Interventional procedure overview of temperature control to improve neurological outcomes after cardiac arrest
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Evidence summary
Population and studies description
This interventional procedures overview is based on 27,292 patients from 8 systematic reviews and meta-analyses and 1 RCT. There is an overlap between included primary studies (RCTs) within 7 of the systematic reviews. So, the actual number of patients in RCTs who had TTM with hypothermia was 3,082 patients, and those with normothermia was 1,610 patients. Another systematic review with 6 observational studies included 1,845 patients in the TTM with hypothermia group and 12,762 patients in the control group (TTM without hypothermia).
This is a rapid review of the literature, and a flow chart of the complete selection process is shown in figure 1. This overview presents 9 studies as the key evidence in table 2 and table 3, and lists 39 other relevant studies in table 5.
Most systematic reviews and meta-analyses were published between 2021 and 2023. Seven of the systematic reviews included the same 8 to 10 RCTs published up to 2021 (Fernando 2021, Granfeldt 2021, Elbadawi 2022, Sanfilippo 2021, Zhu 2022, Arrich 2023, Duhan 2023). Therefore, there is an overlap between included primary studies within the 7 systematic reviews. Only 1 systematic review and meta-analysis included observational studies (Yin 2022). One study did a network meta-analysis of different TTM strategies (Fernando 2021).
The systematic reviews listed first authors from Canada, Austria, Denmark, USA, Italy and China.
Seven systematic reviews included RCTs with adult patients after cardiac arrest with both OHCA and/or IHCA, SR or NSR and TTM was done pre-hospital or after hospital arrival. Two studies limited inclusion to patients with OCHA who remained unresponsive following signs of ROSC (Fernando 2021, Granfeldt 2021). One systematic review included patients with only IHCA (Yin 2022) and another systematic review focused on OHCA caused by NSR (Zhu 2022).
The mean age of patients in 3 systematic reviews was approximately 57 to 77 years (Fernando 2021, Granfeldt 2021, Elbadawi 2022). Most of the included population in 2 of these studies were male, ranging from 50% to 100% (Fernando 2021, Granfeldt 2021,).
Studies reported mainly survival, neurological outcomes and adverse events. The modified Rankin Scale, and CPC scale were the validated measures used to describe level of function and neurological outcomes in the studies.
The quality of evidence was assessed using GRADE methodology. The level of evidence was judged to be of low certainty in 3 systematic reviews (Fernando 2021, Granfeldt 2021, Arrich 2023). The Cochrane review included studies published from 2000 to 2021. Cooling methods varied across studies.
Follow up varied across studies ranging from hospital discharge to 6 months.
The RCT in patients with coma after IHCA was underpowered and was terminated early as interim analysis failed to show any difference in outcomes between the hypothermic temperature control (32 to 34oC) for 24 hours and normothermic groups (Wolfrum 2022).
Table 2 presents study details.
Study no. | First author, date country | Studies/Patients (male: female) | Age | Study design | Inclusion criteria | Intervention and comparator | Follow up |
|---|---|---|---|---|---|---|---|
1 | Fernando (2021) Canada | 10 RCTs (between 2000-2021) (N = 4,218 patients with OHCA; range 30 to 1,861) Range 60 to 89% male patients with initial SR, (3 studies, n=502) patients with initial NSR (2 studies, n=452), mixed populations regardless of initial rhythm (5 studies, n=3,264). | Mean age range 56-75 years | Systematic review with network meta-analysis | Adult patients with OHCA and decreased level of consciousness post-ROSC for 10 minutes; with any initial cardiac rhythm; randomised to receive TTM with treatment arms of at least 2 different target temperatures, and with at least 1 arm having a targeted temperature ≤ 37.0°C; TTM continued for 24 hours; and reporting at least 1 outcome. | 4 different target temperatures evaluated. Normothermia (37.0°C to 37.8°C) (n = 1,390) TTM with deep hypothermia (31.0°C to 32.0°C) (n = 276) TTM with moderate hypothermia (33.0°C to 34.0°C) (n = 2,086) TTM with mild hypothermia (35.0°C to 36.0°C) (n = 466) | 6 months for primary and secondary outcomes |
2 | Granfeldt 2021 Denmark | Total 32 RCTs 9 RCTs (between 2001-2021) on TTM (n=2,968, range 16 to 1,861) % male, range TTM with hypothermia 56 to 100 Normothermia 63 to 80 | Mean normothermia 51-80 years Hypothermia 52-77 years | Systematic review with network meta-analysis | Adult patients with cardiac arrest in any setting (in-hospital or out-of-hospital) who underwent TTM | Normothermia (no TTM, no clear description of TTM, or TTM to maintain normothermia generally 36.5°C to 38.0°C) required active cooling. TTM with hypothermia (at 32.0°C to 34.0°C) | 90-180 days |
3 | Elbadawi A 2022 USA | 8 RCTs (n=2,927) with OHCA (1 included 27% IHCAs) 72% men (TTM with hypothermia n=1,462 versus normothermia n=1,465) | Mean 62.4 years | Systematic review and meta-analysis | Adults with coma after cardiac arrest with SR or NSR, any targeted degree of hypothermia compared with normothermia, reporting survival and neurological outcomes. | TTM with hypothermia (varied from 31.7°C to 34.0°C) versus normothermia | Weighted mean follow up 4.9 months. |
4. | Sanfilippo F 2021 Italy | 8 RCTs (n=3,855 patients; TTM at 32-34C, n=1,930; Normothermia n=1,925). | Not reported | Systematic review and meta-analysis | RCTs only, adult patients with both OHCA and/or IHCA, (SR or NSR), with TTM done after hospital arrival, reporting survival and neurological outcomes. | TTM range set at 32.0–34.0°C compared to controls (TTM with "actively controlled normothermia avoiding fever [3 RCTs, n=1,688]" or "uncontrolled" normothermia [5 RCTs, n=237]). | Ranged from 2 weeks or hospital discharge to 6 months. |
5 | Zhu YB 2022 China | 14 RCTs [published between 2007-2021] n=4,009, (range from 10-776); with 2,022 patients in the TTM group and 1,987 patients in without-TTM group. | Not reported | Systematic review and meta-analysis | Adult survivor patients with OHCA caused by NSR asystole, or pulseless electrical activity who underwent TTM, regardless of the methods (evaporative cooling, infusion of cold saline, and surface or systemic cooling), duration of TTM, and targeted temperature (32.0 -34.0°C). | Patients with NSR with TTM with hypothermia (32.0-34.00C) or without TTM (36.0-38.00C) (6 studies) Patients with NSR who had TTM (32.0-34.0°C) before hospital admission compared with in-hospital TTM (32.0°C -38.0°C) (8 studies) | Ranged from hospitalisation to 180 days. |
6 | Yin L 2022 China | 6 retrospective controlled cohort studies with a total of 14,607 patients (TTM group: 1,845, control group: 12,762). | Not reported | Systematic review and meta-analysis | Observational studies with more than 10 adult patients with IHCA; treated with TTM after ROSC and comparing with a control group; reporting discharge survival and neurological outcomes. | TTM with hypothermia compared with control group with no TTM with hypothermia | Hospital discharge |
7 | Duhan S 2023 USA | 12 RCTs with 4,262 inpatients after a cardiac arrest. N=2,146 in therapeutic hypothermia (<36°C) arm versus n=2,116 in normothermia (≥36°C) arm 25% were female. | 65 years in the therapeutic hypothermia arm and 64 years in the normothermia arm. | Systematic review and meta-analysis | RCTs with adults (aged ≥18 years) with OHCA or IHCA, comparing therapeutic hypothermia (<36°C ) with normothermia (≥36°C), reporting clinical outcomes: mortality or neurological outcomes. | Therapeutic hypothermia (<36°C) with normothermia (≥36°C ) Cooling methods: External cooling in 6 studies, internal and external cooling in 5 studies, not mentioned in 1 study. Mean cooling duration was 26 hours, and the warming duration ranged from 6 to 72 hours or until functional recovery. | Varied from hospital discharge, or 1 to 6 months. |
8 | Arrich J 2023 Austria, Denmark. | 12 studies (RCTs and quasi RCTs) with 3,956 patients who had had a cardiac arrest (in or out of hospital) and were successfully resuscitated. | Not reported | Systematic review and meta-analysis (Cochrane review) | RCTs and quasi-RCTs in adults comparing therapeutic hypothermia after cardiac arrest with standard treatment (control). Studies with adults cooled by any method, applied within 6 hours of cardiac arrest, to target body temperatures of 32°C to 34°C. | Therapeutic hypothermia (body target temperature 32°C to 34°C), regardless of how body temperature was reduced, applied within 6 hours of arrival at hospital versus control (standard treatment following cardiac arrest, i.e. no cooling or fever prevention). | 6 months |
9 | Wolfrum S 2022 Germany | N=249 patients after IHCA (126 randomised to hypothermic temperature control and 123 to normothermia) 64% (152/236) male | 72.6±10.4 years | RCT HACA in-hospital trial | patients 18 years and above who remained unconscious (Glasgow Coma Scale score ≤8) for more than 45 minutes after IHCA, irrespective of the initial rhythm or aetiology of cardiac arrest, induction of hypothermic temperature control within 4 hours of return of spontaneous circulation. | hypothermic temperature control (32-34°C) for 24 hours versus normothermia (avoid fever, temperature >37°C). in hypothermia group slow rewarming was done at a rate of 0.25°C/h to achieve a targeted temperature of 37.5°C. Target temperature (<34°C) was reached within 4.2 hours in the hypothermic group in 72% of patients and temperature was controlled for 48 hours at 37.0°C in the normothermia group. | 180 days |
Procedure technique
All studies detailed the interventions and comparators used. They compared different target temperature ranges of hypothermia with normothermia.
One systematic review with network meta-analysis compared 3 temperature ranges of hypothermia: 31.0°C to 32.0°C (deep hypothermia), 33.0°C to 34.0°C (moderate hypothermia), and 35.0°C to 36.0°C (mild hypothermia) with normothermia (37.0°C to 37.8°C; Fernando 2021)
One systematic review with meta-analysis compared TTM with hypothermia (at 32.0°C to 34.0°C) with normothermia which involved active cooling as part of TTM (Granfeldt 2021). In another meta-analysis, TTM in the hypothermia arm in the included trials varied from 31.7°C to 34.0°C (Eldbadawi 2022).
One systematic review with meta-analysis compared TTM with hypothermia at 32.0°C to 34.0°C with "actively controlled" (avoiding fever) or "uncontrolled" normothermia (Sanfilippo 2021).
Three studies also compared the methods of temperature management (evaporative cooling, infusion of cold saline, and surface or systemic cooling), timing (in-hospital or pre-hospital cooling), and duration of TTM (Granfeldt 2021, Zhu 2022, Yin 2022).
Efficacy
Survival with good functional/neurological outcomes
Optimal target temperature
A systematic review and network meta-analysis of 10 RCTs (n=4,218 patients) on TTM in comatose survivors of OHCA showed no difference in 6-month functional outcome between any target temperature in the hypothermic range of 31.0°C and 36.0°C and normothermia (37.0°C to 37.8°C) during TTM. Compared with normothermia, there was no effect on survival with good functional outcome using deep hypothermia (OR 1.30 [95% CI 0.73 to 2.30]), moderate hypothermia (OR 1.34 [95% CI 0.92 to 1.94]), or mild hypothermia (OR 1.44 [95% CI 0.74 to 2.80]). Also, there was no effect using deep hypothermia when compared with moderate hypothermia (OR 0.97 [95% CI 0.61 to 1.54]) or mild hypothermia (OR 0.90 [95% CI 0.44 to 1.86]); or comparing mild hypothermia with moderate hypothermia (OR 1.07 [95% CI 0.62 to 1.87](; GRADE, all low uncertainty; Fernando 2021).
In a systematic review and meta-analysis on TTM in adult patients with cardiac arrest, pooled analysis showed that TTM with hypothermia of a target 32.0°C to 34.0°C compared with normothermia (no TTM, no clear description of TTM, or TTM to maintain normothermia) did not result in favourable neurological outcomes at hospital discharge or 30 days (3 studies, RR 1.30, [95% CI 0.83 to 2.03]) and at 90 to 180 days (5 studies, RR 1.21, [95% CI 0.91 to 1.61]; GRADE low certainty of evidence; Granfeldt 2021). In the same study, 3 RCTs compared different temperature targets (TTM trial, [Neilsen 2013], between 33.0°C and 36.0°C and 2 other trials [Lopez-de-Sa 2012, 2018] between 32.0°C, 33.0°C, and 34.0°C) and found no difference in neurological outcomes (GRADE low certainty of evidence).
A meta-analysis of 8 RCTs showed that there was no statistically significant difference between TTM with hypothermia (varied from 31.7°C to 34.0°C) and normothermia in rates of favourable neurological outcome (38% versus 34%, RR 1.31; [95% CI, 0.99 to 1.73], p=0.06, I2=56%), Sensitivity analysis, excluding the large TTM2 trial showed higher rates of favourable neurological outcome with TTM with hypothermia compared with normothermia (RR 1.45, [95% CI, 1.17 to 1.79], p<0.001, I2=1%; Elbadawi 2022).
A meta-analysis of 8 RCTs showed that TTM with hypothermia at 32.0°C to 34.0°C does not improve neurological outcome compared with normothermia (RR: 1.17, [95% CI 0.97 to 1.41], p=0.10; I2=60%). A subgroup analysis showed improved neurological outcomes with TTM at 32.0°C to 34.0°C when compared with 'uncontrolled normothermia' (RR 1.50, 95% CI 1.19 to 1.89; p=0.0007) but had no improved neurological outcome when compared with 'actively controlled' normothermia (RR 1.02, [95% CI 0.88 to 1.17], p=0.79; Sanfilippo 2021).
In a systematic review and meta-analysis of 12 studies, a pooled analysis of all 11 studies comparing conventional cooling methods with different types of control treatment (no cooling, fever control or temperature management at 36°C) showed better neurological outcomes with cooling to 36°C, (42% [817/1,969] versus 38% [733/1,945]; RR 1.41, 95% CI 1.12 to 1.76; I2=67%, p=0.003). Significant heterogeneity was mainly driven by including 2 studies (TTM1 trial [Nielsen 2013], and TTM2 trial [Dankiewicz 2021]). The pooled analysis of 8 studies (n=2,870) comparing conventional cooling with control (no cooling or fever control) showed a better neurological outcome for the conventional cooling group (cooling to 33°C (40% [572/1,435] versus control 35% [505/1,435]; RR 1.60, 95% CI 1.15 to 2.23; I2 = 68%, p=0.005). Heterogeneity was caused by including TTM2 trial (Dankiewicz 2021). A pooled analysis of 3 studies comparing the effects of conventional cooling with TTM at 36°C, found no evidence of a difference in neurological outcome (46% [245/534] versus 45% [228/510]; RR 1.78, 95% CI 0.70 to 4.53; I2 = 73%, p=0.23). The certainty of the evidence was low for all. One study comparing haemofiltration cooling with haemofiltration normothermia showed that there was no difference in neurological outcome between the 2 groups (32% [7/22] versus 45% [9/20]; RR 0.71, 95% CI 0.32 to 1.54; p=0.38; Arrich 2023).
In a meta-analysis of 14 RCTs on TTM for adults with OHCA caused by NSR, a pooled analysis of 5 studies comparing TTM with hypothermia to TTM without hypothermia showed that it was not associated with favourable neurological outcomes (RR 1.39, [95% CI 0.92 to 2.11]; p=0.11, I2=0%; Zhu Y-B 2022).
In a systematic review and meta-analysis of 6 retrospective controlled studies (with 14,607 patients with IHCA) comparing TTM with hypothermia (n=1,845) to control (TTM without hypothermia, n= 12,762), there were no statistically significant differences between the 2 groups in favourable neurological outcomes (OR =1.06, [95% CI: 0.56 to 2.02], p=0.85, I2 =79%). A subgroup analysis according to small or large study sample size also showed no significant improvement between the 2 groups in neurological outcomes (Yin 2022).
In a meta-analysis of 12 RCTs comparing therapeutic hypothermia (<36°C) with normothermia (≥36°C) in patients after a cardiac arrest, therapeutic hypothermia was associated with a significant decrease in poor neurologic outcomes compared with normothermia (therapeutic hypothermia 58% [1,249/2,135] versus normothermia 61% [1,287/2,106]; RR 0.90, 95% CI 0.83 to 0.98, p=0.02, I2=61%; Duhan 2023).
An RCT of 249 patients comparing hypothermic temperature control (32°C to 34°C) for 24 hours (in 126 patients) with normothermia (in 123 patients) after IHCA reported no statistically significant difference in favourable functional outcome (Cerebral Performance Category 1 or 2) by day 180 (22.5% (27/120) versus 23.7% (28/118), RR, 1.04 [95% CI, 0.78 to 1.44]; p=0.822; Wolfrum 2022).
Methods of TTM: Endovascular versus surface cooling methods
In the systematic review and meta-analysis on TTM in adult patients with cardiac arrest, a pooled analysis of 3 RCTs targeting hypothermia at 33.0°C or 34.0°C comparing endovascular cooling with surface cooling (that is, using fans, or applying cooling pads or ice packs) did not result in a statistically significant improvement in survival with a favourable neurologic outcome (RR 1.22, [95% CI: 0.95 to 1.56]; GRADE low uncertainty of evidence; Granfeldt 2021).
TTM duration
In the systematic review and meta-analysis on TTM in adult patients with cardiac arrest, 1 RCT (Kirkegaard 2017) with 355 patients who had TTM with hypothermia of 32.0°C to 34.0°C comparing 24 hours to 48 hours of TTM found no difference in neurological outcomes (GRADE low certainty; Granfeldt 2021).
Timing of initiation of TTM
In the systematic review and meta-analysis on TTM in adult patients with OHCA, a pooled analysis of 10 trials reported that pre-hospital cooling did not result in favourable neurological outcomes at hospital discharge when compared with no pre-hospital cooling (RR 1.00, [95% CI 0.90 to 1.11], p=0.76, I2=0%). Subgroup analyses of different cooling methods (5 studies assessing post-cardiac arrest rapid intravenous cold fluid infusion, 2 studies assessing intra-cardiac arrest intravenous cold fluid infusion, and 2 studies assessing intra-cardiac arrest intra-nasal cooling) also found no difference in favourable neurological outcome at hospital discharge between groups (Granfeldt 2021).
In the meta-analysis of 14 RCTs on TTM for adults patients with OHCA caused by NSR, a pooled analysis of 5 studies comparing pre-hospital TTM with in-hospital TTM showed that pre-hospital TTM did not result in favourable neurological outcomes (RR 1.13, [95% CI 0.93 to 1.18]; p=0.22, I2 = 0%; Zhu Y-B 2022).
Overall survival
Optimal target temperature
The systematic review and network meta-analysis of 10 RCTs (n=4,218 patients) on TTM in comatose survivors of OHCA showed no difference in 6-month overall survival between any target temperature in the hypothermic range of 31.0°C and 36.0°C and normothermia. Compared with normothermia, there is no effect on overall survival using deep hypothermia (OR 1.27, [95% CI 0.70 to 2.32]), moderate hypothermia (OR 1.23, [95% CI 0.86 to 1.77]), or mild hypothermia (OR 1.26, [95% CI 0.64 to 2.49]). Also, there was no effect on overall survival using deep hypothermia when compared with moderate hypothermia (OR 1.03, [95% CI 0.64 to 1.68]) or mild hypothermia (OR 1.01, [95% CI 0.47 to 2.14]) or when comparing mild hypothermia with moderate hypothermia (OR 1.02, [95% CI 0.79 to 1.32; Fernando 2021).
In the systematic review and meta-analysis on TTM in adult patients with cardiac arrest, a pooled analysis showed that TTM with hypothermia at a target 32.0°C to 34.0°C compared with normothermia (no TTM, no clear description of TTM, or TTM to maintain normothermia) did not result in an improvement in survival at hospital discharge or 30 days (5 studies, RR 1.12, [95% CI 0.92 to 1.35]) or at 90 to 180 days (5 studies, RR 1.08, [95% CI 0.89 to 1.30]; GRADE low certainty of evidence; Granfeldt 2021).
The meta-analysis of 8 RCTs showed that there was no significant difference in long-term mortality between the TTM with hypothermia and normothermia groups (56% versus 57%, RR 0.96; [95% CI 0.87 to 1.06], p=0.45, I2=41%; Elbadawi 2022). Similarly, a subgroup analysis of patients with cardiac arrest caused by SR (RR 0.87; [95% CI, 0.68 to 1.11]; p=0.09; I2=59%) and patients with cardiac arrest caused by NSR (RR 1.00; [95% CI, 0.94 to 1.05]; p= 0.40; I2=0%) showed no significant difference between the groups (Elbadawi 2022).
The meta-analysis of 8 RCTs showed that TTM with hypothermia at 32.0°C to 34.0°C did not improve survival when compared with normothermia (RR 1.06 [95% CI 0.94 to 1.20], p=0.36; I2=40%). Subgroup analyses showed that TTM with hypothermia at 32.0°C to 34.0°C is associated with improved survival when compared with passively controlled normothermia (RR 1.31 [95% CI 1.07 to 1.59], p=0.008) but showed no improved survival when compared with 'actively controlled' normothermia (RR 0.97, [95% CI 0.90 to 1.04], p=0.41; Sanfilippo 2021).
In a systematic review of 12 studies, a pooled analysis of all 9 studies comparing conventional cooling methods with different types of control treatment (no cooling, fever control or temperature management at 36°C) found that there was no survival benefit for cooling at 36°C, (46% [886/1,936] versus 45% [866/1,935]; RR 1.07, 95% CI 0.95 to 1.20; I2=34%, p=0.26). The pooled analysis of 7 studies (n=2,875) comparing conventional cooling with control (no cooling or fever control) showed no survival benefit for the conventional cooling group (cooling to 33°C (45% [638/1,434] versus control 43% [616/1,441]; RR 1.17, 95% CI 0.96 to 1.42; I2 = 48%, p=0.11), Heterogeneity was caused by including TTM2 trial (Dankiewicz 2021). A pooled analysis of 2 studies comparing the effects of conventional cooling with TTM at 36°C, found no survival benefit for the conventional cooling group (49% [248/502] versus 51% [250/494]; RR 0.98, 95% CI 0.86 to 1.10; I2 = 0%, p=0.70). The certainty of the evidence was low for all. One study comparing haemofiltration cooling with haemofiltration normothermia showed that there was no difference in survival between the 2 groups (RR 0.71, 95% CI 0.32 to 1.54; p=0.38; Arrich 2023).
In the meta-analysis of 14 RCTs on TTM for adults with OHCA caused by NSR, a pooled analysis of 6 studies (n=1,323) comparing TTM with hypothermia to TTM without hypothermia showed that TTM with hypothermia did not statistically significantly improve survival (RR 1.00; [95% CI 0.94 to 1.05]; p=0.89, I2=0%; Zhu Y-B 2022).
In the systematic review and meta-analysis of 6 retrospective controlled studies (with 14,607 patients with IHCA), comparing TTM plus hypothermia (n= 1,845) to control (TTM without hypothermia, n=12,762), there were no statistically significant differences between the 2 groups in survival to hospital discharge (OR 1.02, [95% CI 0.77 to 1.35], p=0.89, I2 =47%; Yin 2022). A subgroup analysis of 2 studies with 1,327 patients with cardiac arrest caused by SR (TTM group 428 versus control group 899) showed that TTM did not show any significant improvement in survival to hospital discharge (OR 0.89, [95% CI 0.71 to 1.13], p=0.35, I2 =0%). A subgroup analysis according to small or large sample size also showed no significant improvement between the 2 groups in terms of survival to hospital discharge (Yin 2022).
Methods of TTM: endovascular versus surface cooling methods
In the systematic review and meta-analysis on TTM in adult patients with cardiac arrest, a pooled analysis of 3 RCTs targeting 33.0°C or 34.0°C comparing endovascular cooling with surface cooling (that is, using fans, or applying cooling pads or ice packs) did not result in a statistically significant improvement in survival to hospital discharge or 28 days (RR 1.14, [95% CI 0.93 to 1.38]; Granfeldt 2021).
Timing of TTM initiation
In the systematic review and meta-analysis on TTM in adult patients with OHCA, a pooled analysis of 10 trials reported that pre-hospital cooling did not result in improved survival to hospital discharge when compared with no pre-hospital cooling (RR 1.01 [95% CI 0.92 to 1.11], p=0.93, I2=0%). Subgroup analyses of different cooling methods (6 studies assessing post-cardiac arrest rapid intravenous cold fluid infusion, 2 studies assessing intra-cardiac arrest intravenous cold fluid infusion, and 2 studies assessing intra-cardiac arrest intra-nasal cooling) also found no difference in survival to hospital discharge between groups (Granfeldt 2021).
In the meta-analysis of 14 RCTs on TTM for adults with OHCA caused by NSR, a pooled analysis of 8 studies (n=2,686) comparing use of pre-hospital TTM with in-hospital TTM showed that pre-hospital TTM did not statistically significantly improve survival (RR 0.99, [95% CI 0.97 to 1.01], p=0.32, I2 =0%; Zhu Y-B 2022).
Quality of life
In the systematic review and meta-analysis of 12 studies, 2 studies reported quality-of-life outcomes. One study (Dankiewicz 2021) reported that there was no difference in quality of life between the hypothermia and normothermia groups when assessed using EQ-5DL and VAS. Another study (Cornberg 2015b, a sub-study to Nielsen 2013), comparing TTM at 33°C versus TTM at 36°C reported that the mean Mental Component Summary score of SF-36 was 49.1±12.5 for survivors in the 33°C group compared with 49.0±12.2 in the 36°C group (p=0.77). The mean Physical Component Summary scores were 46.8±13.8 for survivors in the 33°C group and 47.5±13.8 in the 36°C group (p=0.44; Arrich 2023).
Safety
Mortality
In the meta-analysis of RCTs comparing therapeutic hypothermia (<36°C) with normothermia (≥36°C) in patients after a cardiac arrest, no significant difference in mortality was observed between the groups (RR 0.97, 95% CI 0.90 to 1.06, p=0.55, I2=38%; Duhan 2023).
The RCT of 249 patients comparing hypothermic temperature control (32°C to 34°C) for 24 hours (in 126 patients) with normothermia (in 123 patients) after IHCA reported no statistically significant difference in mortality by day 180 (72.5% [87/120] versus 71% [84/118], RR 1.03 [95% CI, 0.79 to 1.40, p=0.822; Wolfrum 2022).
In-hospital mortality
In the systematic review and meta-analysis of 8 RCTS, a pooled analysis of 5 studies showed that there was no statistically significant difference in in-hospital mortality between the TTM plus hypothermia and the normothermia groups (65% versus 72%; RR 0.88; [95% CI 0.77 to 1.01]; p=0.07; I2=35%; Elbadawi 2022).
The RCT of 249 patients comparing hypothermic temperature control (32°C to 34°C) for 24 hours (in 126 patients) with normothermia (in 123 patients) after IHCA reported no statistically significant difference in in-hospital mortality (62.5% [75/120] versus 57.6% [68/118], RR 1.11 [95% CI, 0.86 to 1.46, p=0.443; Wolfrum 2022).
Arrhythmia
In the network meta-analysis of 10 RCTs (n=4,218 patients) on TTM for OCHA, compared with normothermia, arrhythmia was more common among patients receiving TTM with deep hypothermia (OR 3.58, [95% CI 1.77 to 7.26], GRADE high certainty) and moderate hypothermia (OR 1.45, [95% CI 1.08 to 1.94], GRADE high certainty); Fernando 2021).
In the systematic review and meta-analysis of 8 RCTs, a pooled analysis of 4 studies showed higher risk for ventricular arrhythmias among TTM with hypothermia groups compared to normothermia groups (23% [312/1,368] versus 17% [229/1,376]; RR 1.36; [95% CI 1.17 to 1.58]; p<0.001; I2=0%; Elbadawi 2022).
The meta-analysis of 8 RCTs showed that TTM with hypothermia at 32.0°C to 34.0°C increases the risk of arrhythmias compared to normothermia (TTM at 32.0°C to 34.0°C [306/1,346] versus normothermia [227/1,356]; RR 1.35, [95% CI 1.16 to 1.57], p=0.0001, I2=0%; Sanfilippo 2021).
In the systematic review and meta-analysis of 12 RCTs, a pooled analysis of 3 studies (n=2,163 patients) showed higher incidence of severe haemodynamically compromising or long lasting arrhythmias among patients who had therapeutic cooling compared to control groups (RR 1.40; [95% CI 1.19 to 1.64]). The certainty of evidence was low (Arrich 2023).
Bleeding
In the network meta-analysis of 10 RCTs (n=4,218 patients) on TTM with hypothermia for OCHA, compared with normothermia, there were no statistically significant differences in the incidence of bleeding across the various hypothermia range of temperature comparisons (deep hypothermia [OR 1.21, 95% CI 0.68 to 2.15], moderate hypothermia [OR 1.10, 95% CI 0.78 to 1.55], or mild hypothermia [OR 1.21, 95% CI 0.66 to 2.21], GRADE all low or very low certainty; Fernando 2021).
In the systematic review and meta-analysis of 8 RCTS, there was no statistically significant difference between the TTM plus hypothermia and the normothermia groups in rates of bleeding complications (7% [95/1,346] versus 7% [89/1,357]; RR 1.10; [95% CI, 0.83 to 1.44]; p=0.51; I2=0%; Elbadawi 2022).
In the systematic review and meta-analysis of 12 RCTs, a pooled analysis of 4 studies (n=3,636 patients) comparing therapeutic cooling to control groups showed no difference in rates of bleeding of any severity between the groups (RR 1.09; [95% CI 0.94 to 1.27]). The certainty of evidence was low (Arrich 2023).
Pneumonia
In the network meta-analysis of 10 RCTs (n=4,218 patients) on TTM with hypothermia for OCHA, compared with normothermia, there were no statistically significant differences in the incidence of pneumonia across the various temperature comparisons (deep hypothermia [OR 0.91, 95% CI 0.42 to 2.09]), moderate hypothermia [OR 1.24, 95% CI 0.79 to 1.95], or mild hypothermia [OR 0.98, 95% CI 0.41 to 2.33], GRADE all low or very low certainty; Fernando 2021).
In the systematic review and meta-analysis of 8 RCTS, there was no statistically significant difference between the TTM plus hypothermia and the normothermia groups in rates of pneumonia (23% versus 17%; RR 1.36; [95% CI 1.17 to 1.58]; p=0.42; I2 =0%; Elbadawi 2022).
In the systematic review and meta-analysis of 12 RCTs, a pooled analysis of 4 studies (n=3,634 patients) showed a higher incidence of pneumonia among patients who had therapeutic cooling compared to control groups (RR 1.09; [95% CI 1.00 to 1.18]). The certainty of evidence was low (Arrich 2023).
Sepsis
In a pair-wise meta-analysis of 10 RCTs (n=4,218 patients) on TTM with hypothermia for OCHA, compared with normothermia, the incidence of sepsis was more common among patients receiving moderate hypothermia (33.0°C to 34.0°C; OR 1.36, [95% CI 0.88 to 2.10]; Fernando 2021).
In the systematic review and meta-analysis of 8 RCTS, there was no statistically significant difference between the TTM plus hypothermia and the normothermia groups in rates of sepsis (10% versus 8%; RR 1.24; [95% CI, 0.97 to 1.59]; p=0.08; I2=0%; Elbadawi 2022).
In the systematic review and meta-analysis of 12 RCTs, a pooled analysis of 3 studies (n=3,054 patients) comparing therapeutic cooling to control groups showed no difference in rates of sepsis between the groups (RR 1.17; [95% CI 0.94 to 1.45]; Arrich 2023).
Seizures
In a pair-wise meta-analysis of 10 RCTs (n=4,218 patients) on TTM with hypothermia for OCHA, compared with normothermia, there was no statistically significant difference in the incidence of seizures for moderate hypothermia (33.0°C to 34.0°C; OR 0.95, 95% CI 0.67 to 1.35; Fernando 2021).
In the systematic review and meta-analysis of 12 RCTs, a pooled analysis of 3 studies (n=1,783 patients) comparing therapeutic cooling to control groups showed no difference in incidence of seizures between the groups (RR 1.11; [95% CI 0.95 to 1.30]; Arrich 2023).
Hypokalaemia
In the systematic review and meta-analysis of 12 RCTs, a pooled analysis of 2 studies (n=975 patients) showed higher incidence of hypokalaemia among patients who had therapeutic cooling compared to control groups (RR 1.38; [95% CI 1.03 to 1.84]). The certainty of evidence was very low (Arrich 2023).
Anecdotal and theoretical adverse events
Expert advice was sought from consultants who have been nominated or ratified by their professional society or royal college. They were asked if they knew of any other adverse events for this procedure that they had heard about (anecdotal), which were not reported in the literature. They were also asked if they thought there were other adverse events that might possibly occur, even if they had never happened (theoretical).
They listed the following anecdotal adverse events:
peripheral vasoconstriction with increased afterload
the use of neuromuscular blockers may mask seizures.
They listed the following theoretical adverse events:
injury to skin from some external cooling systems.
Five professional expert questionnaires for this procedure were submitted. Find full details of what the professional experts said about the procedure in the specialist advice questionnaires for this procedure.
Validity and generalisability
Most of the key papers included are systematic reviews with meta-analyses. There was a significant amount of overlap identified across the systematic reviews included in the overview; much of the available evidence identified in this review is based on the same RCTs. Evidence was mainly for adult patients resuscitated from OHCA with SR and NSR.
Targeted temperature in the hypothermia arm in the trials included in the systematic reviews varied from 31.0°C to 36.0°C. Control group management also varied, and a variety of patient populations was included.
There is a lack of standardised TTM protocols in TTM trials included in the meta-analyses. Substantial heterogeneity in terms of patient characteristics, devices used to achieve cooling, TTM strategies, initiation time, duration of the procedure, and timing of outcome measurements was noted.
The recent TTM2 trial included in these systematic reviews included patients from 14 countries and is generalisable.
One RCT evaluated TTM in adult IHCA. The RCT was terminated early because of ineffectiveness.
There is no long-term data greater than 6 months.
Recent systematic reviews have conflicting conclusions on therapeutic hypothermia.
Ongoing trials:
NCT04217551: Influence of Cooling Duration on Efficacy in Cardiac Arrest Patients (ICECAP; shockable and non-shockable rhythm). A multicentre, randomised, adaptive allocation clinical trial to determine if increasing durations of induced hypothermia of 33.0°C (6, 12, 18, 24, 30, 36, 42, 48, 60, and 72 hours) are associated with an increasing rate of good neurological outcomes, and to identify the optimal duration of induced hypothermia for neuroprotection in comatose survivors of cardiac arrest. Estimated enrolment: 1,800 participants, primary outcome modified Rankin Scale states to capture changes in functional status; location USA; estimated study completion date: July 2025.
NCT05564754: Sedation, Temperature and Pressure After Cardiac Arrest and Resuscitation (STEPCARE). A RCT of 3500 patients who are comatose after cardiac arrest, all patients will be randomised to a control or an intervention arm for sedation, temperature and blood pressure targets. These are
Continuous deep sedation for 36 hours or minimal sedation (SEDCARE)
Fever management with or without a feedback-controlled device (TEMPCARE)
A mean arterial pressure target of > 85 mmHg or > 65 mmHg (MAPCARE).
Participants will be followed up at 30 days and 6 months. The primary outcome will be survival at 6 months. Location: Finland, Sweden, study completion date June 2026.
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