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Authors; Diksha Kumar, Khai Tran, and Zahra Premji.
An estimated 35,000 cardiac arrests occur annually in Canada, with the majority of them occurring outside of hospital settings.1 The abrupt loss of cardiac function is associated with poor clinical outcomes; the rate of survival to hospital discharge for out-of-hospital cardiac arrest (OCHA) ranges between 3.9% and 7.1%.2 Survival after cardiac arrest not only requires the coordination of emergency services to facilitate immediate resuscitation and return of circulation, but also critical care over the next 24 hours to ensure that the brain is adequately supplied with oxygenated blood.3 Fever is common among patients following cardiac arrest and resuscitation, and is thought to worsen brain damage.4 Brain injury is a major cause of both mortality and decreased function, therefore its prevention is an imperative aspect of post–cardiac arrest care.5
Hypothermic targeted temperature management (TTM) has been widely practised within this patient population to control body temperature.4 Also known as therapeutic hypothermia, the intervention involves the use of feedback-controlled intravascular cooling techniques in comatose patients to achieve a target body temperature typically in the range of 32°C to 34°C.3 Canadian guidelines have recommended therapeutic hypothermia for unresponsive patients following OCHA; however, the evidence base has been largely inconclusive.2 Results from a recently published randomized controlled trial (RCT)6 showed that hypothermic TTM may not provide significantly clinical improvements over targeted normothermia at 37°C, which raises the question of whether existing hypothermic TTM protocols in critical care settings are of clinical value to this patient population.
The objective of this report is to identify and review current evidence regarding the comparative clinical effectiveness of normothermia versus hypothermia in adult patients after cardiac arrest and summarize identified evidence-based guidelines and recommendations regarding TTM.
A limited literature search was conducted by an information specialist on key resources including MEDLINE, the Cochrane Library, the University of York Centre for Reviews and Dissemination (CRD) databases, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. For question 1, the main search concepts were cardiac arrest, hypothermia, and normothermia. No filters were applied to limit the retrieval by study type. For question 2, the main search concepts were cardiac arrest and temperature management. Search filters were applied to this search to limit retrieval to guidelines. When possible, retrieval was limited to the human population. The search was also limited to English-language documents published between January 1, 2016, and December 16, 2021.
One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.
Selection Criteria.
Articles were excluded if they did not meet the selection criteria outlined in Table 1, were duplicate publications, or were published before 2016. Systematic reviews (SRs) in which all relevant studies were captured in other more recent or more comprehensive systematic reviews were excluded. Primary studies retrieved by the search were excluded if they were captured in 1 or more included SR. Guidelines with unclear methodology were also excluded.
The included publications were critically appraised by 1 reviewer using the following tools as a guide: A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2)7 for SR, the Professional Society for Health Economics and Outcomes Research (ISPOR) questionnaire8 for network meta-analyses, the Downs and Black checklist9 for randomized and non-randomized studies, and the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument10 for guidelines. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.
A total of 280 citations were identified in the literature search. Following screening of titles and abstracts, 228 citations were excluded and 52 potentially relevant reports from the electronic search were retrieved for full-text review. Two potentially relevant publications were retrieved from the grey literature search for full-text review. Of these potentially relevant articles, 40 publications were excluded for various reasons and 14 publications met the inclusion criteria and were included in this report. These comprised 2 SRs, 1 RCT, 7 non-randomized studies, and 4 evidence-based guidelines. Appendix 1 presents the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA)11 flow chart of the study selection. Additional references of potential interest are provided in Appendix 6.
Additional details regarding the characteristics of included publications are provided in Appendix 2.
Two SRs were identified, both published in 2021.5,12 The authors of 1 SR, which included RCTs published up to June 21, 2021, conducted a network meta-analysis (NMA) of 10 RCTs.5 Similarly, the other SR included RCTs that were published up to June 17, 2021, and included a meta-analysis of 9 RCTs.12 A table outlining the overlap between included primary studies within the 2 SRs included in this report is provided in Appendix 5.
The included RCT, published in 2016, was of non-blinded, parallel design.13 Seven non-randomized studies published between 2016 and 2021 were also identified, including 6 retrospective cohort studies14-19 and 1 observational post hoc analysis of an RCT.20
Additionally, 4 guidelines with recommendations regarding post–cardiac arrest TTM were included in this report.2,21-23 The most recent guideline, published in 2018, was developed by the French Intensive Care Society (FICS) and French Society of Anesthesia and Intensive Care Medicine.21 Two of the included guidelines were published in 2017, 1 by the American Academy of Neurology (AAN),22 and the other developed jointly by the Canadian Cardiovascular Society (CCS), Canadian Cardiovascular Critical Care Society, and Canadian Association of Interventional Cardiology.2 The final guideline from 2016 was developed by the Canadian Critical Care Society (CCCS), Canadian Neurocritical Care Society, and Canadian Critical Care Trials Group.23 Methods for the collection, selection, and synthesis of evidence informing the recommendations were reported in 3 guidelines, stating that a comprehensive literature search was performed2,22,23 and that the evidence was reviewed by committee members.2,22 Two guidelines classified the level of evidence for a recommendation from “very low” or “low” to “high.”21,23 The AAN guideline graded evidence as Class I, II, III, or IV.22 The authors of the CCS guideline used Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology to assess the quality of evidence.2 Final recommendations were made using Delphi methodology,21,23 GRADE methodology,2,21 and nominal group technique.23 The strength of recommendations was classified in various ways; 2 of the included guidelines referred to them as either “strong” or “conditional,”2,23 1 graded them as A, B, C, or U (insufficient evidence),22 and the other organized them as positive or negative and as strong or weak.21
One of the SRs listed first authors from Canada,5 and the other listed first authors from Denmark.12 The included primary clinical studies were conducted in Israel,17 Singapore,13,18 South Korea,16 Switzerland,14 the Netherlands,20 and Turkey.15 Two of the included guidelines were Canadian,2,23 1 was from the US,22 and 1 was from France.21
Both SRs5,12 included RCTs with adult patients after cardiac arrest, with the SR by Fernando et al. (2021)5 limiting inclusion to patients with OCHA who remained unresponsive following signs of return of spontaneous circulation (ROSC). The SR by Fernando et al. (2021)5 included 4,218 participants across 10 RCTs, and the SR by Granfeldt et al. (2021)12 included 2,968 participants from 9 RCTs.12 Patients’ mean age was similar between the 2 SRs (approximately 63 years5 and 6412 years). The majority of the included population in both SRs were male, ranging from 60% to 88.9% in 1 SR5 and from 56% to 100% in the other.12
There was some variation in the patient population among the 8 primary studies included in this report. All studies included adult patients hospitalized following cardiac arrest.13-20 The mean age of the patients ranged between 52.5 years and 65 years.13-20 Sex was reported in 7 of the 8 primary studies, and the majority of patients across the studies were male, ranging from 53.4% to 81.5%. One retrospective cohort study16 and 1 observational post hoc analysis20 limited inclusion to patients with OCHA, whereas the others did not specify between in-hospital and out-of-hospital cardiac arrest. The RCT13 and retrospective cohort study18 by Pang et al. included primarily patients who had an in-hospital cardiac arrest (90.5% to 92.4% of participants) and specifically comprised patients on extracorporeal life support. Three of the included retrospective cohort studies15,17,19 reviewed patient data from patients in the intensive care unit (ICU).
The relevant target population of the 4 included guidelines2,21-23 in this report was adult patients with cardiac arrest. One guideline21 contained recommendations for a broader population: both adult and pediatric patients with cardiac arrest, traumatic brain injury, stroke or other brain injuries, and shock. Authors of the CCS guideline2 specified that the recommendations pertained to patients with OCHA. The guideline developed by FICS21 was broadly intended for clinicians who provide neurologic care to critically ill patients. The intended users of the 3 other included guidelines2,22,23 were clinicians who provide care for patients with cardiac arrest; the AAN guideline22 is specifically for nontraumatic cardiac arrest and the CCS is guideline for OCHA.2
The SR with NMA by Fernando et al. (2021)5 compared normothermia (37°C to 37.8°C) with 3 temperature ranges of hypothermia: 31°C to 32°C (which they referred to as “deep hypothermia”), 33°C to 34°C (“moderate hypothermia”), and 35°C to 36°C (“mild hypothermia”). The SR with meta-analysis by Granfeldt et al. (2021)12 compared normothermia, whether it involved active cooling as part of TTM or not, with hypothermic TTM (32°C to 34°C).
Normothermia was defined in various ways in the included primary clinical studies. Therapeutic normothermia was described as a body temperature maintained at 36°C,14,19 37°C,13 36°C to 37°C,20 or higher than 35.5°C.16 Three retrospective studies15,17,18 considered normothermia as a comparison group but did not specify a temperature range; however, 115 of the studies considered normothermia as a non-TTM intervention. Targeted normothermia was specified to be maintained for 28 hours in the retrospective cohort study by Casamento et al. (2016).19
Hypothermia was also defined in various ways in the included primary studies. Targeted hypothermia was described as body temperature maintained at 33°C,14 34°C,13 32°C to 34°C,17,19,20 33°C to 35°C,15 or lower than 35.5°C.16 Hypothermia was specified as maintained for 24 hours in the studies by Pang et al.13,18 and Casamento et al. (2016).19
All included guidelines presented recommendations regarding TTM as part of in-hospital care following cardiac arrest.2,21-23 The AAN guideline defined therapeutic hypothermia, or hypothermic TTM, as cooling to a core body temperature of 32°C to 34°C.22 The CCS guideline broadly defined the intervention considered, TTM, as a strategy of intentional temperature management of a patient after cardiac arrest, which consists of active patient cooling, subsequent rewarming, and extended fever control.2
Several clinical outcomes of relevance were described in the studies included in this review. These outcomes included the following: survival with good neurologic outcome,5,12,13,18 overall survival,5,12,13,15-20 mortality,13-15,17,19 ICU or hospital length of stay,13-15,18,19 neurologic status,13-16,20 protocol adherence,14 quality of life,20 time spent in temperature target range,19 medication prescription,14,19 and adverse events.5,13,14,17-19
The modified Rankin Scale, Cerebral Performance Categories scale, and Pittsburgh Cardiac Arrest Category scale were the validated measures used to describe neurologic outcomes in 2 SRs,5,12 1 RCT,13 and 5 non-randomized studies.14-16,18,20 The modified Rankin Scale is commonly used to measure the degree of disability of people who have suffered a stroke or other causes or neurologic disability.24 The scale ranges from 0 to 6, with 0 for no symptoms, 3 for moderate disability (requires some help but able to walk without assistance), and 6 for dead.24 The Cerebral Performance Categories are the gold standard for describing the level of function and impairment after cardiac arrest.25 The categories, which rank from 1 to 5, are as follows: good cerebral performance, moderate cerebral disability, severe cerebral disability, coma or vegetative state, and brain death.25 Finally, the Pittsburgh Cardiac Arrest Category is a 4-level illness severity score with the following rankings: awake, coma with mild cardiopulmonary failure, coma with severe cardiopulmonary failure, and deep coma.26 Studies that investigated survival with good neurologic outcome defined a favourable neurologic outcome as any of the following: modified Rankin Scale score of 0 to 3,5,12 Cerebral Performance Categories scale score of 1 or 2,5,12,13,18 Pittsburgh Cardiac Arrest Category score of 1 or 2,5 or blinded assessment from a health professional indicating no, mild, or moderate disability.5
The authors of 1 retrospective cohort study14 reported protocol adherence as a primary outcome, and patients were considered to have adhered to the protocol if their body core temperature was within a range of 1°C around the target temperatures of 33°C and 36°C for the hypothermia and normothermia groups, respectively.
The authors of 2 retrospective cohort studies14,19 reported several outcomes related to the prescription and dose of catecholamines, sedatives, and relaxants administered to patients in the targeted normothermia and hypothermia groups.
The 4 guidelines included in this report regarded survival with good neurologic function as an outcome for consideration when developing recommendations.2,21-23
Additional details regarding the strengths and limitations of the included publications are provided in Appendix 2.
Both SRs5,12 used comprehensive search and selection strategies, which is evident because most RCTs relevant to this report were excluded on the basis of inclusion within the SRs. Both SRs by Fernando et al. (2021)5 and Granfeldt et al. (2021)12 had registered published protocols with detailed search strategies. Fernando et al. (2021)5 searched 6 databases (MEDLINE, PubMed, Embase, Scopus, Web of Science, and the Cochrane Database of Systematic Reviews), conducted further surveillance searches, and performed a grey literature search, including the reference lists of all included studies and existing SR on TTM. Granfeldt et al. (2021) searched 3 databases (PubMed, Embase, and the Cochrane Central Register of Controlled Trials) as well as the International Clinical Trials Registry Platform and ClinicalTrials.gov for registered ongoing and unpublished trials. However, it is unclear whether content experts were consulted during the review process of either of the SRs5,12 and, in the case of Fernando et al. (2021),5 it is unclear whether trial registries were searched as part of the grey literature search outlined in the published protocol. Research questions and inclusion criteria were clearly reported and consisted of components of population, intervention, comparison, and outcomes.5,12 Although Fernando et al. (2021)5 explained their selection of RCTs for inclusion in the review, Granfeldt et al. (2021)5,12 did not justify their selection of randomized and non-randomized controlled studies for inclusion. The study selection and data extraction processes were performed in duplicate, and the included studies were described in adequate detail in supplementary materials.5,12 Reasons for exclusion cannot be easily verified because neither of the SRs published a list of excluded studies.
In terms of conducting meta-analyses, authors of both SRs5,12 justified combining the data in a meta-analysis or NMA and used assessment tools by Cochrane to assess the risk of bias of included studies. Statistical heterogeneity among trials were assessed using visual inspection of forest plots, the I2 statistic, and the Chi-square test.5,12 Heterogeneity was observed in the results of the reviews, but the authors investigated the potential sources of any heterogeneity in the results and discussed its impact in the findings.5,12
Fernando et al. (2021)5 initially performed pairwise MA using the random-effects model, and then evaluated the feasibility of conducting an NMA by checking the availability of evidence, transitivity assumption, connectivity, and agreement between direct and indirect evidence. With the assumption of a common heterogeneity parameter, the frequentist random-effects model was chosen to combine the included data.5 However, the authors did not provide a justification about why the analyses were performed with a frequentist instead of a Bayesian approach. Due to insufficient data, the authors were unable to conduct subgroup analyses or meta-regression to explain statistical heterogeneity.5 The authors presented a network graph of included studies, and given the geometry of the NMA, the comparisons between normothermia and deep and moderate hypothermia were direct, and the comparison between normothermia and mild hypothermia was indirect.5 In addition, Fernando et al. (2021)5 provided a clear summary of the main findings but did not perform any sensitivity analyses.
Several aspects of the included RCT13 were clearly described, such as the study objective, primary and secondary outcomes, patient characteristics, interventions, potential confounders, main findings, estimates of random variability, and adverse events. However, in reviewing the results section, it was unclear whether 1 of the 12 participants in the normothermia group was lost to follow-up given the discrepancy between the total number of participants and the number of patients discharged or deceased. The single-centre study was conducted in a tertiary referral centre, which may not be representative of where most patients seek immediate care after a cardiac arrest. In addition, due to the non-blinded design, investigators, outcomes assessors, and patients were aware of the treatment administered, which may have increased the risk of performance bias and detection bias. It is unclear whether the study was adequately powered because of its sample size of 21 participants. This RCT was also published as a letter to the editor, thus it is unclear whether the methodology and findings have been subject to peer review.
Overall, the reporting was clear across the 7 non-randomized studies14-20 in terms of study objectives, patient characteristics, potential confounders, interventions, and estimates of random variability. In 3 studies,14,19,20 the characteristics of the patients lost to follow-up were not described. The authors of 2 studies17,18 did not specify a temperature range for the normothermia group. In Kocayigit et al. (2021),15 it was unclear when the survival and good neurologic results outcomes were measured. The external validity of the study findings to other similar settings was generally considered poor because 4 of the included non-randomized studies14,15,17,18 were single-centre, retrospective cohort studies. The other 3 studies consisted of patient data derived from either multiple centres19,20 or national registries,16 which may have increased generalizability. None of the included studies were conducted in Canada, which may limit relevance of the results in the Canadian context. Threats to the internal validity of the studies were primarily due to the non-randomized nature of the studies: 6 of the included studies14-19 were of retrospective cohort design, which means the investigators, outcome assessors, and patients may have been aware of the intervention. Additionally, there is uncertainty about whether there was a high level of compliance with the intervention and whether the recorded patient data are accurate. Participants across the intervention and comparator groups appeared to be recruited at the same sites or from the same population and over the same periods of time. Some studies16,17,19,20 considered potential confounders when adjusting main outcomes, whereas other studies15,18 did not take into account baseline differences between the groups. Only 1 included study19 provided power calculations, but sample size was noted to be a limitation in 3 studies.14,17,18
All included guidelines described a clear scope and purpose.2,21-23 Evidence of some stakeholder involvement was evident in the development of all guidelines; however, it was unclear whether the views and preferences of the target patient population were sought.2,21-23 In terms of rigour of development, all included guidelines conducted a comprehensive search to collect evidence to support recommendations and did not specify whether other systematic methods, such as screening and study selection in duplicate, were undertaken.2,21-23 The guidelines also did not provide a procedure for future updates.2,21-23 Nonetheless, the supporting evidence was clearly appraised and used to support recommendations, and there was an evident process and methodology for the development of recommendations.2,21-23 There was an explicit link between the recommendations and the supporting evidence, with varying strengths of recommendations associated with different levels of evidence.2,21-23 All relevant recommendations were easily identifiable and clearly presented.2,21-23 The authors of the guidelines adequately described potential facilitators and barriers to application of recommendations but did not provide intended users with additional guidance on how to implement the recommendations and monitor the implementation of relevant interventions.2,21-23 Finally, all the included guidelines appeared to have editorial independence, with clear disclosures of competing interests.2,21-23
Appendix 4 presents the main study findings and authors’ conclusions.
Two SRs,5,12 1 RCT,13 and 1 retrospective cohort study18 evaluated the effect of TTM on survival rate with good neurologic or functional outcome. A favourable neurologic or functional outcome was defined as any of the following: modified Rankin Scale score of 0 to 3,5,12; Cerebral Performance Categories scale score of 1 or 2,5,12,13,18; Pittsburgh Cardiac Arrest Category score of 1 or 2,5 or blinded assessment from a health professional indicating no, mild, or moderate disability.5 No statistically significant differences were identified in the survival rate with good neurologic outcome between the normothermia and hypothermia groups.5,12,13,18 The SRs with NMA and meta-analysis reported odds ratios5 and risk ratios,12 respectively; however, the estimates were not statistically significant, suggesting no differences between interventions.
Two SRs, 1 RCT, 5 retrospective cohort studies, and 1 observational post hoc analysis of an RCT also evaluated overall survival, recorded at an unspecified time point,15,17 at hospital discharge,5,12,16,18,19 or within 30 days,12 90 days,5,12,20 6 months,5,12,13 or 1 year after discharge.20 The authors of 1 retrospective cohort study19 found a significantly greater proportion of survivors at discharge in the normothermia group compared with the hypothermia (TTM 32°C to 34°C) group, but no statistically significant differences were reported in the other studies.5,12,13,15-18,20
Hospital and ICU mortality rates were evaluated in 1 RCT18 and 4 of the retrospective cohort studies14,15,17,19 included in this report. There were no statistically significant differences between the normothermia and hypothermia groups.
One RCT13 and 4 retrospective cohort studies14,15,18,19 reported the average length of ICU14,19 or hospital13,15,18 stay as either a mean with standard deviation14 or median with interquartile range.13,15,18,19 The authors of 1 retrospective cohort study found that patients in the normothermia group who received standard supportive therapy experienced significantly longer hospital stays compared with patients in the hypothermia (TTM at 33°C to 35°C) group.15 There were no significant differences between the groups reported in the other studies.13,14,18,19
Neurologic status and function were measured in the studies included in this report using Cerebral Performance Categories scale scores13-16,20 and modified Rankin Scale scores.14 The authors of 1 retrospective cohort study15 found that a significantly greater proportion of patients in the hypothermia (TTM at 33°C to 35°C) group had good neurologic results, defined as a Cerebral Performance Categories scale score of either 1 or 2, compared with patients in normothermia (non-TTM) group. Although this finding was in favour of targeted hypothermia, no statistically significant differences were identified among the groups in other studies that also investigated this outcome.13,14,16,20
One retrospective cohort study by Duggelin et al. (2021)14 investigated the proportion of patients adherent to the TTM protocol at 24 hours. Using a Cox proportional hazard model, it was demonstrated that a significantly higher proportion patients in the normothermia (36°C) group were adherent to the TTM protocol compared with patients in the hypothermia (33°C) group.14
Quality of life at 1-year follow-up, measured using the 36-Item Short Form Survey, was reported in 1 included observational post hoc analysis.20 Patients in both groups reported similar physical and mental component scores.20 The risk ratio estimates were not statistically significant, suggesting no differences between interventions.
The authors of 1 retrospective cohort study19 evaluated the median proportion of time spent in the prescribed temperature range among patients in the hypothermia (TTM 32 to 34°C) versus normothermia (TTM 36°C) groups and found no statistically significant differences.
The proportion of patients receiving sedatives and relaxants and the mean or median doses prescribed were reported in 2 retrospective cohort studies.14,19 There were no statistically significant differences in the proportion of patients receiving propofol, morphine, midazolam, fentanyl, and pethidine for sedation, but 1 of the studies found that a significantly lower proportion of patients in the normothermia (TTM 36°C) group received at least 1 dose of muscle relaxant compared with patients in the hypothermia (TTM 32 to 34°C) group. Patients in the normothermia (TTM 36°C) group were reported to have received significantly lower doses of midalozam14,19 and fentanyl19 compared with patients in the hypothermia (TTM 32 to 34°C) group.
Several adverse events were reported in the studies included in this report: arrhythmia,5,13,14,19 bleeding,5,13,14,18,19 pneumonia,5,13,14 sepsis,5 seizures,5,17 limb ischemia,13,18 acute renal failure,13,18 continuous renal replacement therapy,13,18,19 thrombosis,14 bradycardia,14 hypoxic ischemia encephalopathy,18 stroke,18 ischemic hepatitis,18 cardiovascular instability,19 and mechanical ventilation.19 The authors of Duggelin et al. (2021)14 found that there was a significantly lower incidence of bradycardia among patients in the normothermia (TTM 36°C) group compared with patients in the hypothermia (TTM 33°C) group. However, no statistically significant differences were identified among the groups in other studies or for other adverse events.5,13,17-19
Among the 4 included guidelines, all strongly recommended the use of TTM to improve survival and neurologic outcome in patients resuscitated from OCHA with a shockable cardiac rhythm (ventricular tachycardia or ventricular fibrillation).2,21-23 The CCCS guideline23 extended the strong recommendation to patients presenting with pulseless ventricular tachycardia. In terms of patients with in-hospital cardiac arrest, the FICS guideline issued a positive recommendation for TTM at the level of expert opinion.21 However, the CCCS guideline contained a strong recommendation supported by low-level evidence in favour of TTM for patients with in-hospital cardiac arrest.23
The CCS guideline strongly recommended hypothermia (between 33°C and 36°C) for eligible patients who undergo TTM. The AAN guideline22 similarly specified in their recommendation that the TTM intervention should be hypothermia (32°C to 34°C for 24 hours); however, they also issued a lower-level recommendation supported by the same level of evidence for normothermia (36°C for 24 hours followed by 8 hours of rewarming to 37°C and temperature maintenance below 37.5°C until 72 hours) in patients who are comatose with either a shockable or non-shockable initial cardiac rhythm. The FICS guideline21 contains a weak recommendation for hypothermic (32°C to 36°C) TTM. Recommendations in the CCCS guideline23 do not state target temperature ranges for TTM.
With regard to specific technical recommendations, the CCS issued a lower-level recommendation supporting the use of surface cooling or intravascular cooling techniques.2
Although there was a high quantity of eligible publications identified in this report for the clinical effectiveness question, the quality of the included primary studies5,12-20 was low. Some limitations were explicitly acknowledged by authors of the individual studies included in this review, such as the lack of generalizability of a single-centre retrospective cohort study and small sample sizes. Moreover, the critical appraisal performed as part of this review identified some important limitations of the included studies. For example, some of the included non-randomized studies represented outcomes with unclear time points and follow-up periods and lacked detail on important adverse events. With the exception of 1 RCT included in the SR by Fernando et al. (2021),5 none of the studies included in this report were conducted in a Canadian setting, which could be a limitation.
Furthermore, there was a significant amount of overlap identified across the 2 SRs included in this report; much of the available evidence identified in this review is based on the same trials. The 1 RCT included in this report that did not overlap with the SRs is a preliminary study with 21 participants. This limits the available evidence base to address research questions regarding the clinical effectiveness of targeted and non-targeted normothermia for patients in critical care after cardiac arrest.
The SRs included in this report had several strengths in methodology, but authors of both SRs5,12 reported heterogeneity in study characteristics, such as patient populations and interventions, among the included RCTs and did not perform subsequent meta-regression or subgroup analyses to investigate the heterogeneity due to insufficient data. The NMA by Fernando et al. (2021)5 also lacked direct comparative evidence evaluating the differences between normothermia and mild hypothermia (35°C to 36°C).
Although the guidelines included in this report were generally of high quality, some relevant recommendations regarding TTM were categorized as conditional and supported by low-quality evidence, as stated by guideline authors. The guidelines did not contain any recommendations pertaining to the management of fever and shivering or specifics on the timing of TTM therapy.
This report identified 2 SRs (1 with an NMA5 and 1 with a meta-analysis12), 1 RCT,13 and 7 non-randomized studies14-20 published since 2016 informing the comparative clinical effectiveness of normothermia versus hypothermia for adult patients after cardiac arrest. Overall, there were no statistically significant differences across all the studies for several clinical effectiveness and patient-related outcomes: survival with good neurologic outcome, overall survival, hospital mortality, quality of life, and time spent in the temperature target range. There was an indication that targeted normothermia at 36°C may offer slight benefits over hypothermic TTM. Outcomes in favour of normothermia, such as greater proportion of survivors at discharge, protocol adherence, and decreased dose and use of prescribed sedatives and relaxants, were identified in 2 retrospective cohort studies.14,19 However, the studies14,19 were characterized to be of low quality and with potentially limited generalizability to the Canadian context. Therefore, there is limited evidence to suggest that normothermic TTM may provide more clinical benefits over hypothermic TTM.
In addition, 4 evidence-based guidelines published since 2016 were identified regarding the use of TTM for adult patients after cardiac arrest. In general, TTM was strongly recommended by all included guidelines, particularly for adult patients resuscitated from OCHA. Patients presenting with shockable initial cardiac rhythm versus non-shockable cardiac rhythm were also more strongly recommended for TTM. Unlike the clinical evidence identified in this report, guidelines — particularly those developed by Canadian and American organizations — strongly recommended the use of hypothermia for eligible patients, either in the 33°C to 36°C or 32°C to 34°C ranges. The guidelines included in this report were found to be of moderate to high quality. It is important to acknowledge that these guidelines are older compared with some of the clinical studies included in this report, with the latest 1 published in 2018, which may be the cause of discrepancies between the evidence used to inform the recommendations and the current literature on the topic.
Baseline characteristics, such as age, location of cardiac arrest (in hospital vs. out of hospital), and initial cardiac rhythm, may play a role in determining which patients are mostly likely to benefit from either modality of TTM. Larger RCTs and additional SRs with less heterogeneity may allow for the necessary means to identify such subgroups.
American Academy of Neurology
Canadian Critical Care Society
Canadian Cardiovascular Society
Grading of Recommendations, Assessment, Development and Evaluations
intensive care unit
network meta-analysis
out-of-hospital cardiac arrest
randomized controlled trial
return of spontaneous circulation
systematic review
targeted temperature management
Selection of Included Studies.
Characteristics of Included Systematic Review and Network Meta-Analysis.
Characteristics of Included Primary Clinical Studies.
Characteristics of Included Guidelines.
Note that this appendix has not been copy-edited.
Strengths and Limitations of Systematic Reviews and Network Meta-Analysis Using AMSTAR 27 and the ISPOR Questionnaire.
Strengths and Limitations of Clinical Studies Using the Downs and Black Checklist.
Strengths and Limitations of Guidelines Using AGREE II.
Note that this appendix has not been copy-edited.
Summary of Findings by Outcomes for Survival.
Summary of Findings by Outcomes for Mortality.
Summary of Findings by Outcomes for ICU and Hospital Length of Stay.
Summary of Findings by Outcomes for Neurological Status.
Summary of Findings by Outcomes for Protocol Adherence.
Summary of Findings by Outcomes for Quality of Life.
Summary of Findings by Outcomes for Time Spent in Temperature Target Range.
Summary of Findings by Outcomes for Medication Prescription.
Summary of Findings by Outcomes for Adverse Events.
Summary of Recommendations in Included Guidelines.
Note that this appendix has not been copy-edited.
Overlap in Relevant Primary Studies Between Included Systematic Reviews.
Note that this appendix has not been copy-edited.
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About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.
Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.
Questions or requests for information about this report can be directed to Requests@CADTH.ca
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