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

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This CoSTR is a draft version prepared by ILCOR, with the purpose to allow the public to comment and is labeled “Draft for Public Comment". The comments will be considered by ILCOR. The next version will be labelled “draft" to comply with copyright rules of journals. The final COSTR will be published on this website once a summary article has been published in a scientific Journal and labeled as “final”.

Conflict of Interest Declaration

The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy.

The following Task Force members and other authors declared an intellectual conflict of interest (Hirsch KG, Hsu CH, Reynolds JC, Callaway CW, Neumar RW). The following members declared speaker fees related to this topic (Böttiger BW, O’Neil BJ, Skrifvars MB). This was managed by the Task Force Chairs and Conflicts of Interest committees.

CoSTR Citation

Soar J, Nolan JP Andersen LW, Böttiger BW, Couper K, Deakin CD, Drennan I, Hirsch KG, Hsu CH, Nicholson TC, O’Neil BJ, Paiva EF, Parr MJ, Reynolds JC, Sandroni C, Wang TL, Callaway CW, Donnino MW, Granfeldt A, Holmberg MJ, Lavonas EJ, Morrison LJ, Nation K, Neumar RW, Nikolaou N, Skrifvars MB, Welsford M, Morley PT, Berg KM Temperature Management in Adult Cardiac Arrest Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, 2021 August XX. Available from: http://ilcor.org

Methodological Preamble (and Link to Published Systematic Review if applicable)

The continuous evidence evaluation process for the production of Consensus on Science with Treatment Recommendations (CoSTR) started with a systematic review (Granfeldt A, Holmberg M, Nolan JP, Andersen LW for the International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force. Targeted Temperature Management in Adult Cardiac Arrest: Systematic Review and Meta-Analysis, Resuscitation 2021 In Press) (PROSPERO CRD42020217954 on October 28, 2020) conducted by ESR group [Asger Granfeldt, Mathias J. Holmberg, Lars W. Andersen] with involvement of clinical content experts [Jerry Nolan and Jasmeet Soar]. These data were taken into account when formulating the Treatment Recommendations.

PICOST

The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

1) Use of TTM


Population

Adults in any setting (in-hospital or out-of-hospital) with cardiac arrest

Intervention

TTM [TTM studies targeting hypothermia at 32-34 C included in the systematic review]

Comparison

No TTM [TTM studies targeting normothermia or fever prevention included in the systematic review]

Outcomes

Any clinical outcome




2) Timing

Population

Adults in any setting (in-hospital or out-of-hospital) with cardiac arrest and treated with TTM

Intervention

TTM induction before a specific time point (e.g. prehospital or intra-cardiac arrest, i.e. before return of spontaneous circulation (ROSC))

Comparison

TTM induction after that specific time point

Outcomes

Any clinical outcome


3) Temperature

Population

Adults in any setting (in-hospital or out-of-hospital) with cardiac arrest treated with TTM

Intervention

TTM at a specific temperature (e.g. 33°C)

Comparison

TTM at a different specific temperature (e.g. 36°C)

Outcomes

Any clinical outcome


4) Duration

Population

Adults in any setting (in-hospital or out-of-hospital) with cardiac arrest treated with TTM

Intervention

TTM for a specific duration (e.g. 48 hours)

Comparison

TTM at a different specific duration (e.g. 24 hours)

Outcomes

Any clinical outcome


5) Method

Population

Adults in any setting (in-hospital or out-of-hospital) with cardiac arrest treated with TTM

Intervention

TTM with a specific method (e.g. external)

Comparison

TTM with a different specific method (e.g. internal)

Outcomes

Any clinical outcome


6) Rewarming

Population

Adults in any setting (in-hospital or out-of-hospital) with cardiac arrest treated with TTM

Intervention

TTM with a specific rewarming rate

Comparison

TTM with a different specific rewarming rate or no specific rewarming rate

Outcomes

Any clinical outcome


Outcomes: For all PICOs, clinical outcomes will include, but not necessarily be limited to, ROSC, survival/survival with a favorable neurological outcome at hospital discharge/30 days, and survival/survival with a favorable neurological outcome after hospital discharge/30 days (e.g. 90 days, 180 days, 1 year). The final depended on the available data and subsequent outcome prioritization by the ILCOR ALS Task Force.

Study Designs: Controlled trials in humans including randomized controlled trials and non-randomized trials (e.g. pseudo-randomized trials). Observational studies, ecological studies, case series, case reports, reviews, abstracts, editorials, comments, letters to the editor, or unpublished studies will not be included. Studies assessing cost-effectiveness will be included for a descriptive summary.

Timeframe: All years and all languages were included as long as there was an English abstract; unpublished studies (e.g., conference abstracts, trial protocols) were excluded. Literature search On October 30, 2020, and updated for clinical trials on June 17, 2021.

PROSPERO Registration CRD42020217954 on October 28, 2020

Risk of bias in controlled trials (primarily randomized trials) was assessed using version 2 of the Cochrane Risk-of-Bias tool for individually-randomized parallel-group trials. Risk of bias was assessed for each outcome within a trial but is reported at the trial level as the highest risk of bias score across all outcomes. In most included trials, the risk of bias was the same across all outcomes. If the bias was different for different outcomes, this was noted

Consensus on Science

The search identified 2328 unique records of which 139 full-text articles were assessed for eligibility. Thirty-eight manuscripts representing 31 trials were identified. One additional trial was identified after review of references, yielding a total of 32 trials published between 2001 and 2021. The search identified one cost-effectiveness analysis from 2009. The search for registered ongoing or unpublished trials identified nine trials although many were registered multiple years ago and had unknown recruitment status . No trials assessing rewarming rate were identified.

A priori, a random effects model was used for the meta-analysis. A random effects model assigns a relatively higher weight to smaller studies such that they have a greater influence on the point estimate than would be expected based on the trial sizes.

Use of TTM

In the systematic review, studies were pooled such that the intervention (labeled as TTM in the PICOST) was targeting hypothermia (32-34 C), and the comparator (labeled as 'no TTM in the PICOST') was targeting normothermia or fever prevention. To avoid confusion and accurately reflect the content of the trials included, we have replaced the term TTM with hypothermia and no TTM with normothermia or fever prevention. To provide additional clarity for interpreting future clinical trials, systematic reviews and CoSTRs, the task force proposes new ILCOR definitions for the various forms of TTM use in post-cardiac arrest care under “Justification and Evidence to Decision Framework Highlights”.

For the critical outcome of survival to hospital discharge, we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 5 RCTs (Bernard 2002 557, HACA 2002 549, Laurent 2005 432, Lascarrou 2019 2327, Dankiewicz 2021 2283) involving 2836 adults that showed no difference between hypothermia and normothermia or fever prevention (RR 1.12; 95% CI 0.92 to 1.35 or 55 patients more/1000 survived with the intervention [95% CI, 37 fewer patients/1000 to 161 more patients/1000 survived with the intervention]).

For the critical outcome of favorable neurological outcome at hospital discharge or 30 days, we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 3 RCTs (Bernard 2002 557, HACA 2002 549, Dankiewicz 2021 2283) involving 2139 adults that showed no difference between hypothermia and normothermia or fever prevention (RR 1.30; 95% CI 0.83 to 2.03 or 115 patients more/1000 survived with the intervention [95% CI, 65 fewer patients/1000 to 395 more patients/1000 survived with the intervention]).

For the critical outcome of survival to 90 or 180 days , we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 5 RCTs (HACA 2002 549, Laurent 2005 432, Hachimi-Idrissi 2005 187, Lascarrou 2019 2327, Dankiewicz 2021 2283) involving 2776 adults that showed no difference between hypothermia and normothermia or fever prevention (RR 1.08, 95% CI 0.89 to 1.30 or 35 patients more/1000 survived with the intervention [95% CI, 48 fewer patients/1000 to 130 more patients/1000 survived with the intervention]).

For the critical outcome of favorable neurological outcome at 90 or 180 days, we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 5 RCTs (HACA 2002 549, Laurent 2005 432, Hachimi-Idrissi 2005 187, Lascarrou 2019 2327, Dankiewicz 2021 2283) involving 2753 adults that showed no difference between TTM(hypothermia) and TTM(normothermia or fever prevention) (RR 1.21, 95% CI 0.91 to 1.61 or 76 patients more/1000 survived with the intervention [95% CI, 33 fewer patients/1000 to 222 more patients/1000 survived with the intervention]).

Pre-hospital cooling

For the critical outcome of survival to hospital discharge, we identified moderate certainty evidence (downgraded for serious risk of bias) from 10 RCTs (Kim 2007 3064, Kamarainen 2009 900, Bernard 2010 737, Bernard 2012 747, Kim 2014 45, Scales 2017 187, Debaty 2014 1832, Bernard 2016 797, Castren 2010 729, Nordberg 2019 1677) involving 4808 adults that showed no difference between prehospital cooling and no prehospital cooling (RR 1.01, 95% CI 0.92 to 1.11 or 2 patients more/1000 survived with the intervention [95% CI, 19 fewer patients/1000 to 27 more patients/1000 survived with the intervention]).

For the critical outcome of favorable neurological outcome at hospital discharge, we identified moderate certainty evidence (downgraded for serious risk of bias) from 9 RCTs (Kamarainen 2009 900, Bernard 2010 737, Bernard 2012 747, Kim 2014 45, Scales 2017 187, Debaty 2014 1832, Bernard 2016 797, Castren 2010 729, Nordberg 2019 1677) involving 4666 adults that showed no difference between prehospital cooling and no prehospital cooling (RR 1.00, 95% CI 0.90 to 1.11 or 0 fewer patients/1000 survived with the intervention [95% CI, 22 fewer patients/1000 to 24 more patients/1000 survived with the intervention]).

Specific temperature comparisons

33 C v 36 C

For the critical outcome of favorable neurological outcome at hospital discharge, we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 1 RCT (Nielsen 2013 2197) involving 938 adults that showed no difference between 33 C and 36 C (RR 0.96, 95% CI 0.83 to 1.11 or 18 fewer patients/1000 survived with the intervention [95% CI, 78 fewer patients/1000 to 50 more patients/1000 survived with the intervention]).

For the critical outcome of survival at 180 days, we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 1 RCT (Nielsen 2013 2197) involving 939 adults that showed no difference between 33 C and 36 C (RR 0.99, 95% CI 0.88 to 1.12 or 5 fewer patients /1000 survived with the intervention [95% CI, 63 fewer patients/1000 to 63 more patients/1000 survived with the intervention]).

For the critical outcome of favorable neurological outcome at 180 days, we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 1 RCT (Nielsen 2013 2197) involving 933 adults that showed no difference between 33 C and 36 C (RR 0.98, 95% CI 0.86 to 1.13 or 10 fewer patients /1000 survived with the intervention [95% CI, 68 fewer patients/1000 to 63 more patients/1000 survived with the intervention]).

32 C v 34 C

For the critical outcome of survival at 90 days, we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 1 RCT (Lopez-de-Sa, 2018 1807) involving 101 adults that showed no difference between 32 C and 34 C (RR 0.91, 95% CI 0.72 to 1.14 or 64 fewer patients /1000 survived with the intervention [95% CI, 200 fewer patients/1000 to 100 more patients/1000 survived with the intervention]).

For the critical outcome of favorable neurological outcome at 90 days, we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 1 RCT (Lopez-de-Sa, 2018 1807) involving 92 adults that showed no difference between 32 C and 34 C (RR 0.97, 95% CI 0.72 to 1.32 or 20 fewer patients /1000 survived with the intervention [95% CI, 180 fewer patients/1000 to 208 more patients/1000 survived with the intervention]).

For the critical outcome of survival at 180 days, we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 1 RCT (Lopez-de-Sa, 2012 2826) involving 36 adults that showed no difference between 32 C and 34 C (RR 4.0, 95% CI 0.98 to 16.30 or 333 more patients /1000 survived with the intervention [95% CI, 2 fewer patients/1000 to 1000 more patients/1000 survived with the intervention]).

For the critical outcome of favorable neurological outcome at 180 days, we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 1 RCT (Lopez-de-Sa, 2012 2826) involving 36 adults that showed no difference between 32 C and 34 C (RR 2.25, 95% CI 0.84 to 6.0 or 278 more patients /1000 survived with the intervention [95% CI, 36 fewer patients/1000 to 1000 more patients/1000 survived with the intervention]).

33 C v 34 C

For the critical outcome of survival at 90 days, we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 1 RCT (Lopez-de-Sa, 2018 1807) involving 98 adults that showed no difference between 33 C and 34 C (RR 1.03 , 95% CI 0.81 to 1.31 or 21 more patients /1000 survived with the intervention [95% CI, 136 fewer patients/1000 to 221 more patients/1000 survived with the intervention]).

For the critical outcome of favorable neurological outcome at 90 days, we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 1 RCT (Lopez-de-Sa, 2018 1807) involving 88 adults that showed no difference between 33 C and 34 C (RR 1.07, 95% CI 0.79 to 1.45 or 45 more patients /1000 survived with the intervention [95% CI, 134 fewer patients/1000 to 286 more patients/1000 survived with the intervention]).

33 C v 32 C

For the critical outcome of survival at 90 days, we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 1 RCT (Lopez-de-Sa, 2018 1807) involving 101 adults that showed no difference between 33 C and 32 C (RR 1.06 , 95% CI 0.83 to 1.36 or 42 more patients /1000 survived with the intervention [95% CI, 118 fewer patients/1000 to 249 more patients/1000 survived with the intervention]).

For the critical outcome of favorable neurological outcome at 90 days, we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 1 RCT (Lopez-de-Sa, 2018 1807) involving 93 adults that showed no difference between 33 C and 32 C (RR 1.08, 95% CI 0.80 to 1.45 or 51 more patients /1000 survived with the intervention [95% CI, 127 fewer patients/1000 to 285 more patients/1000 survived with the intervention]).

Duration of cooling

For the critical outcome of survival at 6 months, we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 1 RCT (Kirkegaard 2017 341) involving 351 adults that showed no difference between 48 hours of TTM and 24 hours of TTM (RR 1.10, 95% CI 0.96 to 1.27 or 66 more patients /1000 survived with the intervention [95% CI, 26 fewer patients/1000 to 178 more patients/1000 survived with the intervention]).

For the critical outcome favorable neurological outcome at 6 months, we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 1 RCT (Kirkegaard 2017 341) involving 351 adults that showed no difference between 48 hours of TTM and 24 hours of TTM (RR 1.08, 95% CI 0.93 to 1.25 or 51 more patients /1000 survived with the intervention [95% CI, 45 fewer patients/1000 to 159 more patients/1000 survived with the intervention]).

Method of temperature control

For the critical outcome of survival to hospital discharge/28 days, we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 3 RCTs (Pittl 2013 607, Deye 2015 182, Look 2015 66) involving 523 adults that showed no difference between endovascular cooling and surface cooling (RR 1.14, 95% CI 0.93 to 1.38 or 56 more patients /1000 survived with the intervention [95% CI, 28 fewer patients/1000 to 152 more patients/1000 survived with the intervention]).

For the critical outcome of favorable neurological outcome at hospital discharge/28 days, we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 3 RCTs (Pittl 2013 607, Deye 2015 182, Look 2015 66) involving 523 adults that showed no difference between endovascular cooling and surface cooling (RR 1.22, 95% CI 0.95 to 1.56 or 64 more patients /1000 survived with the intervention [95% CI, 15 fewer patients/1000 to 163 more patients/1000 survived with the intervention]).

Rewarming

No RCTs of rewarming were identified.

Treatment Recommendations

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 32-34oC remains uncertain.

Comatose patients with mild hypothermia after ROSC should not be actively warmed to achieve normothermia (good practice statement).

We recommend against the routine use of prehospital cooling with rapid infusion of large volumes of cold IV fluid immediately after ROSC (strong recommendation, moderate certainty evidence).

We suggest surface or endovascular temperature control techniques when temperature control is used in comatose patients after ROSC (weak recommendation, low certainty of evidence).

When a cooling device is used, we suggest using a temperature control device that includes a feedback system based on continuous temperature monitoring to maintain the target temperature (good practice statement).

We suggest active prevention of fever for at least 72 hours in post-cardiac arrest patients who remain comatose (good practice statement).

Justification and Evidence to Decision Framework Highlights

  • This topic was prioritized by the ALS Task Force based on new RCTs of TTM since our previous systematic review, CoSTR (Callaway 2015 s84, Soar 2015 e71) and advisory statement in (Donnino 2015 2448, Donnino 2015 97) in 2015.
  • All members of the Task Force agreed that we should continue to recommend active temperature control in post-cardiac arrest patients, although the evidence for this is limited.
  • Further details of Task Force discussions are provided in the evidence to decision tables (ETDs).

Defining Post-Cardiac Arrest Temperature Management Strategies

  • The term TTM on its own is not helpful and it is preferable to use the terms active temperature control, hypothermia, normothermia, or fever prevention. To provide additional clarity for interpreting future clinical trials, systematic reviews and CoSTRs we propose the following terms are used:
    • o Hypothermic TTM (H-TTM) = active temperature control with the target temperature below the normal range.
  • o Normothermic TTM (N-TTM) = active temperature control with the target temperature in the normal range.
  • o Fever prevention TTM (FP-TTM) = monitoring temperature and actively preventing and treating temperature above the normal range
  • o No TTM = no protocolised active temperature control strategy.

Hypothermia v normothermia or prevention of fever

  • The majority of the Task Force favored fever prevention for comatose patients following ROSC as opposed to hypothermia, based on the systematic review and because this intervention requires fewer resources and had fewer side effects than hypothermia treatment.
  • The Task Force noted that in the TTM2 trial (Dankiewicz 2021 2283), pharmacological measures (acetaminophen), uncovering the patient, and lowering ambient temperature were used to maintain a temperature of ≤ 37.5 C (99.5 F) in the normothermia/fever prevention group. If the temperature was > 37.7 C (99.9 F) a cooling device was used and set at a target temperature of ≤ 37.5 C (99.5 F). 95% of patients in the hypothermia group and 46% in the fever prevention group received temperature control with a device.
  • We chose prevention of fever as opposed to normothermia in the treatment recommendation.
  • The Task Force acknowledged that the systematic review found no difference in overall outcomes between patients treated with hypothermia and normothermia or fever prevention.
  • Several members of the Task Force were keen to leave open the option to use hypothermia (33oC). The discussions included:
  • No trials have shown that normothermia is better than hypothermia.
  • Among non-shockable cardiac arrest patients, the Hyperion trial (Lascarrou 2019 2327) showed better survival with favorable functional outcome in the hypothermia group (although 90-day survival was not significantly different and the Fragility Index was only 1).
  • Although our systematic review did not find evidence favoring TTM with hypothermia in multiple subgroups, there remained a view that some populations of cardiac arrest patient could potentially benefit from hypothermia treatment at 32-34 C. Specifically, the largest TTM studies (TTM1 and TTM2) have mainly included cardiac arrests with a primary cardiac cause and this may not reflect the total population of post cardiac arrest patients treated (Chen 2018 33).
  • There was a suggestion that we should only advocate fever prevention for those with a primary cardiac arrest in the main treatment recommendation – our systematic review did not find any evidence supporting targeting hypothermia in patients with a cardiac arrest due to other causes.
  • Concerns were raised that the TTM2 trial cooling rates were too slow and that the time to target temperature was outside the therapeutic window. In animal studies rapid induction of hypothermia after ROSC is required for a beneficial effect (Arrich 2021 47). The time to target temperature in TTM-2 is consistent with virtually all other human observational studies and RCTs including those where there was no delay caused by the need for consent/randomization (see ETD). Of the RCTs included, only the Bernard study (Bernard 2002 557) had a rapid time (2 hours after ROSC) to achieve target temperature (33.5 C). It remains possible that there is a therapeutic window within which hypothermia is effective that has not been rigorously tested in randomized clinical trials.
  • There was a unanimous desire to leave open the opportunity for further research on post-cardiac arrest hypothermia, not least because animal models have shown consistent and convincing evidence of benefit.
  • Finally, there are concerns that poor implementation of temperature control may lead to patient harm - for example the publication of the TTM trial in 2013 (Nielsen 2013 2197) may have led to some clinicians abandoning temperature control after cardiac arrest which in turn was associated with worse outcomes (Bray 2017 39, Salter 2018 1722, Nolan 2021 304). Whether this was caused by abandoning the use of temperature control is uncertain.
  • In our meta-analysis we decided to use a random effects model a priori (as opposed to fixed effects). The point estimates of the random-effects meta-analysis favors hypothermia. However, the random effects model assigns a relatively higher weight to smaller studies; thus, the smaller and older less methodologically robust studies published in 2002 (Bernard 2002 557, HACA 2002 549) had a greater influence on the point estimate than would be expected based on the trial sizes.
  • We chose the term 'comatose' instead of 'unresponsive' to define the population of patients who do not wake up after ROSC. Another option considered was 'unconscious' – in the TTM2 trial this was defined as not being able to obey verbal commands and no verbal response to pain after sustained ROSC. The Task Force acknowledges that patients are unconscious and sedated after ROSC for a number of reasons in addition to a hypoxic ischemic brain injury including the need for airway protection with a tracheal tube, lung injury, and to facilitate interventions.
  • We have made no comments on sedation use or its duration but noted that in the TTM2 trial, patients in the normothermia/fever prevention arm were sedated for 40 hours to ensure a similar duration of sedation to the hypothermia arm.
  • There was discussion about the definitions of normothermia and fever. Among a diverse cohort of 35,488 hospital patients the 99% range for normal temperature was 35.3-37.7°C, and 95% range was 35.7 to 37.3 C (Obermeyer 2017 j5468). Whether these ranges can be generalized to the adult post cardiac arrest patient population is uncertain.
  • In addition, in our systematic review and meta-analysis we looked at comparisons between 33 v 36 C (Nielsen 2013 2197), 32 v 34 C (Lopez-de-Sa 2018 1807, Lopez-de-Sa 2012 2826), 33 v 34 C (Lopez-de-Sa 2018 1807) and 33 v 32 C (Lopez-de-Sa 2018 1807). There was no difference between control and intervention groups for all these comparisons and the certainty of evidence was low for all comparisons.
  • The comparison between 33 v 36 C (Nielsen 2013 2197) was included in a sensitivity analysis of 33 C v normothermia/fever prevention, as 36 C falls within the normothermia temperature range – this did not change the point estimates in favor of either group.
  • Although there was no direct evidence in our systematic review, the Task Force made a good practice statement supporting the avoidance of active warming of patients who have passively become mildly hypothermia (e.g. 32-36 ) immediately after ROSC there was concern that this may be a harmful intervention. The Task Force noted that in the TTM2 trial, patients in the normothermia/fever prevention arm with an initial temperature above 33 C were not actively warmed. The Task Force noted that in the Hyperion trial (Lascarrou 2019 2327), patients allocated to normothermia whose temperature was below 36.5 C at randomization were warmed at 0.25 - 0.5 C/hour and then maintained at 36.5 - 37.5 C.

Prehospital cooling

  • Our TR for prehospital cooling is unchanged from our 2015 recommendation.
  • We found no evidence that any method of prehospital cooling improved outcomes.
  • The rapid infusion of large amounts of cold fluid immediately after achieving ROSC and in the prehospital setting could theoretically be harmful, as indicated by increased rates of rearrest and pulmonary edema in the largest of the included studies (Kim 2014 45). Any potential harm from this therapy may relate specifically to the prehospital setting, where there may be less control over the environment, fewer personnel, and reduced monitoring capabilities.
  • We have not made a treatment recommendation about intra-arrest cooling for OHCA.

Cooling devices

  • Task Force members agreed that based on our systematic review either surface or endovascular cooling should be suggested when cooling is required.
  • There was no consensus on whether a feedback surface cooling device should be routinely used so this was added as a good practice statement as there is no evidence that this approach improves outcomes. There was consensus that temperature should be continually monitored by the cooling device in order to maintain a stable temperature.
  • There was a comment that endovascular cooling may be superior for temperature control – there are two recent systematic reviews with conflicting conclusions: Bartlett ES (Bartlett 2020 82) ­ showed intravascular cooling is associated with improved neurological outcome, but Kim JG (Kim 2020 14) found no association with survival or neurological outcomes.

Duration of temperature control and rewarming

  • Our TR is a good practice statement is based on trials controlling temperature for at least 72 h in those patients who remained sedated or comatose.
  • One trial showed no difference between 24 and 48 hours of hypothermia (Kirkegaard 2017 3410)
  • This could mean strategies such as 72 hours of active temperature control with avoidance of fever, or up to 24 hours of hypothermia followed by 48 hours of fever prevention if hypothermia treatment is used.
  • We did not identify any RCTs of rewarming patients treated with hypothermia and note that a rate of 0.33 C/hour was used in TTM2 trial (Dankiewicz 2021 2283) , and 0.25 to 0.5 C/hour in the Hyperion study (Lascarrou 2019 2327).

Knowledge Gaps

  • There are no RCTs of no TTM versus fever prevention TTM.
  • There are few RCTs of TTM after eCPR.
  • There are no large RCTs of TTM after in-hospital cardiac arrest.
  • Is there a therapeutic window within which hypothermic TTM (H-TTM) is effective in the clinical setting?
  • If a therapeutic window exists, are there clinically feasible cooling strategies that can rapidly achieve therapeutic target temperatures within the therapeutic window?
  • Is the clinical effectiveness of hypothermia dependent on providing the appropriate dose (target temperature and duration) based on the severity of brain injury?
  • Are there unidentified subsets of post-cardiac arrest patient who would benefit from H-TTM as currently practiced?
  • Is TTM using a cooling device with feedback more effective than TTM without a feedback controlled cooling device?

Attachments

Evidence-to-Decision Table: Should TTM vs. no TTM be used for cardiac arrest?

Evidence-to-Decision Table: Should prehospital cooling vs. no prehospital cooling be used for cardiac arrest?

Evidence-to-Decision Table: Should endovascular cooling vs. surface cooling be used for cardiac arrest?

Evidence-to-Decision Table: Duration of TTM?

References

References listed alphabetically by first author last name in this citation format (Circulation)

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Debaty G, Maignan M, Savary D, et al. Impact of intra-arrest therapeutic hypothermia in outcomes of prehospital cardiac arrest: a randomized controlled trial. Intensive Care Med. 2014;40(12):1832-1842.

Deye N, Cariou A, Girardie P, et al. Endovascular Versus External Targeted Temperature Management for Patients With Out-of-Hospital Cardiac Arrest: A Randomized, Controlled Study. Circulation. 2015;132(3):182-193.

Donnino MW, Andersen LW, Berg KM, Reynolds JC, Nolan JP, Morley PT, Lang E, Cocchi MN, Xanthos T, Callaway CW, Soar J; ILCOR ALS Task Force. Temperature Management After Cardiac Arrest: An Advisory Statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation and the American Heart Association Emergency Cardiovascular Care Committee and the Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation. Circulation. 2015 ;132(25):2448-56.

Donnino MW, Andersen LW, Berg KM, Reynolds JC, Nolan JP, Morley PT, Lang E, Cocchi MN, Xanthos T, Callaway CW, Soar J; ILCOR ALS Task Force. Temperature Management After Cardiac Arrest: An Advisory Statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation and the American Heart Association Emergency Cardiovascular Care Committee and the Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation. Resuscitation. 2016; 98:97-104.

Hachimi-Idrissi S, Corne L, Ebinger G, Michotte Y, Huyghens L. Mild hypothermia induced by a helmet device: a clinical feasibility study. Resuscitation. 2001;51(3):275-281.

Hachimi-Idrissi S, Zizi M, Nguyen DN, et al. The evolution of serum astroglial S-100 beta protein in patients with cardiac arrest treated with mild hypothermia. Resuscitation. 2005;64(2):187-192.

Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549-556.

Kamarainen A, Virkkunen I, Tenhunen J, Yli-Hankala A, Silfvast T. Prehospital therapeutic hypothermia for comatose survivors of cardiac arrest: a randomized controlled trial. Acta Anaesthesiol Scand. 2009;53(7):900-907.

Kim F, Olsufka M, Longstreth WT, Jr., et al. Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline. Circulation. 2007;115(24):3064-3070.

Kim F, Nichol G, Maynard C, 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.

Kim JG, Ahn C, Shin H, Kim W, Lim TH, Jang BH, Cho Y, Choi KS, Lee J, Na MK. Efficacy of the cooling method for targeted temperature management in post-cardiac arrest patients: A systematic review and meta-analysis. Resuscitation. 2020;148:14-24.

Kirkegaard H, Soreide E, de Haas I, 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):341-350.

Lascarrou JB, Merdji H, Le Gouge A, et al. Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm. N Engl J Med. 2019;381(24):2327-2337.

Laurent I, Adrie C, Vinsonneau C, et al. High-volume hemofiltration after out-of-hospital cardiac arrest: a randomized study. J Am Coll Cardiol. 2005;46(3):432-437.

Look X, Li H, Ng M, et al. Randomized controlled trial of internal and external targeted temperature management methods in post- cardiac arrest patients. Am J Emerg Med. 2018;36(1):66-72.

Lopez-de-Sa E, Rey JR, Armada E, et al. Hypothermia in comatose survivors from out-of-hospital cardiac arrest: pilot trial comparing 2 levels of target temperature. Circulation. 2012;126(24):2826-2833.

Lopez-de-Sa E, Juarez M, Armada E, et al. A multicentre randomized pilot trial on the effectiveness of different levels of cooling in comatose survivors of out-of-hospital cardiac arrest: the FROST-I trial. Intensive Care Med. 2018;44(11):1807-1815.

Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J Med. 2013;369(23):2197-2206.

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;162:304-311.

Nordberg P, Taccone FS, Truhlar A, et al. Effect of Trans-Nasal Evaporative Intra-arrest Cooling on Functional Neurologic Outcome in Out-of-Hospital Cardiac Arrest: The PRINCESS Randomized Clinical Trial. JAMA. 2019;321(17):1677-1685.

Obermeyer Z, Samra JK, Mullainathan S. Individual differences in normal body temperature: longitudinal big data analysis of patient records. BMJ. 2017;359:j5468.

Pittl U, Schratter A, Desch S, et al. Invasive versus non-invasive cooling after in- and out-of-hospital cardiac arrest: a randomized trial. Clin Res Cardiol. 2013;102(8):607-614.

Salter R, Bailey M, Bellomo R, Eastwood G, Goodwin A, Nielsen N, Pilcher D, Nichol A, Saxena M, Shehabi Y, Young P; Australian and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation (ANZICS-CORE). Changes in Temperature Management of Cardiac Arrest Patients Following Publication of the Target Temperature Management Trial. Crit Care Med. 2018;46(11):1722-1730.

Scales DC, Cheskes S, Verbeek PR, et al. Prehospital cooling to improve successful targeted temperature management after cardiac arrest: A randomized controlled trial. Resuscitation. 2017;121:187-194.

Soar J, Callaway CW, Aibiki M, Böttiger BW, Brooks SC, Deakin CD, Donnino MW, Drajer S, Kloeck W, Morley PT, Morrison LJ, Neumar RW, Nicholson TC, Nolan JP, Okada K, O'Neil BJ, Paiva EF, Parr MJ, Wang TL, Witt J; Advanced Life Support Chapter Collaborators. Part 4: Advanced life support: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation. 2015; 95:e71-120.

Taccone FS, Hollenberg J, Forsberg S, Truhlar A, Jonsson M, Annoni F, Gryth D, Ringh M, Cuny J, Busch HJ, Vincent JL, Svensson L, Nordberg P; PRINCE; PRINCESS investigators. Effect of intra-arrest trans-nasal evaporative cooling in out-of-hospital cardiac arrest: a pooled individual participant data analysis. Crit Care. 2021 Jun 8;25(1):198.


TTM, Targeted Temperature Management, Temperature

Discussion

GUEST
Benjamin Abella
Conflicts of interest: Speakers bureau
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.
Reply
GUEST
ALS Task Force
Thank you for your feedback. The ALS task Force considered the two publications and considered giving a stronger statement for the use of hypothermia at 32-34oC in some subpopulations – however our systematic review of the available evidence did not identify any subpopulation for which hypothermia at 32-34oC improves any important or critical outcomes. There was also a view from some TF members not to include this statement about subpopulations at all. The CoSTR statement represents the consensus of the ALS Task Force and states that there is uncertainty about this issue.
profile avatar
Federico Semeraro
(1 posts)
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).
Reply
GUEST
ALS Task Force
Thank you for raising this issue – the ILCOR ALS Task Force has provided a treatment recommendation for national councils (e.g., AHA) to adapt for treatment guidelines for clinical practice. Our treatment recommendation is advocating fever prevention and we have provided the upper limit of temperature to achieve fever prevention and as done in the TTM study - the commentary with the CoSTR addresses this issue.
GUEST
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
Reply
GUEST
ALS Task Force
Thank you for your feedback. This was a difficult topic on which to achieve TF consensus on treatment recommendations. The rationale for the recommendations is provided in the justifications section. As stated in response to others, our systematic review did not identify any subpopulation for which hypothermia at 32-34oC improves any important or critical outcomes. There was also a view from some TF members not to include this statement at all. The CoSTR statement represents the consensus of the ALS Task Force and states that there is uncertainty about this issue.
GUEST
Fabio Silvio Taccone
Conflicts of interest: Speakers bureau
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 …)
Reply
GUEST
ALS Task Force
Thank you for your feedback. The ALS TF has followed the GRADE convention and used the term 'suggest' in treatment recommendations that are weak recommendations based on low or very -low certainty evidence.
Nguyen quan
(1 posts)
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
Reply
GUEST
Jana F.
I agree with Dr. Nguyen. Also here in Germany the reuslts of the TTM studies may not apply to our patients. The cardiac arrest times are longer, on the other hand patients are cooled much earliert than in the TTM trials. These may be important factors for the effectiveness of hypothermia.
GUEST
ALS Task Force
Thank you for your feedback based on your personal experiences in Vietnam. We did not identify any evidence of benefit for 33 C in patients with a longer duration of CPR. In addition, hypothermia treatment at 33 C requires greater resource in terms of cooling interventions than actively preventing fever by targeting a temperature ≤ 37.5 C.
GUEST
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.
Reply
GUEST
ALS Task Force
Thank you for your comments. Firstly, the ALS Task Force (TF) debated the terms 'comatose' or 'unresponsive', or 'patients who do not awaken soon after ROSC' in the treatment recommendation, and chose 'comatose'. National Councils such as the AHA will be able to provide more detail in their clinical practice guidelines. Our systematic review did not identify any subpopulation for which hypothermia at 32-34oC improves any important or critical outcomes. There was also a view from some TF members not to include the sub population statement at all. The CoSTR statement represents the consensus of the ALS Task Force and states that there is uncertainty about this issue. We have not gone any further than this and made a treatment recommendation on this issue – a similar statement was included in the 2015 treatment recommendation. The TF was concerned that actively rewarming patients who present with mild hypothermia after ROSC may be harmful, and this led to this good practice statement. We accept that alternative rewarming approaches may be possible and this is an area that requires further study. We agree that the issue of shivering requires further study and the ALS TF will consider addressing this in the future.
GUEST
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
Reply
GUEST
ALS Task Force
Thank you for this response. Recommendations 1. We agree that temperature control in cardiac arrest survivors should not be abandoned all together. This will require all National Councils to spread this message to clinicians involved in the care of post cardiac arrest survivors. Whether there has been harm from a decrease in the use of hypothermia after ROSC is uncertain. Two observational studies have looked at this [ 1. Salter, R., et al., Changes in Temperature Management of Cardiac Arrest Patients Following Publication of the Target Temperature Management Trial. Crit Care Med, 2018. 46(11): p. 1722-1730. 2. Nolan, J.P., et al., 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: p. 304-311.] The first study from Australia and New Zealand found no significant difference in the slope or “stepwise change” after the publication of the TTM1 trial. This is the most appropriate analysis for a before/after study. In the more naïve analysis, there were also no significant association when adjusting for appropriate variables (i.e., not including temperature variables). In the second study from the United Kingdom, they found similar results when the appropriate model (i.e., accounting for time trends but not including temperature variables) was used. The treatment recommendation suggests the active prevention of fever as opposed to targeting mild hypothermia for at least 72 hours. Justifications 1. We agree that there is wide global variation in cardiac arrest outcomes. In addition there are differences in clinical practices between settings. The TTM studies were done in a range of settings predominantly in Europe where there is also a wide range of outcomes and practices. Our treatment recommendations will need to be adapted by National Councils for local circumstances. 2. and 3. We are aware of these observation studies (Callaway 2020, e208215; Nishikimi 2021, e741) and considered these when making our treatment recommendations. Our systematic review that included RCTs did not find any benefit for hypothermia treatment in any subgroup. 4. We have reviewed numerous studies of time to achieve hypothermia and the time taken in the TTM2 trial was in keeping with these. Time from ROSC to a temperature < 34°C was approximately 5 hours in the TTM2 trial with a time from ROSC to randomization of approximately 2 hours and time from randomization to < 34°C of approximately 3 hours. Data from multiple other randomized trials (including the unpublished CAPITAL-CHILL trial), and from observational studies, have found similar or longer times. The one trial that had a shorter time is the 2002 Bernard trial. The overwhelming evidence, from both randomized trials and “real-life” observational data therefore suggests that a time to target of approximately 5 hours is consistent with clinical practice elsewhere. – this is addressed in more detail with refences in our further responses and the COSTR Evidence to Decision Tables.
GUEST
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.
Reply
GUEST
ALS Task Force
Thank you for this response. We have considered all the current available RCT evidence in order to make our treatment recommendations and not just the recently published TTM2 trial, although this study did stimulate our update of the previous CoSTR. We did not identify any sub-populations supporting the use of mild hypothermia in our systematic review and hence our broad recommendation.
profile avatar
Edilberto Amorim
(1 posts)
#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.
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GUEST
ALS Task Force
Thank you for raising this issue – the ILCOR ALS Task Force has provided a consensus on the science and treatment recommendation for National Councils (e.g., AHA) to adapt for treatment guidelines for clinical practice. As stated in the responses to others, our systematic review did not identify any subpopulations where mild hypothermia was beneficial. National Councils will provide more detailed guidance for clinical practice based on local and regional values and preferences.
GUEST
Jana F.
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?
Reply
GUEST
ALS Task Force
Thanks you for your comment. We have carried out a systematic review [Granfeldt A, Holmberg MJ, Nolan JP, Soar J, Andersen LW; International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force. Targeted temperature management in adult cardiac arrest: Systematic review and meta-analysis. Resuscitation. 2021;167:160-172.] that included the RCTs. The Task Force members are also aware of and considered the animal and observational data in making these treatment recommendations.
GUEST
Andreas Schäfer
Conflicts of interest: Speakers bureau
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".
Reply
GUEST
ALS Task Force
Thanks you for your comment. We have carried out a systematic review [Granfeldt A, Holmberg MJ, Nolan JP, Soar J, Andersen LW; International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force. Targeted temperature management in adult cardiac arrest: Systematic review and meta-analysis. Resuscitation. 2021;167:160-172.] that included these earlier RCTs. We agree that many aspects of post resuscitation care have changed since these previous RCTs. We would go further and describe these as improvements in care – our meta-analysis used a random effects model that actually gave the older studies a greater weighting than many task force members considered justified given the changes in practice since when these studies took place. We agree changes in prognostication and delaying withdrawal of life support could be an important factor. We address the issues of propofol and speed of cooling in our response to Nichol.
GUEST
Graham Nichol
Conflicts of interest: Grants
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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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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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. 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Reply
GUEST
ALS Task Force
We thank Professor Nichol for his detailed feedback and provide a point by point response at https://we.tl/t-FpHoQ6S2Co.
GUEST
Graham Nichol
Conflicts of interest: Grants
https://www.dropbox.com/s/40djh9uladt47eu/20210912%20Nichol%20Response%20to%20ILCOR%20Statement%20on%20IH%20TTM%20After%20CA.docx?dl=0
Reply
GUEST
. Wilhelm Behringer, Benjamin Abella, Kjetil Sunde
Conflicts of interest: Speakers bureau
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.
Reply
GUEST
ALS Task Force
We thank the commenters and provide a response at https://we.tl/t-M4JcwWRIO3
GUEST
. Wilhelm Behringer, Benjamin Abella, Kjetil Sunde
Conflicts of interest: Speakers bureau
https://www.magentacloud.de/share/iuov1lurtw
Reply
GUEST
Colleen Bland
Conflicts of interest: Financial relationships
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.
Reply
GUEST
ALS Task Force
Thank you for your feedback. The average time to reach target temperature in the TTM study was similar to other published studies including where there have been no delays due to trial recruitment and randomisation – we have addressed this issue in previous responses. Our systematic review did not identify any sub populations where hypothermia was beneficial.

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