the clinical significance of the increased rate of bradycardia requiring pacing reported in the TTM2 is incompletely defined. Can Alternative Analyses Help? Multiple alternative analyses of TTM2 trial data could help better elucidate the effect hypothermia versus normothermia in patients resuscitated from CA. The TTM2 investigators noted that a limitation of the trial was a potential heterogeneous intervention effect, depending on the mode of cooling, and hence different speeds of cooling used at different enrolling sites.(19, 23) An analysis that stratified results by enrolling site could yield insight into the clinical heterogeneity of the effect of hypothermia versus normothermia. There are multiple factors that could have modified the effect of hypothermia as compared to normothermia in the TTM2 trial, as outlined above. An analysis that adjusted for or restricted to optimal method of IH/TTM (e.g., IVTM) as well as receipt of good concurrent care (e.g., type of P2Y12 inhibitor; sedation without propofol; insertion of an ICD) would inform consideration of whether hypothermia does or does not improve outcomes in patients resuscitated from cardiac arrest. However, such an analysis would likely lack power to detect a difference in outcomes as it appears from reports to date that a minority of patients received such care. Until the results of alternative analyses become available, it seems premature to place too much credence on the results of the TTM2 trial. Does More Positive External Evidence Exist? Evidence external to that of the TTM2 trial suggests that hypothermia improves outcomes as compared to normothermia. The HYPERION trial demonstrated that in patients with a first-recorded rhythm that is non-shockable, 10.2% of patients in the hypothermia group were alive with a CPC score of 1 or 2 at 90 days, as compared to 5.7% in the normothermia group (difference, 4.5 percentage points; 95% confidence interval [CI], 0.1 to 8.9; P = 0.04).(52) As well, there was no significant difference in adverse events between the hypothermia and normothermia group. When the original TTM trial was published post-resuscitation practices changed at many hospitals to favor use of a target temperature of 36C as opposed to 33C. Several large multicenter before-after studies conducted outside the US have demonstrated that this change in practice was independently associated with increased mortality.(53, 54) Multiple retrospective analyses of multicenter observational data from the US demonstrate that there is a significant relationship between the duration of ischemia and the effect of hypothermia in patients resuscitated from CA.(55, 56) It seems implausible that if is truly no benefit to hypothermia in patients resuscitated from cardiac arrest, such a dose-response relationship exists between greater hypothermia and better outcomes. Collectively, these data suggest that it is plausible that, notwithstanding the results of the TTM2 trial as well as a systematic review of trials completed to data, hypothermia improves outcomes compared to normothermia in patients resuscitated from cardiac arrest. Summary There are multiple plausible explanations why hypothermia as compared to normothermia did not improve neurologic outcome in the TTM2 trial. The large sample size of TTM2 dilutes the benefit of hypothermia observed in prior trials when pooled together in a systematic review. The results of the TTM2 trial lack face validity as compared to the strong biologic rationale in favor of hypothermia. The TTM2 investigators did not implement the intervention as intended, implemented it in a manner that disfavored hypothermia versus normothermia, and appear to have not consistently provided good concurrent care. There is abundant positive external evidence which suggests that hypothermia is beneficial compared to normothermia in patients resuscitated from CA. In summary, despite the proclamations of the TTM2 investigators to the contrary, in fact hypothermia compared to normothermia likely improves outcomes in patients resuscitated from CA when delivered with optimal methods and good concurrent care. Figure 1: Temperature vs. Time from Restoration of Spontaneous Circulation in HACA Trial(18) Figure 2: Survival with Hypothermia versus Normothermia Over Time in TTM2 Trial(20) Table 1: Predictors of Death or Neurologic Impairment Six Months After Cardiac Arrest(17) Factor Odds Ratio (95% CI) P Value Age, per additional year 1.04 (1.005, 1.08) 0.02 Time to ROSC, per additional minute 1.06 (1.01, 1.12) 0.01 Time to Temp. Target, per additional min. 1.005 (1.002, 1.009) 0.006 First rhythm non-shockable 13.8 (3.4, 56.1) <0.001 Arterial Blood pH, per unit increase 0.009 (0.001, 0.38) 0.04 Data corrected from original publication Table 2: Characteristics of Randomized Trials of Hypothermia vs. Normothermia in Patients Resuscitated From Cardiac Arrest Population Treatment Group Treatment Method Temperature Target, °C Estimated Time from Onset of Arrest to Target Temperature, mins. Favorable Neurologic Outcome, % P Value Bernard(41) Unconscious adults Resuscitated from Out of Hospital VF Normothermia (n=34) n/a n/a 261 0.046 Hypothermia (n=43) Cold Packs 33°C ~270 491 HACA(18) Unconscious adults Resuscitated from Witnessed Out of Hospital VF or Pulseless VT Normothermia (n=138) n/a n/a 392 0.009 Hypothermia (n=137) Cooling Tent 32-34°C ~420 552 TTM(21) Unconscious adults Resuscitated from Out of Hospital VF, Pulseless Electrical Activity (PEA) or Witnessed Asystole Mild Hypothermia (n=466) 76% Surface; 24% IVTM 36°C n/a 483 0.51 Moderate Hypothermia (n=473) 76% Surface; 24% IVTM 33°C >660 473 Hyperion(52) Unconscious adults Resuscitated from PEA or Asystole of Any Cause Mild Hypothermia (n=297) 81% Surface; 15% IVTM 37°C n/a 54 0.04 Moderate Hypothermia (n=284) 89% Surface; 15% IVTM 33°C ~710 104 TTM2(20) Unconscious adults Resuscitated from Out of Hospital CA of Presumed Cardiac or Unknown Cause Hypothermia (n=931) 69% Surface; 31% IVTM 36°C n/a 455 Not Stated Normothermia (n=930) 70% Surface; 30% IVTM 33°C ~550 45 5 1Primary outcome was good neurologic outcome, defined as discharge home or to a rehabilitation facility 2Primary outcome was favorable neurologic outcome within six months, defined as a Pittsburgh cerebral-performance category of 1 (good recovery) or 2 (moderate disability) on a five- category scale 3Primary outcome was mortality at end of study follow up. 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Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549-56. 19. Dankiewicz J, Cronberg T, Lilja G, Jakobsen JC, Belohlavek J, Callaway C, et al. Targeted hypothermia versus targeted Normothermia after out-of-hospital cardiac arrest (TTM2): A randomized clinical trial-Rationale and design. Am Heart J. 2019;217:23-31. 20. Dankiewicz J, Cronberg T, Lilja G, Jakobsen JC, Levin H, Ullen S, et al. Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest. N Engl J Med. 2021;384(24):2283-94. 21. Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, et al. Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J Med. 2013;369(23):2197-206. 22. Kirkegaard H, Soreide E, de Haas I, Pettila V, Taccone FS, Arus U, et al. Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial. JAMA. 2017;318(4):341-50. 23. Jakobsen JC, Dankiewicz J, Lange T, Cronberg T, Lilja G, Levin H, et al. Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest: a statistical analysis plan. Trials. 2020;21(1):831. 24. Yannopoulos D, Zviman M, Castro V, Kolandaivelu A, Ranjan R, Wilson RF, et al. Intra-cardiopulmonary resuscitation hypothermia with and without volume loading in an ischemic model of cardiac arrest. Circulation. 2009;120(14):1426-35. 25. Paradis NA, Martin GB, Rivers EP, Goetting MG, Appleton TJ, Feingold M, et al. Coronary perfusion pressure and the return of spontaneous circulation in human cardiopulmonary resuscitation. JAMA. 1990;263(8):1106-13. 26. Kim F, Nichol G, Maynard C, Hallstrom A, Kudenchuk PJ, Rea T, et al. 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Effect of different methods of cooling for targeted temperature management on outcome after cardiac arrest: a systematic review and meta-analysis. Crit Care. 2019;23(1):285. 31. Stub D, Schmicker RH, Anderson ML, Callaway CW, Daya MR, Sayre MR, et al. Association between hospital post-resuscitative performance and clinical outcomes after out-of-hospital cardiac arrest. Resuscitation. 2015;92:45-52. 32. Branca D, Vincenti E, Scutari G. Influence of the anesthetic 2,6-diisopropylphenol (propofol) on isolated rat heart mitochondria. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 1995;110(1):41-5. 33. Branca D, Roberti MS, Vincenti E, Scutari G. Uncoupling effect of the general anesthetic 2,6-diisopropylphenol in isolated rat liver mitochondria. Arch Biochem Biophys. 1991;290(2):517-21. 34. Branca D, Roberti MS, Lorenzin P, Vincenti E, Scutari G. Influence of the anesthetic 2,6-diisopropylphenol on the oxidative phosphorylation of isolated rat liver mitochondria. 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Bjelland TW, Hjertner O, Klepstad P, Kaisen K, Dale O, Haugen BO. Antiplatelet effect of clopidogrel is reduced in patients treated with therapeutic hypothermia after cardiac arrest. Resuscitation. 2010;81(12):1627-31. 44. Bednar F, Kroupa J, Ondrakova M, Osmancik P, Kopa M, Motovska Z. Antiplatelet efficacy of P2Y12 inhibitors (prasugrel, ticagrelor, clopidogrel) in patients treated with mild therapeutic hypothermia after cardiac arrest due to acute myocardial infarction. J Thromb Thrombolysis. 2016;41(4):549-55. 45. Steblovnik K, Blinc A, Mijovski MB, Fister M, Mikuz U, Noc M. Ticagrelor Versus Clopidogrel in Comatose Survivors of Out-of-Hospital Cardiac Arrest Undergoing Percutaneous Coronary Intervention and Hypothermia: A Randomized Study. Circulation. 2016;134(25):2128-30. 46. Nichol G, Strickland W, Shavelle D, Maehara A, Ben-Yehuda O, Genereux P, et al. Prospective, multicenter, randomized, controlled pilot trial of peritoneal hypothermia in patients with ST-segment- elevation myocardial infarction. Circ Cardiovasc Interv. 2015;8(3):e001965. 47. Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2018;138(13):e210-e71. 48. Birnie DH, Sambell C, Johansen H, Williams K, Lemery R, Green MS, et al. Use of implantable cardioverter defibrillators in Canadian and US survivors of out-of-hospital cardiac arrest. CMAJ. 2007;177(1):41-6. 49. Forkmann M, Kolschmann S, Holzhauser L, Ibrahim K, Guenther M, Christoph M, et al. 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https://www.dropbox.com/s/40djh9uladt47eu/20210912%20Nichol%20Response%20to%20ILCOR%20Statement%20on%20IH%20TTM%20After%20CA.docx?dl=0

Wilhelm Behringer, University of Jena, Germany Benjamin Abella, University of Pennsylvania, USA Kjetil Sunde, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Norway We have some comments to the draft recommendation: “We suggest actively preventing fever by targeting a temperature ≤ 37.5 for those patients who remain comatose after ROSC from cardiac arrest (weak recommendation, low certainty evidence). Whether subpopulations of cardiac arrest patients may benefit from targeting hypothermia at 32-34°C remains uncertain.” In the evaluation of science, under “How substantial are the desirable anticipated effects?” the summery data are shown in two Forrest plots, one with evaluation of outcome at hospital discharge or 30 days, and one with evaluation of outcome at 90 or 180 days. We are concerned about 1) Splitting and analysing of data for two different outcome assessment time points and 2) study selection. First, the largest study showing no difference in outcome between 32-34°C and normothermia (Dankiewicz 2021) was included in both analyses, while three large studies showing a beneficial effect of 32-34°C (Bernard 2002, Lascarrou 2019, Hachimi-Idrissi 2005) were each included in only one analysis. Splitting the analysis in two different outcome evaluation time points reduced the number of eligible studies, and greatly reduced power. It was previously shown, in critical care randomized clinical trials (RCTs), that no influence of time point of outcome evaluation on pooled effect estimates is to be expected, and that splitting data to different time points is not required [1]. Secondly, the authors included one study (Laurent 2005), in which patients underwent hemofiltration in addition to cooling. The authors of a previous Cochrane meta-analysis on the same topic regarded inclusion of this work as introducing considerable clinical heterogeneity and did therefore not pool the data of this study [2]. Additionally, in the same meta-analysis, the authors identified one additional study (Mori 2000) [2], which was not included in the ILCOR meta-analysis. However, this study was only published as an abstract, and its inclusion can therefore be discussed. Thus, we performed a meta-analysis, based on the previous Cochrane meta-analysis [2], pooling all available RCTs with outcome evaluation within 6 months (see figure below or https:// https://www.magentacloud.de/share/iuov1lurtw). In this analysis, the pooled results showed a better neurological outcome with TTM32-34 compared to normothermia (RR 1.27, 95% CI 1.02 to 1.58). If we exclude the Mori study, the results show OR 1.43 (95% CI 1.01-2.02), p=0.04, and RR 1.21 (95% CI 0.99-1.48), p=0.06. We are of the opinion that a meta-analysis should pool all available RCTs on TTM32-34 versus normothermia for outcome evaluation at any time point in one analysis, carefully considering clinical heterogeneity. With these considerations, we believe the broader data may suggest a beneficial effect of TTM32-34 versus normothermia. In addition, delay and duration of cooling, methods used, non-blinded pragmatic trials and selection of patients are of concern, the latter recently highlighted in two investigations [3, 4] suggesting a benefit of TTM32-34 vs TTM36 in patients with more significant post-arrest injury. We therefore believe the conclusion that TTM32-34 treatment is ineffective for all post-arrest patients is premature, and are concerned about the one size fits all strategy concerning neurological long term outcome in patients with moderate to severe post-arrest disease. In addition, we believe that a significant knowledge gap exists in the recent trials performed regarding methodology of TTM. Animal data, but also newborn data (5) show that there is a therapeutic window, and that delay in cooling might reduce the impact of TTM. In the recent pragmatic trials TTM and TTM2 trials, time from ROSC to randomization has been from 180-240 min – thereafter TTM has been initiated. Thus, time from cardiac arrest to reaching target temperature is several hours, and the groups (TTM33 vs TTM36 (TTM) and TTM33 vs normothermia (TTM2)) are similar for many hours after cardiac arrest and ROSC. In newborns, the RCT by Laptook et al [5] showed that the beneficial effects of TTM was lost if TTM was initiated later than 6 hours after the hypoxic ischemic insult. In the pediatric TTM study by Moler et al [6], comparing TTM33 for 48 hrs vs normothermia, showing 20 vs 12% good outcome after 12 months (70% relative difference, but NS), TTM treatment was initiated 5.9 hours after ROSC. Thus, this in mind, we believe that a future explanatory RCT should be performed comparing TTM33 with normothermia, optimizing the possible effects of hypothermia with a short duration between ROSC and randomization/initiation of treatment (< 60-90 min). This would give a more definitive answer whether TTM32-34 is of benefit or not. Such a study should use a common treatment protocol and preferably use one method of cooling (or at least equipment/tools with similar cooling time), with a duration of 48 hours (considering the positive trends/results from the 24 vs 48 hrs RCT from 2017 by Kirkegaard el [7] with a substudy on cognitive function by Evald et al [8]. Only patients with moderate to severe reperfusion injuries should be included, excluding patients with mild and very severe reperfusion injuries. [1] Roth D, Heidinger B, Havel C, Herkner H. Different Mortality Time Points in Critical Care Trials: Current Practice and Influence on Effect Estimates in Meta-Analyses. Crit Care Med. 2016;44:e737-41. [2] Arrich J, Holzer M, Havel C, Mullner M, Herkner H. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev. 2016;2:CD004128. [3] Callaway CW, Coppler PJ, Faro J, Puyana JS, Solanki P, Dezfulian C, et al. Association of Initial Illness Severity and Outcomes After Cardiac Arrest With Targeted Temperature Management at 36 degrees C or 33 degrees C. JAMA Netw Open. 2020;3:e208215. [4] Nishikimi M, Ogura T, Nishida K, Hayashida K, Emoto R, Matsui S, et al. Outcome Related to Level of Targeted Temperature Management in Postcardiac Arrest Syndrome of Low, Moderate, and High Severities: A Nationwide Multicenter Prospective Registry. Crit Care Med. 2021;49:e741-e50. [5] Laptook AR. Therapeutic Hypothermia for Preterm Infants with Hypoxic-Ischemic Encephalopathy: How Do We Move Forward? J Pediatr. 2017;183:8-9. [6] Moler FW, Silverstein FS, Holubkov R, Slomine BS, Christensen JR, Nadkarni VM, et al. Therapeutic hypothermia after out-of-hospital cardiac arrest in children. New England Journal of Medicine. 2015;372:1898-908. [7] Kirkegaard H, Soreide E, de Haas I, Pettila V, Taccone FS, Arus U, et al. Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial. Jama. 2017;318:341-50. [8] Evald L, Bronnick K, Duez CHV, Grejs AM, Jeppesen AN, Soreide E, et al. Prolonged targeted temperature management reduces memory retrieval deficits six months post-cardiac arrest: A randomised controlled trial. Resuscitation. 2019;134:1-9.

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The science community has spent many years and dollars to determine the optimal target for rapid post-arrest cooling. Those involved in both TTM1 & 2 failed to test rapid cooling or find an optimal target. These 2 null studies did support no harm in cooling or preventing fever if initiated after the current 6H window in most protocols. The option to control normothermia with a device if unable to meet that window in a pure cardiac, witness resusciated survivor of OHCA may reduce mortality over no control as shown in HACA & Bernard. Meeting the therapuetic window may in fact require advanced devices. The rates of arrhythmia and thrombus formations or death in TTM2 would not support IVTM over advanced surface cooling. Removing options for lower targets down to 32C would negate the benefit seen in certain patients with alternate illness severities. We have too much pro-cooling evidence to longer support deeper cooling and no superiority evidence to replace. Extending upper limits to 37.5 in TTM2 patient cohort mimics only seems a reasonable option for physician choice.