Temperature Control in Adult Cardiac Arrest: ALS TF SR

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 were recused from the discussion as they declared a conflict of interest: (none applicable)

The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: (none applicable)

CoSTR Citation

Granfeldt A, Holmberg MJ, Soar J, Nolan JP, Skrifvars M, Berg KM, Drennan I, on behalf of the ILCOR ALS Task Force. Temperature Control in Adult Cardiac Arrest Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, 2023 December. 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 2021 160) and is updated following the publication of an updated systematic review (Granfeldt 2023 epub) (PROSPERO CRD42020217954 on October 28, 2020) conducted by an expert systematic review group and ALS task force content experts. These data were taken into account by the ALS task force when formulating the Treatment Recommendations.

PICOST

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

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 outcomes will depend 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ecological studies, case series, case reports, reviews, abstracts, editorials, comments, letters to the editor, or unpublished studies will not be included.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 will be included as long as there is an English abstract; unpublished studies (e.g., conference abstracts, trial protocols) will be excluded. Original literature search On October 30, 2020, and updated for clinical trials on June 17, 2021. For the updated systematic review, the literature search was conducted on May 31, 2023 and on June 3, 2023 for ongoing clinical trials.

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 original 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.

The updated search identified 391 unique records of which 12 full-text articles were assessed for eligibility). Six studies were excluded yielding a total of six new studies, investigating different aspects of temperature control.

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. Fixed effects meta-analyses were conducted when less than 3 trials were included and as post-hoc sensitivity analyses.

Note on terminology:

• The term targeted temperature management (used in the 2021 CoSTR) has been updated as below for clarity: Hypothermic temperature control = active temperature control with the target temperature below the normal range.
• Normothermic temperature control = active temperature control with the target temperature in the normal range.
• Fever prevention temperature control = monitoring temperature and actively preventing and treating temperature above the normal range
• No temperature control = no protocolised active temperature control strategy.

Use of hypothermic temperature control

In the systematic reviews, studies were pooled such that the intervention was targeting hypothermia (32-34 °C), and the comparator was targeting normothermia or fever prevention.

For the critical outcome of survival to hospital discharge, we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 6 RCTs (Bernard 2002 557, HACA 2002 549, Laurent 2005 432, Lascarrou 2019 2327, Dankiewicz 2021 2283, Wolfrum 2022 1357) involving 3074 adults that showed no difference between hypothermia and normothermia or fever prevention (RR 1.07; 95% CI 0.91 to 1.25 or 32 patients more/1000 survived with the intervention [95% CI, 41 fewer patients/1000 to 114 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 4 RCTs (Bernard 2002 557, HACA 2002 549, Dankiewicz 2021 2283. Wolfrum 2022 1357) involving 2377 adults that showed no difference between hypothermia and normothermia or fever prevention (RR 1.16; 95% CI 0.81 to 1.66 or 59 patients more/1000 survived with the intervention [95% CI, 70 fewer patients/1000 to 243 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 6 RCTs (HACA 2002 549, Laurent 2005 432, Hachimi-Idrissi 2005 187, Lascarrou 2019 2327, Dankiewicz 2021 2283, Wolfrum 2022 1357) involving 3014 adults that showed no difference between hypothermia and normothermia or fever prevention (RR 1.06, 95% CI 0.91 to 1.23 or 25 patients more/1000 survived with the intervention [95% CI, 38 fewer patients/1000 to 97 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 6 RCTs (HACA 2002 549, Laurent 2005 432, Hachimi-Idrissi 2005 187, Lascarrou 2019 2327, Dankiewicz 2021 2283, Wolfrum 2022 1357) involving 2991 adults that showed no difference between temperature control (hypothermia) and no temperature control (normothermia and fever prevention) (RR 1.16; 95% CI 0.92 to 1.47 or 57 patients more/1000 survived with the intervention [95% CI, 28 fewer patients/1000 to 166 more patients/1000 survived with the intervention]).

In-hospital cardiac arrest subgroup

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 2 RCTs (Lascarrou 2019 2327 and Wolfrum 2022 1357) involving 397 adults that showed no difference between hypothermic temperature control and normothermia (normothermia or fever prevention) (RR 1.09, 95% CI 0.80 to 1.50 or 24 patients more/1000 survived with the intervention [95% CI, 53 fewer patients/1000 to 132 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 2 RCTs (Lascarrou 2019 2327 and Wolfrum 2022) 1357 involving 397 adults that showed no difference between hypothermic temperature control and normothermia (normothermia and fever prevention) (RR 1.21, 95% CI 0.80 to 1.83 or 34 patients more/1000 survived with the intervention [95% CI, 32 fewer patients/1000 to 134 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 2 RCTs (Nielsen 2013 2197, Kwon 2021 362) involving 990 adults that showed no difference between 33 °C and 36 °C (RR 1.01, 95% CI 0.88 to 1.15 or 4 more patients /1000 survived with the intervention [95% CI, 42 fewer patients/1000 to 53 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]).

31 °C v 34 °C

For the critical outcome of survival at 30 days, we identified moderate certainty evidence (downgraded for serious imprecision) from 1 RCT (Le May 2021 1494) involving 367 adults that showed no difference between 31 °C and 34 °C (RR 0.95, 95% CI 0.80 to 1.13 or30 fewer patients /1000 survived with the intervention [95% CI, 120 fewer patients/1000 to 78 more patients/1000 survived with the intervention]).

For the critical outcome of survival at 180 days, we identified moderate certainty evidence (downgraded for serious imprecision) from 1 RCT (Le May 2021 1494) involving 367 adults that showed no difference between 31 °C and 34 °C (RR 0.96 , 95% CI 0.80 to 1.14 o 24 fewer patients /1000 survived with the intervention [95% CI, 118 fewer patients/1000 to 83 more patients/1000 survived with the intervention]).

For the critical outcome of favorable neurological outcome at 90 days, we identified moderate certainty evidence (downgraded for serious imprecision) from 1 RCT (Le May 2021 1494) involving 367 adults that showed no difference between 31 °C and 34 °C (RR 0.97 , 95% CI 0.80 to 1.16 o 17 fewer patients /1000 survived with the intervention [95% CI, 113 fewer patients/1000 to 90 more patients/1000 survived with the intervention]).

Duration of cooling

For the critical outcome of survival at 1 months, we identified very low certainty evidence (downgraded for very serious risk of bias and serious imprecision) from 1 RCT (Tahara 2021 368) involving 173 adults that showed no difference between 12-24 hours temperature control and 36 hours of temperature control (RR 1.03, 95% CI 0.89 to 1.18 or 24 more patients /1000 survived with the intervention [95% CI, 88 fewer patients/1000 to 145 more patients/1000 survived with the intervention]).

For the critical outcome of favorable neurological outcome at 1 month, we identified very low certainty evidence (downgraded for very serious risk of bias and serious imprecision) from 1 RCT (Tahara 2021 368) involving 173 adults that showed no difference between 12-24 hours temperature control and 36 hours of temperature control (RR 0.95, 95% CI 0.75 to 1.21 or 31 fewer patients /1000 survived with the intervention [95% CI, 156 fewer patients/1000 to 131 more patients/1000 survived with the intervention]).

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 hypothermic temperature control and 24 hours of hypothermic temperature control (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 hypothermic temperature control and 24 hours of hypothermic temperature control (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

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 (Lascarrou 2021 434) involving 50 adults that showed no difference between rewarming at 0.25C°/h vs 0.50C°/h (RR 0.88, 95% CI 0.56 to 1.38 or 77 fewer patients /1000 survived with the intervention [95% CI, 282 fewer patients/1000 to 243 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 (Lascarrou 2021 434) involving 50 adults that showed no difference between rewarming at 0.25C°/h vs 0.50C°/h (RR 1.00, 95% CI 0.59 to 1.70 or 0 fewer patients /1000 survived with the intervention [95% CI, 213 fewer patients/1000 to 364 more patients/1000 survived with the intervention]).

Duration of fever prevention after initial temperature control

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 (Hassager 2023 888) involving 789 adults that showed no difference between temperature control at 36 °C for 24 hours followed by targeting 37°C for 48 hours or until awakening (for a total duration of 72 hours) vs temperature control at 36 °C for 24 hours followed by targeting 37°C for 12 hours or until awakening (for a total duration of 36 hours) (RR 0.0.99, 95% CI 0.90 to 1.08 or 7 fewer patients /1000 survived with the intervention [95% CI, 80 fewer patients/1000 to 56 more patients/1000 survived with the intervention]).

For the critical outcome of favorable neurological outcome at discharge within 90 days, we identified low certainty evidence (downgraded for serious risk of bias and serious imprecision) from 1 RCT (Hassager 2023 888) involving 789 adults that showed no difference between temperature control at 36 °C for 24 hours followed by targeting 37°C for 48 hours or until awakening (for a total duration of 72 hours) vs temperature control at 36 °C for 24 hours followed by targeting 37°C for 12 hours or until awakening (for a total duration of 36 hours) (RR 0.0.98, 95% CI 0.89 to 1.08 or 14 fewer patients /1000 survived with the intervention [95% CI,74 fewer patients/1000 to 54 more patients/1000 survived with the intervention]).

Treatment Recommendations

We suggest actively preventing fever by targeting a temperature 37.5°C 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^oC 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 36–72 hours in post-cardiac arrest patients who remain comatose (good practice statement).

Justification and Evidence to Decision Framework Highlights

• The update of this topic was prioritized by the ALS Task Force, prompted by additional trial data and the publication of an updated review (Arrich 2023 Cd004128)

• Much of the content below is unchanged since 2022. Additional points reflecting the new evidence identified are included.

• 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).

Hypothermia v normothermia or prevention of fever

• The majority of the Task Force favored fever prevention temperature control for comatose patients following ROSC as opposed to hypothermic temperature control, based on the systematic reviews and because this intervention requires fewer resources and had fewer side effects than hypothermic temperature control.
• 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 hypothermic temperature control (33^oC). 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 reviews did not find evidence favoring temperature control 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 temperature control 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 temperature control 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.

• Although there was no direct evidence in our systematic reviews, 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 °C) 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.

• 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 reviews and meta-analyses 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.

Prehospital cooling (Unchanged)

• Our TR for prehospital cooling stays 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 (Unchanged)

• 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

• Our previous TR was a good practice statement 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) and one trial showed no difference between 12-24 and 36 hours of hypothermia (Tahara 2021 368).
• One trial comparing temperature control for a total duration of 36 hours vs. 72 hours showed no difference in outcomes (Hassager 2023 888). The trial included temperature control targeting 36°C for 24 hours followed by active fever prevention for 12 hours (total duration of 36 hours) or 48 hours (total duration of 72 hours)
• The same trial included temperature control with a surface cooling device at one site and an intravenous cooling device at the other site. Whether results are applicable to temperature control without a device or different cooling devices is unknown.
• Non–device-based treatment of fever was allowed in both groups
• The task force was not able to reach consensus on a treatment recommendation on duration of temperature control or fever prevention. After discussion about the lack of consistency in the interventions and comparators across the available studies, the task force agreed that there was not enough trial evidence to support a recommendation specifically on how long to prevent fever. All task force members agreed on the good practice statement, which allows for a range of duration that is supported by the limited data and by expert opinion.

Rewarming

• We identified one study comparing rewarming at 0.25C°/h vs 0.50C°/h with no difference between groups (Lascarrou 2021 434). The task force discussed that although there is no evidence that active rewarming is harmful, expert opinion is that it is generally unwarranted and can be avoided.

Knowledge Gaps

• There is limited data on no temperature control versus fever prevention temperature control.
• There are few RCTs of temperature control after eCPR.
• There are no large RCTs of temperature control after in-hospital cardiac arrest.
• Is there a therapeutic window within which hypothermic temperature control 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 hypothermic temperature control as currently practiced?
• Is temperature control using a cooling device with feedback more effective than temperature control without a feedback-controlled cooling device?

Attachments: TTM ETD 2024 Dec 13

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