Interventional procedure overview of temperature control to improve neurological outcomes after cardiac arrest

Systematic reviews

Abdalla M, Mohamed A, Mohamed W et al. (2019) Targeted temperature management after cardiac arrest: updated meta-analysis of all-cause mortality and neurological outcomes. Int J Cardiol Heart Vasc; 24:100400

N=9 RCTs (n=1592 patients) with data for IHCA and OHCA were included in the meta-analysis.

Mortality was lower in TTM group (OR 0.637, 95% CI 0.436–0.93, p=0.019, n=1592). Also demonstrated reduction in poor neurological outcomes (OR 0.582, 95% CI 0.363–931, p= 0.024, n = 1567). Subgroup analysis was done, after excluding IHCA patients, and demonstrated reduction in poor neurological outcome (OR 0.562, 95% CI 0.331–0.955, p= 0.033, n = 1480) and mortality in OHCA patients (OR 0.674, 95% CI 0.454–999, p= 0.049, n = 1505).

More recent and comprehensive systematic reviews and meta-analysis included captured all relevant studies.

Aneman A, Frost S, Parr M et al. (2022) Target temperature management following cardiac arrest: a systematic review and Bayesian meta-analysis. Critical Care; 26:58, 1-13.

Systematic review and Bayesian meta-analysis.

7 RCTs with 3792 adult survivors from cardiac arrest undergoing TTM for at least 12 h comparing TTM versus no TTM or with a separation>2°C between intervention and control groups.

The posterior probability distributions did not support the use of TTM at 32–34°C compared to 36°C also including active control of fever to reduce the risk of death and unfavourable neurological outcome at 90–180 days. Any likely benefit of hypothermic TTM is smaller than targeted in RCTs to date

More recent and comprehensive systematic reviews and meta-analysis included captured all relevant studies.

Annoni F, Peluso L, Fiore M et al. (2020) Impact of Therapeutic Hypothermia During Cardiopulmonary Resuscitation on Neurologic Outcome: A Systematic Review and Meta-analysis. Resuscitation, 162, 365-371.

Systematic review and meta-analysis

8 studies (n = 3493 patients, including 4 randomised trials, RCTs) were included.

Compared to controls (standard in-hospital TTM), the use of intra-arrest therapeutic hypothermia was not associated with improved favourable neurological outcomes (OR 0.96 [95% CIs 0.68–1.37]; p = 0.84), increased ROSC rate (OR 1.11 [95% CIs 0.83–1.49]; p = 0.46) or survival (OR 0.91 [95% CIs 0.73–1.14]; p = 0.43). Trans-nasal evaporative cooling and cold fluids were explored in 2 RCTs each and no differences were observed on FO, event when only patients with an initial shockable rhythm were analysed (OR 1.62 [95% CI 1.00–2.64]; p = 0.05]).

More recent updated systematic reviews and meta-analysis included.

Arrich J, Holzer M, Havel C et al. (2016) Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev; 2:CD004128

Systematic review and meta-analysis

N= 6 RCTs (1412 patients)

Comparing conventional cooling methods versus no cooling (4 trials; n=437), we found that participants in the conventional cooling group were more likely to reach a favourable neurological outcome (RR 1.94, 95% CI 1.18 to 3.21); a 30% survival benefit (RR 1.32, 95% CI 1.10 to 1.65, 3 studies; n=383). The incidence of pneumonia (RR 1.15, 95% CI 1.02 to 1.30; 2 trials; N=1205) and hypokalaemia (RR 1.38, 95% CI 1.03 to 1.84; 2 trials; N= 975) was slightly increased among participants receiving therapeutic hypothermia, and no significant differences in reported adverse events between hypothermia and control groups were noted.

More recent updated systematic reviews and meta-analysis included.

Barbarawi M, Alabdouh A, Barbarawi O et al. (2020) Targeted temperature management in cardiac arrest patients with an initial non-shockable rhythm: a systematic review and meta-analysis. Shock; 54(5):623–30.

Systematic review and meta-analysis

N=30 studies included (25 observational and 5 RCTs, n=10,703 patients, 4,023 had TTM and 6,680 had standard care). TSA was done on RCTs.

Compared with standard care, patients with an initial NSR cardiac arrest and received TTM (target of 32C –34C) had a significantly higher short-term survival (OR 1.44 95% CI 1.15–1.81; P = 0.002), long-term survival (OR 1.52 95% CI 1.03–2.26; P = 0.04), and CPC score of 1 to 2 (OR 1.63 95% CI 1.22–2.17; P = 0.0010). Sensitivity analyses by including only RCTs showed a trend, although not significant, toward better short-term survival (OR 1.25 95% CI 0.82–1.89; P = 0.30), long-term survival (OR 1.15 95% CI 0.80–1.66; P =0.46), and neurologic outcomes (OR 1.51 95% CI 0.81–2.80; P = 0.19). However, TSA done on the RCTs revealed that the results were inconclusive.

More recent updated systematic reviews and meta-analysis included.

Study included expanded inclusion criteria, including retrospective and observational studies.

Bartlett ES, Valenzuela T, Idris A et al. (2020) Systematic review and meta-analysis of intravascular temperature management vs. surface cooling in comatose patients resuscitated from cardiac arrest. Resuscitation;146:82–95.

Systematic review and meta-analysis

N=12 studies

RCTs and observational studies (with 1,573 patients who received IVTM; and 4,008 who received SCM).

Survival was 55.0% in the IVTM group and 51.2% in the SCM group [pooled risk difference 2% (95% CI - 1%, 5%)]. Good neurological outcome was achieved in 40.9% in the IVTM and 29.5% in the surface group [pooled risk difference 5% (95% CI 2%, 8%)]. There was a 6% (95% CI 11%, 2%) lower risk of arrhythmia with use of IVTM and 15% (95% CI 22%, 7%) decreased risk of overcooling with use of IVTM versus SCM. There was no significant difference in other evaluated adverse events between groups.

More recent review of RCTs included.

This review also included observational studies which are prone to high risk of bias.

Bhattacharjee S, Baidya DK, Maitra S. Therapeutic hypothermia after cardiac arrest is not associated with favorable neurological outcome: a meta-analysis. J Clin Anesth. 2016;33:225–32.

Systematic review and meta-analysis

N=1339 patients from 5 RCTs, and 1 quasi-randomised controlled trial comparing therapeutic hypothermia versus no therapeutic hypothermia in post-cardiac arrest patients.

Therapeutic hypothermia does not provide any benefit in favourable neurological outcome (P = .06; odds ratio, 1.80; 95% confidence interval [CI], 0.97-3.35; n = 1384), in survival at hospital discharge (P = .58; odds ratio, 1.16; 95% CI, 0.69-1.96; n = 1399), and in long-term survival (P = .36; odds ratio, 1.32; 95% CI, 0.73-2.39; n = 1292). Therapeutic hypothermia also increases incidence of pneumonia (P = .02; odds ratio, 1.30; 95% CI, 1.04-1.64; n = 1204; number needed to harm, 15).

More recent updated systematic reviews and meta-analysis included.

Calabro L, Bougouin W, Cariou A et al. (2019) Effect of different methods of cooling for targeted temperature management on outcome after cardiac arrest: a systematic review and meta-analysis. Critical Care; 23:285, 1-12.

Systematic review and meta-analysis of RCTs and observational studies. 22 studies (n = 8,027 patients) were included.

When compared to surface cooling, core methods showed a lower probability of unfavourable neurological outcome (OR 0.85 [95% CIs 0.75–0.96]; p = 0.008) but not mortality (OR 0.88 [95% CIs 0.62–1.25]; p = 0.21). No significant heterogeneity was observed among studies. However, these effects were observed in the analyses of non-RCTs. A significant lower probability of both unfavourable neurological outcome and mortality were observed when invasive TTM methods were compared to non-invasive TTM methods and when temperature feedback devices (TFD) were compared to non-TFD methods. These results were significant particularly in non-RCTs.

More updated systematic reviews and meta-analysis included.

Nie C, Dong J, Zhang P et al. (2016) Pre-hospital therapeutic hypothermia after out-of-hospital cardiac arrest: a systematic review and meta-analysis. American Journal of Emergency Medicine 34, 2209–2216

Systematic review and meta-analysis

5 studies

The pooled analysis revealed no differences in survival to hospital discharge, favourable neurological outcomes, and incidence of pulmonary oedema between the treatment group and control group. There were significant differences in body temperature at hospital arrival and the rate of re-arrest.

More recent updated systematic reviews and meta-analysis included.

Garrido CC, Gallego BR, Gracia JCS et al. (2021) The effect of therapeutic hypothermia after cardiac arrest on the neurological outcome and survival—a systematic review of RCTs published between 2016 and 2020. Int. J. Environ. Res. Public Health, 18, 11817, 1-17.

Systematic review

N=17 randomised trials reporting on 5813 adults and 712 children were included.

Although therapeutic hypothermia is a safe technique with few adverse and manageable effects, it has not shown to improve survival rate and neurological status of adult nor paediatric patients. It is possible that its positive effect on neuroprotection could be achieved only by preventing hyperthermia although further investigation is needed.

More comprehensive and updated systematic reviews and meta-analysis added.

Hakim SM, Ammar MA, Reyad MS. (2018) Effect of therapeutic hypothermia on survival and neurological outcome in adults suffering cardiac arrest: a systematic review and meta-analysis. Minerva Anestesiol;84(6):720–30.

N=10 studies (7 RCTs, 2 retrospective, 1 cohort study) involving 3259 patients were included in meta-analysis.

Pooling all eligible studies showed a favourable effect for TH on survival and neurological recovery. However, sensitivity analysis for RCTs showed no benefit on either outcome, while observational trials showed benefit for neurological recovery with just marginally significant benefit regarding survival. Studies including patients with shockable rhythms demonstrated benefit for both outcome measures, while those including patients with any rhythms demonstrated benefit for neurological recovery but not for survival. TH did not benefit patients with non-shockable rhythms. Trials using external cooling favoured TH regarding survival and neurological outcome but those using systemic cooling with or without external cooling did not show such benefit. When the overall incidence of complications was pooled, there was a statistically significant shift in odds ratio favouring normothermic management over TH.

More recent updated systematic reviews and meta-analysis included.

Hillerson DB, Laine ME, Bissell BD et al. (2022) Contemporary targeted temperature management: Clinical evidence and controversies. Perfusion 1-15.

Review describes the pathophysiology, physiologic aspects, clinical trial evidence, changes in post-cardiac arrest care, potential risks, as well as controversies of TTM.

the American Heart Association guidelines for post-cardiac arrest care recommend TTM in patients who remain comatose after ROSC. Recently, the TTM2 randomised controlled trial found no significant difference in neurologic function and mortality at 6-months between traditional hypothermia to 33°C versus 37.5°C. While TTM has been evaluated for decades, current literature suggests that the use of TTM to 33° when compared to a protocol of targeted normothermia does not result in improved outcomes. Instead, perhaps active avoidance of fever may be most beneficial.

Review

Hunter BR, O'Donnell DP, Allgood KL et al. (2014) No benefit to pre-hospital initiation of therapeutic hypothermia in out-of-hospital cardiac arrest: A systematic review and meta-analysis. Acad Emerg Med. 2014; 21(4):356–364.

More recent updated systematic reviews and meta-analysis included.

Kalra R, Arora G, Patel N et al. (2018) Targeted temperature management after cardiac arrest: systematic review and meta-analyses. Anesth Analg;126 (3):867–75.

Systematic review and meta-analysis

Hypothermia versus normothermia compared in 5 RCTs with 1389 patients whereas pre-hospital hypothermia and in-hospital hypothermia were compared in 6 RCTs with 3393 patients.

We observed no difference in mortality (RR; 0.88, 95% CI: 0.73–1.05) or neurological outcomes (RR; 1.26, 95% CI: 0.92–1.72) between the hypothermia and normothermia strategies. Similarly, no difference was observed in mortality (RR; 1.00, 95% CI: 0.97–1.03) or neurological outcome (RR; 0.96, 95% CI: 0.85–1.08) between the pre-hospital hypothermia versus in-hospital hypothermia strategies.

More recent updated systematic reviews and meta-analysis included.

Karcioglu O, Topacoglu H, Dikme O et al. (2018) A systematic review of safety and adverse effects in the practice of therapeutic hypothermia. American Journal of Emergency Medicine; 36, 1886–1894.

Systematic review

N=19 studies therapeutic hypothermia in patients resuscitated from OHCA.

There is a considerable incidence of side effects attributed to the procedure, for example, from life-threatening ventricular arrhythmias to self-limited consequences. Most studies analysed in this systematic review indicated that the procedure of TH has not caused severe adverse effects leading to significant alterations in the outcomes following resuscitation from OHCA.

More recent comprehensive updated systematic reviews and meta-analysis included.

Kim YM, Yim HW, Jeong SH et al. (2012) Does therapeutic hypothermia benefit adult cardiac arrest patients presenting with non-shockable initial rhythms?: A systematic review and meta-analysis of randomized and non-randomized studies. Resuscitation. 2012; 83(2):188– 196.

More recent updated systematic reviews and meta-analysis included.

Kim JG, Ahn C, Shin H et al. (2020) Efficacy of the cooling method for targeted temperature management in post-cardiac arrest patients: A systematic review and meta-analysis. Resuscitation, 148, 14-24.

Meta-analysis (4,401 patients from 2 RCT and 7 observational studies).

For mortality, the overall pooled analysis showed no statistically significant difference between ECD and SCD recipients (RR, 0.93; 95% CI 0.86-1.00; I 2 = 0%). Further, no statistically significant difference was observed between RCT (RR, 0.80; 95% CI 0.56-1.14; I 2 = 0%) and OS (RR, 0.94; 95% CI 0.85-1.04; I 2 = 18%) for in-hospital mortality. For good neurological status of survivors after TTM, the overall pooled analysis showed no statistically significant difference between ECD and SCD (RR, 1.08; 95% CI 0.99-1.18; I 2 = 71%). No statistically significant difference was found between ECD and SCD at hospital discharge in RCT (RR, 0.88; 95% CI 0.61-1.28; I 2 = 0%) and at 6 months in OS (RR, 1.03; 95% CI 0.99-1.09; I 2 = 32%).

More recent updated systematic reviews and meta-analysis included.

Liao X, Zhou M, Tang H et al. (2020) Effects of endovascular and surface cooling on resuscitation in patients with cardiac arrest and a comparison of effectiveness, stability, and safety: a systematic review and meta-analysis. Critical Care; 24:27, 1-18

Systematic review and meta-analysis

N=20 studies with 4913 patients (4 RCTs and 16 cohort studies).

11 studies included IHCA patients and OHCA patients, and 9 studies only included OHCA patients.

Among adult patients receiving cardiopulmonary resuscitation, although there is no significant difference between the 2 cooling methods in the time from the start of cardiac arrest to achieve the target temperature, the faster cooling rate and more stable cooling process in EC shorten patients' ICU hospitalisation time and help more patients obtain good neurological prognosis compared with patients receiving SC. Meanwhile, although EC has no significant difference in patient outcomes compared with ArcticSun, EC has improved rates of neurologically intact survival.

Study included observational studies that are prone to high risk of bias.

Lindsay PJ, Buell D, Scales DC. (2018) The efficacy and safety of pre-hospital cooling after out-of-hospital cardiac arrest: a systematic review and meta-analysis. Critical Care (2018) 22:66

Systematic review and meta-analysis pre-hospital TH versus no pre-hospital TH in patients with OHCA.

N= 10 trials (4220 patients)

There were no significant differences between the 2 arms for the primary outcome of neurological recovery (RR 1.04, 95% CI 0.93–1.15) or the secondary outcome of survival to hospital discharge (RR 1.01, 95% CI 0.92–1.11). There was a significantly lower temperature at hospital arrival in patients receiving pre-hospital TH (MD− 0.83, 95% CI − 1.03 to − 0.63). Pre-hospital TH significantly increased the risk of re-arrest (RR 1.19, 95% CI 1.00 to 1.41). No survival differences were observed among subgroups of patients who received intra-arrest TH versus post-arrest TH or who had shockable versus non-shockable rhythms.

More recent updated systematic reviews and meta-analysis included.

Mahmoud A, Elgendy IY, Bavry AA. (2016) Use of Targeted Temperature Management After Out-of hospital Cardiac Arrest: A Meta-Analysis of Randomized Controlled Trials. Am J Med; 129(5) 522-527.e522.

Systematic review and meta-analysis

6 trials with 1391 patients were included.

Targeted temperature management after resuscitation in patients who had an OHCA was associated with a nonsignificant reduction in mortality and poor neurological outcome. Lack of benefit was strongly influenced by inclusion of 1 study that used mild hypothermia in the control arm. These results indicate that only mild hypothermia may be needed to improve outcomes among patients presenting with an OHCA.

More recent updated systematic reviews and meta-analysis included.

Mishra BS, Patnaik R, Rath A et al. (2022) Targeted temperature management in unconscious survivors of post-cardiac arrest: A systematic review and meta-analysis of randomized controlled trials. Indian Journal of Critical Care Medicine; 26, 4, 506-513.

Systematic review and meta-analysis

11 RCTs with 5,305 adult comatose survivors of cardiac arrest who had TTM.

Pooled analysis of 11 RCTs, showed no difference in death caused by any origin in the hypothermia group compared to normothermia group (OR; 0.88, 95% CI: 0.39–1.16). No difference in poor neurological outcome was observed between the 2 groups (OR; 0.86, 95% CI: 0.66–1.12). Trial sequencing analysis for mortality and poor neurological outcome showed that number to achieve power to predict futility has been achieved in both the parameters.

Similar studies included.

Nielsen N, Friberg H, Gluud C et al. (2011) Hypothermia after cardiac arrest should be further evaluated—a systematic review of randomised trials with meta-analysis and trial sequential analysis. Int J Cardiol;151:333–341.

Systematic review with meta-analysis and TSA of RCTs evaluating MIH after cardiac arrest in adults.

5 RCTs (478 patients) were included.

The relative risk (RR) for death was 0.84 (95% confidence interval (CI) 0.70 to 1.01) and for poor neurological outcome 0.78 (95% CI 0.64 to 0.95). For the 2 trials with least risk of bias the RR for death was 0.92 (95% CI 0.56 to 1.51) and for poor neurological outcome 0.92 (95% confidence interval 0.56 to 1.50). TSA indicated lack of firm evidence for a beneficial effect.

More recent updated systematic reviews and meta-analysis included.

Nolan JP, Soar J. (2022) Temperature control after cardiac arrest: friend or foe. Current opinion in critical care; 28 (3), 244-249.

Review

We suggest actively preventing fever by targeting a temperature 37.5 o C or less for those patients who remain comatose following ROSC after cardiac arrest.

Review

Osman M, Munir MB, Regner S et al. (2021) Induced Hypothermia in Patients with Cardiac Arrest and a Non-shockable Rhythm: Meta-analysis and Trial Sequential Analysis. Neurocritical care; 34 (1), 279-286.

meta-analysis and trial sequential analysis (TSA) comparing IHT with no IHT approaches in patients with CA and a non-shockable rhythm. N=9 studies (1 RCT and 8 observational studies) with 10, 386 patients were included.

There was no difference between both groups in terms of favourable neurological outcome (13% versus. 13%, RR 1.34, 95% CI 0.96–1.89, p=0.09, I²=88%), survival at discharge (20% versus. 22%, RR 1.09, 95% CI 0.88–1.36, p=0.42, I²=76%), or survival beyond 90 days (16% versus. 15%, RR 0.92, 95% CI 0.61–1.40, p=0.69, I²=83%). The TSA showed from evidence supporting the lack of benefit of IHT in terms of survival at discharge.

More recent review included.

This review included observational studies prone to high risk of bias.

Patel JK, Parikh PB (2016). Association between therapeutic hypothermia and long-term quality of life in survivors of cardiac arrest: A systematic review. Resuscitation 103 (2016) 54–59.

Systematic review 9 studies with 801 patients. (6 prospective cohort studies, 1 retrospective study, 2 sub-studies of RCTs)

The included studies do not suggest any association between TH implementation in CA with long-term QoL in CA survivors. Further larger scale studies are needed to investigate the sustainability of TH effects long term in this patient population.

More recent updated systematic reviews and meta-analysis included.

Ramadanov N, Arrich J, Klein R et al. (2022) Intravascular versus surface cooling in patients resuscitated from cardiac arrest: A systematic review and network meta-analysis with focus on temperature feedback. Critical Care Medicine; 50 (6), 999-1009.

Network-meta-analysis of 14 studies (4 RCTs, 10 non-randomised observational studies) comparing intravascular cooling (IC), surface cooling with temperature feedback (SCF), and surface cooling without temperature feedback (SCnoF) in patients having TTM for CA.

IC compared with SCnoF was significantly associated with better neurologic outcome (OR, 0.6; 95% CI,0.49–0.74) and survival (OR, 0.8; 95% CI,0.66–0.96). IC compared with SCF, and SCF compared with SCnoF did not show significant differences in neurologic outcome and survival. The rankogram showed that IC had the highest probability to be the most beneficial cooling method, followed by SCF and SCnoF.

This review included observational studies that are prone to high risk of bias.

Schenone AL, Cohen A, Patarroyo G, et al. (2016) Therapeutic hypothermia after cardiac arrest: a systematic review/meta-analysis exploring the impact of expanded criteria and targeted temperature. Resuscitation. 2016;108:102–10.

Systematic review and meta-analysis

11 studies (RCTs and observational studies) reporting achieved temperature during TH after OHCA were included.

Use of TH after OHCA, even within an expanded use, decreased the mortality (OR 0.51, 95%CI [0.41-0.64]) and improved the odds of good neurological outcome (OR 2.48, 95%CI [1.91-3.22]). No statistical heterogeneity was found for either mortality or neurological outcome. No differences in hospital mortality (p=0.86) or neurological outcomes at discharge (p=0.32) were found when pooled outcomes of 34 hypothermia arms grouped by cooling temperature were compared.

Study included expanded inclusion criteria, including retrospective and observational studies.

Shrestha DB, Sedhai YR, Budhathoki P et al. (2022) Hypothermia versus normothermia after out-of-hospital cardiac arrest: A systematic review and meta-analysis of randomized controlled trials. Annals of Medicine and Surgery 74 (2022) 103327

6 RCTs comparing therapeutic hypothermia (32–34 ◦C) with normothermia (≥36 ◦C with control of fever) in adult patients resuscitated after out-of-hospital cardiac arrest

There was no significant difference between the hypothermia and normothermia groups in mortality till 6 months follow up after out-of hospital cardiac arrest (OR 0.88, 95% CI 0.67–1.16; n = 3243; I 2 = 51%), or favourable neurological outcome (OR 1.31, 95% CI 0.93–1.84; n = 3091; I2 = 68%). Rates of arrhythmias were notably higher in the hypothermia group than the normothermia group (OR 1.43, 95% CI 1.20–1.71; n = 3029; I 2 = 4%). However, development of pneumonia showed no significant differences across 2 groups (OR 1.13, 95% CI 0.98–1.31; n = 3056; I2 = 22%).

More comprehensive updated systematic reviews and meta-analysis included.

Stagner Editor's Choice-Effects of targeted temperature management on mortality and neurological outcome: A systematic review and meta-analysis. European Heart Journal: Acute Cardiovascular Care 2018, 7(5) 467–477.

Systematic review, and meta-analyses.

6 RCTs

8 observational studies

OHCA with SR- 2 RCTs, 1 quasi-RCT

OCHA with NSR-5 observational studies.

IHCA with any rhythm -2 observational studies.

Optimal temperature for TTM-2 RCTs.

Pre-hospital versus in-hospital-6 RCTs.

Duration of TTM-1 RCT, 4 observational studies

Endovascular versus surface cooling-1 RCT, 5 observational studies.

TTM cooling methods with feedback temperature control compared to those without (that is, conventional cooling)-2RCTs, 4 observational studies.

Gradual cooling (≤0.5°C/h) compared to rapid cooling (>0.5°/h)- 2 observational studies.

Use of TTM compared to avoidance of fever- 1 observational study

rapid re-warming (≥0.5°C/h) compared to gradual re-warming -1 retrospective cohort study

presence compared to absence of post-re-warming fever-6 observational studies.

Low-quality evidence supports the in-hospital initiation and maintenance of targeted temperature management at 32–36°C among adult survivors of OHCA with an initial shockable rhythm for 18–24 h. The effects of targeted temperature management on other populations, the optimal rate and method of cooling and re-warming, and effects of fever need further study.

More comprehensive updated systematic reviews and meta-analysis included.

Suen KFK, Leung R, Lueng LP et al. (2017) Therapeutic hypothermia for asphyxia out-of-hospital cardiac arrest due to drowning: A systematic review of case series and case reports. THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT, 7, 4, 210-222.

13 studies (with 35 patients from case series and case reports)

Preliminary observation suggests that extended therapeutic hypothermia of 48–72 hours might help prevent reperfusion injury during the intermediate phase of post-cardiac arrest care to benefit patients of drowning-associated asphyxia OHCA. No conclusive recommendation could be made about the duration of and the time of onset of therapeutic hypothermia.

More comprehensive updated systematic reviews and meta-analysis included.

Rout A, Singh S, Sarkar S et al. (2020) Meta-analysis of the usefulness of therapeutic hypothermia after cardiac arrest. Am J Cardiol;133:48–53.

Systematic review and meta-analysis

RCTs comparing TH (32°C to 34°C) with controls (normothermia or temperature ≥36°C) in comatose patients who sustained cardiac arrest.

N=8 RCTs with a total of 2,026 patients (TH n = 1,025 and control n = 1,001) were included.

Irrespective of initial rhythm, TH was associated with significant reduction in poor neurological outcomes (RR 0.87, 95% CI 0.77 to 0.98; p = 0.02) without any difference in mortality (RR 0.94, 95% CI 0.85 to 1.03; p = 0.17). In patients with initial shockable rhythm compared with control, TH reduced mortality (RR 0.85, 95% CI 0.73 to 0.99; p = 0.04) and poor neurological outcomes (RR 0.81, 95% CI 0.67 to 0.99; p = 0.04). Whereas, in patients with initial non-shockable rhythm, TH was associated with decreased poor neurological outcomes after excluding 1 trial (RR 0.95 95% CI 0.91 to 1.00; p = 0.05).

More recent updated systematic reviews and meta-analysis included.

Song L, Wei L, Zhang L et al. (2016) The role of targeted temperature management in adult patients resuscitated from non-shockable cardiac arrests: an updated systematic review and meta-analysis. Biomed Res Int. 2016:2350974. doi: 10.1155/2016/2350974

Systematic review and meta-analysis of 25 trials (with 5715 patients from RCTs and observational studies) on TTM compared to normothermia for patients resuscitated from non-shockable cardiac arrest.

Pooled data showed that TTM not only associated with improved short-term survival (RR = 1.42, 95% CI: 1.28–1.57) and neurological function (RR = 1.63, 95% CI: 1.39–1.91) but also associated with improved long-term survival (RR = 1.64, 95% CI: 1.27–2.12) and neurological recovery (RR = 1.42, 95% CI: 1.07–1.90) in observational cohort studies. However, more frequent infectious complications were reported in hypothermia-treated patients (RR = 1.46, 95% CI: 1.26–1.70) and the quality of the evidence ranged from moderate to very low.

Study included observational studies which are prone to high risk of bias.

Stanger D, Mihajlovic V, Singer J, et al. (2018) Effects of targeted temperature management on mortality and neurological outcome: a systematic review and meta-analysis. Eur Heart J Acute Cardiovasc Care; 7(5):467–77.

Systematic review and meta-analysis (6 RCTs and 8 observational studies).

Overall, low-quality evidence demonstrated that targeted temperature management at 32–36°C, compared to no targeted temperature management, decreased mortality (risk ratio 0.76, 95% confidence interval 0.61–0.92) and poor neurological outcome (risk ratio 0.73, 95% confidence interval 0.60–0.88) among adult survivors of OHCA with an initial shockable rhythm. Targeted temperature management use did not benefit survivors of IHCA nor OHCA survivors with a non-shockable rhythm. Moderate-quality evidence demonstrated no benefit of pre-hospital targeted temperature management initiation. Low-quality evidence showed no difference between endovascular versus surface cooling targeted temperature management systems, nor any benefit of adding feedback control to targeted temperature management systems. Low-quality evidence suggested that targeted temperature management be maintained for 18–24 h.

Recent and updated systematic reviews and meta-analysis included.

Szarpak L, Filipiak KJ, Mosteller L et al. (2021) Survival, neurological and safety outcomes after out-of-hospital cardiac arrests treated by using pre-hospital therapeutic hypothermia: A systematic review and meta-analysis. American Journal of Emergency Medicine 42, 168–177.

Systematic review and meta-analysis

OHCA treated using pre-hospital therapeutic hypothermia

N= 11 studies with 4891 patients.

The survival to hospital discharge did not differ between PTH and control group (RR 1.02; 95%CI 0.93 to 1.12). Among 4891 participants (2466 in PTH group and 2425 in control group), 1087 participants (564 versus 523) had a favourable neurological outcome. Pulmonary oedema occurred in 320 cases in PTH group and 273 in control group with significant heterogeneity (RR 0.90, 95%CI 0.59–1.38; I2 = 80%). The pooled results showed a significant difference in rearrests between the PTH and control group (RR 1.19; 95%CI 1.00 to 1.42).

More recent and comprehensive updated systematic reviews and meta-analysis included.

Villablanca PA, Makkiya M, Einsenberg E, et al. (2016) Mild therapeutic hypothermia in patients resuscitated from out-of-hospital cardiac arrest: A meta-analysis of randomized controlled trials. Ann Card Anaesth; 19 (1):4–14.

Meta-analysis of 6 RCTs

MTH in 1400 patients successfully resuscitated from OHCA.

Overall survival was 50.7%, and favourable neurological recovery was 45.5%. Pooled data demonstrated no significant all-cause mortality (OR, 0.81; 95% CI 0.55-1.21) or neurological recovery (OR, 0.77; 95% CI 0.47-1.24).

More recent updated systematic reviews and meta-analysis included.

Yu T, Longhini F, Wu R et al. (2015) The role of the induction of mild hypothermia in adult patient outcomes after cardiac arrest: Systematic review and meta-analysis of randomized controlled studies. J Int Med Res; 43(4):471–482.

Systematic review comparing mild hypothermia (32-34℃) with normothermia or hypothermia other than mild hypothermia after cardiac arrest, in adults with ROSC.

N=7 RCTs were included.

Mild hypothermia demonstrated no significant beneficial effects in terms of overall mortality or neurological outcomes. In addition, no significant outcome differences were observed between the pre- and in-hospital subgroups.

More recent updated systematic reviews and meta-analysis included.

Zhang XW, Xie JF, Chen JX, et al. (2015) The effect of mild induced hypothermia on outcomes of patients after cardiac arrest: a systematic review and meta-analysis of randomised controlled trials. Crit Care; 19:417.

More recent updated systematic reviews and meta-analysis included.

Zhang Q, Qi Z, Liu B et al. (2018) Predictors of survival and favorable neurological outcome in patients treated with targeted temperature management after cardiac arrest: A systematic review and meta-analysis. Heart & Lung 47 (2018) 602-609.

Systematic review and meta-analyses of 17 studies.

Favourable neurological outcome was associated with significantly higher odds of an initial shockable rhythm (OR: 7.63, 95%CI: 6.51-8.96), bystander CPR (OR: 1.44, 95%CI: 1.14-1.82), male (OR: 1.39, 95%CI: 1.20-1.61). Survival was associated with higher odds of an initial shockable rhythm (OR: 4.88, 95%CI: 3.18-4.79), higher odds of bystander CPR (OR: 1.71, 95%CI: 1.05-2.77). No significant association was found between survival and male. In adult patients treated with TTM, initial shockable rhythm, bystander CPR and male sex were associated with a higher likelihood of favourable neurological outcome. Initial shockable rhythm and bystander CPR were associated with a higher likelihood of survival.

More comprehensive updated systematic reviews and meta-analysis included.