Recent discussions
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Hiroshi Nonogi
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 -
Teresa May
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. -
AMBILI AUGUSTIN
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Ambili Augusrtin
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Carolina Maciel
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. -
Fabio Silvio Taccone
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 …) -
Nguyen quan
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 -
ILCOR Staff
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). -
Alexis Topjian
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 -
Benjamin Abella
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.