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

ALS Task Force Responses to Temperature Control after Cardiac Arrest CoSTR

The systematic review supporting this CoSTR has now been published – 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.]

We have made some minor changes to the CoSTR based on the feedback below and direct feedback to Task Force and ILCOR membership.

The most significant update is avoiding use of the term Targeted temperature management (TTM) in the CoSTR. The term TTM is very closely related to the TTM and TTM2 trials and does not itself signify a specific temperature. In the updated CoSTR we have used the terms temperature control aiming for e.g., hypothermia at 33 C, normothermia, or fever prevention.

We thank all those who have responded with feedback. Nearly all the issues raised were considered by the Task Force in detail and addressed in the Justification section or Evidence to Decision Tables.

We have provided individual responses to all the comments.

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 30. Available from: http://ilcor.org

Methodological Preamble

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 ;167:160-172.) (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 considered 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 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 Temperature Control

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 temperature control with hypothermia, and no TTM with temperature control 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 temperature control 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 temperature control with hypothermia and temperature control with 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 temperature control with hypothermia, and temperature control with 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 temperature control with hypothermia, and temperature control with 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 temperature control with hypothermia, and temperature control with 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 temperature control with hypothermia and 24 hours of temperature control with hypothermia (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 temperature control with hypothermia and 24 hours of temperature control with hypothermia (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 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 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 temperature control 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 Control 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. In addition based on feedback the ALS Task Force has avoided use of the term TTM as this term is now very closely linked with the TTM and TTM2 RCTs. To provide additional clarity for interpreting future clinical trials, systematic reviews and CoSTRs we propose the following terms are used:
  • o Hypothermic Temperature Control = active temperature control with the target temperature below the normal range.
• o Normothermic Temperature Control = active temperature control with the target temperature in the normal range.
• o Fever Prevention Temperature Control = monitoring temperature and actively preventing and treating temperature above the normal range
• o No Temperature Control = 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 <
  37.5C (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 (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 review 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 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 several 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 hypothermic (e.g. 32-36 ) immediately after ROSC as 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 to enable active control of temperature and 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 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 temperature control versus fever prevention.
• · 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 patients 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

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)

Annoni F, Peluso L, Fiore M, Nordberg P, Svensson L, Abella B, Calabro L, Scolletta S, Vincent JL, Creteur J, Taccone FS. Impact of therapeutic hypothermia during cardiopulmonary resuscitation on neurologic outcome: A systematic review and meta-analysis. Resuscitation. 2021;162:365-371.

Arrich J, Herkner H, Müllner D, Behringer W. Targeted temperature management after cardiac arrest. A systematic review and meta-analysis of animal studies. Resuscitation. 2021 May;162:47-55.

Bartlett ES, Valenzuela T, Idris A, Deye N, Glover G, Gillies MA, Taccone FS, Sunde K, Flint AC, Thiele H, Arrich J, Hemphill C, Holzer M, Skrifvars MB, Pittl U, Polderman KH, Ong MEH, Kim KH, Oh SH, Do Shin S, Kirkegaard H, Nichol G. Systematic review and meta-analysis of intravascular temperature management vs. surface cooling in comatose patients resuscitated from cardiac arrest. Resuscitation. 2020 ;146:82-95.

Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557-563.

Bernard SA, Smith K, Cameron P, et al. Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: a randomized controlled trial. Circulation. 2010;122(7):737-742.

Bernard SA, Smith K, Cameron P, et al. Induction of prehospital therapeutic hypothermia after resuscitation from nonventricular fibrillation cardiac arrest*. Crit Care Med. 2012;40(3):747-753.

Bernard SA, Smith K, Finn J, et al. Induction of Therapeutic Hypothermia During Out-of-Hospital Cardiac Arrest Using a Rapid Infusion of Cold Saline: The RINSE Trial (Rapid Infusion of Cold Normal Saline). Circulation. 2016;134(11):797-805.

Bray JE, Stub D, Bloom JE, Segan L, Mitra B, Smith K, Finn J, Bernard S. Changing target temperature from 33°C to 36°C in the ICU management of out-of-hospital cardiac arrest: A before and after study. Resuscitation. 2017;113:39-43.

Callaway CW, Soar J, 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. Circulation. 2015 Oct 20;132(16 Suppl 1):S84-145.

Castren M, Nordberg P, Svensson L, et al. Intra-arrest transnasal evaporative cooling: a randomized, prehospital, multicenter study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness). Circulation. 2010;122(7):729-736.

Chen N, Callaway CW, Guyette FX, Rittenberger JC, Doshi AA, Dezfulian C, Elmer J; Pittsburgh Post-Cardiac Arrest Service. Arrest etiology among patients resuscitated from cardiac arrest. Resuscitation. 2018 ;130:33-40.

Dankiewicz J, Cronberg T, Lilja G, et al. Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest. N Engl J Med. 2021;384(24):2283-2294.

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.