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    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 18,825 patients from 6 systematic reviews and meta-analysis. There is an overlap between included primary studies (RCTs) within the 5 systematic reviews. So the actual number of patients in RCTs who had TTM with hypothermia were 2828 patients and those with normothermia were 1390 patients. Another systematic review with 6 observational studies included 1845 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 6 studies as the key evidence in table 2 and table 3, and lists other 38 relevant studies in table 5.

    The 6 systematic reviews and meta-analyses were published between 2021-22. Five 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). Therefore, there is an overlap between included primary studies within the 5 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 SRs listed first authors from Canada, Denmark, USA, Italy and China.

    All 5 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. 2 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 57-77 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 Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. The level of evidence was judged to be low in 2 systematic reviews (Fernando 2021, Granfeldt 2021).

    Follow up varied across studies ranging from hospital discharge to 6 months.

    Table 2 presents study details.

    Figure 1 Flow chart of study selection

    Table 2 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

    Six 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

    Table 3 Study outcomes

    First author, date

    Efficacy outcomes

    Safety outcomes

    Fernando (2021)

    Canada

    Survival with good functional neurological outcome (at hospital discharge, or the latest time point reported up until 6 months post-discharge)

    NWMA estimates (10 RCTs included)

    TTM with deep hypothermia (31.0°C to 32.0°C) versus normothermia (37.0° to 37.8°C) (OR 1.30, 95% CI 0.73–2.30)

    TTM with moderate hypothermia (33.0°C to 34.0°C) versus normothermia (OR 1.34, 95% CI 0.92–1.94)

    TTM with mild hypothermia (35.0°C to 36.0°C) versus normothermia (OR 1.44, 95% CI 0.74– 2.80) (GRADE all low certainty of evidence).

    TTM with deep hypothermia versus TTM with moderate hypothermia (OR 0.97, 95% CI 0.61–1.54, GRADE low certainty of evidence).

    TTM with deep hypothermia versus TTM with mild moderate hypothermia (OR 0.90, 95% CI 0.44–1.86; GRADE low certainty of evidence)

    TTM with mild hypothermia versus moderate hypothermia (OR 1.07, 95% CI 0.62–1.87; GRADE low certainty of evidence).

    Overall survival (survival at hospital discharge, or the latest time point reported up until 6 months post-discharge)

    NWMA estimates (10 RCTs included)

    TTM with deep hypothermia (31.0°C to 32.0°C) versus normothermia: OR 1.27 (95% CI 0.70 to 2.32)

    TTM with moderate hypothermia (33.0°C to 34.0°C) versus normothermia: OR 1.23 (95% CI 0.86 to 1.77)

    TTM with mild hypothermia (35.0°C to 36.0°C) versus normothermia: OR 1.26 (95% CI 0.64 to 2.49).

    TTM with deep hypothermia versus moderate hypothermia (OR 1.03, [95% CI 0.64 to 1.68])

    TTM with deep hypothermia versus mild hypothermia (OR 1.01, [95% CI 0.47 to 2.14])

    TTM with mild hypothermia versus moderate hypothermia (OR 1.02, [95% CI 0.79 to 1.32

    Adverse events

    NWMA estimates (10 RCTs included, compared TTM with hypothermia with normothermia)

    Arrhythmia:

    TTM with deep hypothermia (31.0°C to 32.0°C): OR 3.58 (95% CI 1.77 to 7.26)

    TTM with moderate hypothermia (33.0°C to 34.0°C): OR 1.45 (95% CI 1.08 to 1.94)

    TTM with mild hypothermia (35.0°C to 36.0°C): OR 1.16 (95% CI 0.76 to 1.78)

    Bleeding:

    TTM with deep hypothermia (31.0°C to 32.0°C): OR 1.21 (95% CI 0.68 to 2.15)

    TTM with moderate hypothermia (33.0°C to 34.0°C): OR 1.10 (95% CI 0.78 to 1.55)

    TTM with mild hypothermia (35.0°C to 36.0°C): OR 1.21 (95% CI 0.66 to 2.21)

    Pneumonia:

    TTM with deep hypothermia (31.0°C to 32.0°C): OR 0.91 (95% CI 0.42 to 2.09)

    TTM with moderate hypothermia (33.0°C to 34.0°C): OR 1.24 (95% CI 0.79 to 1.95)

    TTM with mild hypothermia (35.0°C to 36.0°C): OR 1.21 (95% CI 0.41 to 2.33)

    Pair-wise meta-analysis estimates

    Sepsis:

    TTM with deep hypothermia (31.0°C to 32.0°C): Not available

    TTM with moderate hypothermia (33.0°C to 34.0°C): OR 1.36 (95% CI 0.88 to 2.10)

    TTM with mild hypothermia (35.0°C to 36.0°C): Not available

    • Seizure:

    TTM with deep hypothermia (31.0°C to 32.0°C): Not available

    TTM with moderate hypothermia (33.0°C to 34.0°C): OR 0.95 (95% CI 0.67 to 1.35)

    TTM with mild hypothermia (35.0°C to 36.0°C): Not available

    Granfeldt 2021

    Denmark

    Specific target temperature

    Meta-analyses of TTM with hypothermia at 32-34°C compared to normothermia (9 RCTs)

    Favourable neurological outcome

    at hospital discharge or 30 days (3 RCTs): RR 1.30 (95% CI 0.83 to 2.03), p=0.26, I2=84%.

    at 90 or 180 days (5 RCTs): RR 1.21 (95% CI 0.91 to 1.61), p=0.18, I2=64%.

    Survival

    at hospital discharge or 30 days: RR 1.12 (95% CI 0.92 to 1.35), p=0.25, I2=57%.

    at 90 or 180 days after CA: RR 1.08 (95% 0.89 to 1.30), p=0.43, I2=49%.

    Different temperature targets (3 RCTs)

    3 trials compared different temperature targets and found no difference in outcomes (TTM trial [Neilsen 2013] between 33.0°C and 36.0°C and 2 other trials [Lopez -de-Sa 2012, 2018] found no difference between 32.0°C, 33.0°C, and 34.0°C); (GRADE low certainty of evidence).

    Timing of initiating TTM

    Meta-analyses of pre-hospital cooling versus no pre-hospital cooling (10 trials)

    Favourable neurological outcome at hospital discharge RR 1.00 (95% CI 0.90 to 1.11), p=0.76, I2=0%. (moderate certainty of evidence)

    Survival at hospital discharge RR 1.01 (95% CI 0.92 to 1.11), p=0.93, I2=0% (moderate certainty of evidence)

    Subgroup analysis

    Post-arrest cold IV fluid

    Survival to hospital discharge (6 studies): pre-hospital cooling (447/1,249) versus no pre-hospital cooling (442/1,251) RR 1.00 (95% CI 0.90 to 1.11), p=0.83, I2=0%.

    Favourable neurological outcome at hospital discharge (5 studies): pre-hospital cooling (381/1,181) versus no pre-hospital cooling (383/1177), RR 0.98 (95% CI 0.87 to 1.10), p=0.65, I2=0%.

    Intra-arrest cold IV fluid (2 studies)

    Survival to hospital discharge: pre-hospital cooling (70/741) versus no pre-hospital cooling (71/702), RR 0.93 (95% CI 0.68 to 1.27), p=0.46, I2=0%.

    Favourable neurological outcome at hospital discharge: pre-hospital cooling (70/741) versus no pre-hospital cooling (67/702), RR 0.98 (95% CI 0.71 to 1.35), p=0.90, I2=0%.

    Intra-arrest nasal cooling (2 studies)

    Survival to hospital discharge: pre-hospital cooling (77/428) versus no pre-hospital cooling (6/435) RR 1.15, (95% CI 0.85 to 1.54), p=0.37, I2=0%.

    Favourable neurological outcome at hospital discharge: pre-hospital cooling (64/428) versus no pre-hospital cooling (53/435) RR 1.00 (95% CI 0.90 to 1.11), p=0.25, I2=0%.

    Methods used for TTM

    Endovascular cooling versus surface cooling methods (3 RCTs)

    Survival to hospital discharge or 28 days:

    Endovascular (120/265) versus surface cooling (103/258); RR 1.14 (95% CI 0.93 to 1.38), p=0.21, I2=0%.

    Favourable neurological outcome at hospital discharge or 28 days:

    Endovascular (94/265) versus surface cooling (75/258); RR 1.22 (95% CI 0.95 to 1.56), p=0.12, I2=0%.

    Duration of TTM (1 RCT)

    Kirkegaard 2017 (n=355 OHCA) comparing 48 hours versus 24 hours found no difference in outcomes between durations.

    Elbadawi 2022

    USA

    Long-term mortality:

    TTM with hypothermia versus normothermia: 56.2% (785/1398) versus 56.9% (804/1,411), RR 0.96 (95% CI 0.87 to 1.06); p=0.45; I2=41%.

    OHCA with shockable rhythm: RR 0.87 (95% CI 0.68 to 1.11); p=0.09; I2=59%.

    OHCA with non-shockable rhythm: RR 1.00 (95% CI 0.94 to 1.05); p=0.40; I2=0%.

    Favourable neurological outcome (CPC 1 and 2, modified Rankin score 0 to 3):

    TTM with hypothermia versus normothermia 37.9% (535/1,412) versus 34.2% (479/1,399), RR 1.31 (95% CI 0.99 to 1.73); p=0.06, I2=56%.

    Excluding the TTM2 trial: RR 1.45 (95% CI 1.17 to 1.79); p<0.001, I2=1%.

    TTM with hypothermia versus normothermia

    In-hospital mortality (5 studies): 64.7% (325/502) versus 72.2% (363/503); RR 0.88 (95% CI 0.77 to 1.01); p=0.07; I2=35%.

    Ventricular arrhythmias (4 studies): 22.8% (312/1,368) versus 16.6% (229/1,376); RR 1.36 (95% CI 1.17 to 1.58); p<0.001; I2 =0%.

    Bleeding complications: 7.1% (95/1,346) versus 6.6% (89/1,357); RR 1.10 (95% CI 0.83 to1.44); p=0.51; I2=0%

    Sepsis: 9.5% (128/1,345) versus 7.6% (103/1,357); RR 1.24 (95% CI 0.97to 1.59); p=0.08; I2=0%

    Pneumonia: 22.8% versus 16.6%; RR 1.36 (95% CI 1.17 to1.58); p=0.42; I2=0%.

    Sanfilippo 2021

    Italy

    Survival (8 studies) with varied follow up.

    TTM with hypothermia at 32.0°C –34.0°C compared to normothermia

    (875/1,930) versus (861/1,925); RR 1.06 (95% CI 0.94 to 1.20), p=0.36; I2=40%).

    Subgroup analysis

    TTM with hypothermia at 32.0°C -34.0°C compared to actively controlled normothermia (3 studies)

    (751/1,682) versus (770/1688); RR 0.97 (95% CI 0.90 to 1.04), p=0.41, I2=0%.

    TTM with hypothermia at 32.0°C -34.0°C compared to passively controlled normothermia (5 studies)

    (124/248) versus (91/237), RR 1.31 (95% CI 1.07 to 1.59), p=0.008, I2=0%.

    Neurological outcome (8 studies with varied follow up)

    TTM with hypothermia at 32.0°C –34.0°C compared to normothermia

    (753/1,881) versus (701/1,863); RR 1.17 (95% CI 0.97 to 1.41), p=0.10; I2=60%.

    Subgroup analysis

    TTM with hypothermia at 32.0°C -34.0°C compared to actively controlled normothermia (3 studies)

    (640/1,634) versus (626/1,627); RR 1.02 (95% CI 0.88 to 1.18), p=0.79, I2=51%.

    TTM with hypothermia at 32.0°C -34.0°C compared to passively controlled normothermia (5 studies)

    (113/247) versus (75/236), RR 1.42 (95% CI 0.99 to 2.04), p=0.05, I2=27%.

    Excluding 1 study (Laurent 2005) in which patients received hemofiltration, RR 1.20, (95% CI 0.99 to 1.46), p=0.06.

    TTM with hypothermia at 32.0°C -34.0°C compared to uncontrolled normothermia RR 1.50, (95% CI 1.19 to 189); p=0.0007.

    Bleeding (3 RCTs)

    TTM with hypothermia at 32.0°C -34.0°C versus normothermia RR 1.10; (95% CI 0.83 to 1.44).

    Pneumonia (3 RCTs)

    TTM with hypothermia at 32.0°C -34.0°C versus normothermia RR 1.11, (95% CI 0.96 to 1.29).

    Arrhythmias (3 RCTs): TTM with hypothermia at 32.0°C –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%.

    Zhu YB 2022

    China

    Pooled rate TTM with hypothermia (32.0°C -34.00C) versus without TTM (36.0-38.0°C)

    Mortality (short-term [within 28-90 days] or long-term mortality [more than 180 days]) 6 studies

    TTM with hypothermia (542/677) versus without TTM (520/646); RR 1.00 (95% CI 0.94 to 1.05), p=0.89, I2=0%.

    Good neurological function (defined as a CPC score of 1 or 2; 6 studies)

    TTM with hypothermia (48/618) versus without TTM (33/614); RR 1.39, (95% CI 0.92 to 2.11), p=0.11, I2=0%.

    Subgroup analysis: pre-hospital versus in-hospital pooled rate (8 studies, n=2,686, 1,345 in pre-hospital and 1,341 in-hospital cooling)

    Mortality: RR 0.99 (95% CI 0.97 to 1.01); p=0.32, I2=0%.

    Good neurological function: (6 studies) RR 1.13, (95% CI 0.93 to 1.18), p=0.22, I2=0%.

    Yin L 2022

    China

    Survival to hospital discharge; pooled analysis rate

    6 studies (n=14,607; TTM with hypothermia [512/1,845] versus control TTM without hypothermia [3,870/12,762]): OR 1.02, (95% CI 0.77 to 1.35), p=0.89, I2=47%.

    Favourable neurological outcome

    6 studies (n=14,215, TTM with hypothermia [284/1,641] versus control TTM without hypothermia [2,447/12,547]): OR =1.06 (95% CI 0.56 to 2.02), p=0.85, I2=79%.

    Subgroup analysis: pooled rate

    Survival to hospital discharge:

    Shockable initial rhythm (2 studies, n=1,327, TTM with hypothermia 428 versus control 899): OR 0.89, (95% CI 0.71 to 1.13), p=0.35, I2=0%.

    Small sample size (n≤50 patients; 4 studies, n=1,327 patients, TTM with hypothermia 116 versus control 1,019): OR 0.82, (95% CI 0.17 to 3.99), p=0.81, I2=90%.

    Large sample size (n≥50 patients; 2 studies, 13,599, TTM with hypothermia 1,783 versus control 11,816): OR 0.90, (95% CI 0.80 to 1.02), p=0.11, I2=0%.

    Neurological outcome

    Small sample size: (4 studies, n=1,053 patients, TTM with hypothermia 107 versus control 946): OR=0.97, 95% CI 0.19 to 5.03, I2=86%, p=0.97.

    Large sample size: (2 studies, n=13,165, TTM with hypothermia 1,534 versus control 11,631): OR=0.81, 95% CI 0.69 to 0.94, I2=0%, p=0.006.

    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 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 to2.11]; 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).

    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 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).

    Safety

    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).

    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). Arrhythmia was more common among patients receiving TTM with deep hypothermia (OR 3.58, 95% CI 1.77 to 7.26) and with moderate hypothermia (OR145, 95% CI 1.08 to 1.94) compared with normothermia, 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).

    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).

    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).

    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).

    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).

    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

    • All 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.

    • 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.

    • There are no RCTs evaluating TTM in adult IHCA; only observational studies were assessed.

    • There is no long-term data greater than 6 months.

    • 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.