The European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM) have published recent 2021-2022 guidelines for post-resuscitation care after cardiac arrest syndrome. Targeted temperature management (TTM) is recommended for adult patients after either out- or in-hospital cardiac arrest who remain unresponsive after the return of spontaneous circulation (ROSC). The target temperature recommended is between 32 and 36°C for at least 24 hours. However, there is limited evidence for the optimal temperature range in subpopulations of cardiac arrest patients. A meta-analysis performed on six clinical trials found a TTM target range of 32 to 34°C did not improve survival (risk ratio [RR] 1.08; 95% confidence interval [CI] 0.89 to 1.3) or favorable functional outcome (RR 1.21; 95% CI 0.91 to 1.61) at 90 to 180 days post-cardiac arrest. Pre-hospital cooling also did not improve survival or functional outcome at discharge. One trial that compared 33°C versus 36°C found no difference in neurological outcomes at 180 days and discharge. Three studies that compared different methods of temperature control (e.g., endovascular cooling and surface cooling) found no difference in survival or neurological outcomes at discharge or at 28 days. Based on these findings, the panel prefers fever prevention as it likely requires fewer resources and is associated with less side effects compared to TTM. Yet temperature control between 32 to 36°C may be considered despite these recent findings as some populations may still benefit from treatment. Fever should be actively prevented (> 37.7°C) for at least 72 hours in post-cardiac patients who remain comatose. [1], [2]
The Neurocritical Care Society (NCS) published guidelines in 2017 for the optimal technique of general TTM. In the setting of post-cardiac arrest, certain evidence from the literature was highlighted. Cold saline infusions may be effective at reducing initial temperature upon arrival, but were found to achieve less ROSC compared to standard care. No additional measures to avoid gastric intolerance for patients undergoing TTM seem necessary. The pharmacokinetics of commonly-used analgesics and sedatives may be altered by cooling. There may be higher rates of thrombocytopenia and transfusion of blood products, but no significant difference in bleeding complications. Patients with shock or left ventricular failure may require more monitoring for skin breakdown. [3]
The Taiwan Society of Emergency & Critical Care Medicine published 2021 guidelines for TTM in the setting of post-cardiac arrest. Like previous guidelines, the recommended TTM range is between 32 to 36°C. Neurological outcomes may be improved by keeping body temperature at 33°C for 24 hours post-cardiac arrest in patients with an initial shockable rhythm. The recommendations seem to be based on less-robust evidence with the panel citing specific TTM trials and a meta-analysis of six studies. [4]
A series of recent systematic reviews and meta-analyses evaluated various outcomes associated with TTM. A 2022 systematic review and Bayesian meta-analysis including seven randomized and quasi-randomized trials (three low bias, three intermediate bias, one high bias, very low to low certainty; N= 3,792 patients) compared comatose survivals from cardiac arrest who received TTM for at least 12 hours versus those without TTM treatment (See Table 1). Studies evaluating similar TTM with various duration as well as those investigating hypothermic (32–34 °C) TTM in both intervention and control groups were excluded from the analysis. With evidence of heterogeneity but no evidence of publication bias, there was a mean RR for death of 0.96 (95% CrI 0.82 to 1.04) and a RR for unfavorable neurological outcomes of 0.93 (95% CrI 0.84 to 1.02). Studies with no explicit mention of normothermia temperature definition in the control groups were excluded from the sensitivity analysis to reduce the heterogeneity, resulting in a change in the RR for death to 0.99 (95% CrI 0.69 to 1.14) and for unfavorable neurological outcomes to 0.96 (95% CrI 0.68 to 1.12). Moreover, four studies lacking the active avoidance of fever in control arms were excluded resulting in a reduced probability to achieve an absolute risk reduction of > 2% for death or unfavorable neurological outcome to ≤ 50%. As the posterior probabilities for favorable treatment effects of TTM at 32–34 °C were highest for an absolute risk reduction of 2-4% for death (28-53% chance) and unfavorable neurological outcome (63-78% chance), this analysis did not support the use of TTM at 32–34 °C as compared to ≥ 36 °C also including active control of fever to reduce the risk of death and unfavorable neurological outcome at 90-180 days. [5]
Another 2022 systematic review and meta-analysis included six retrospective controlled studies (N= 14,607) to compare the discharge survival and neurological outcomes in patients treated with TTM (n= 1,845) versus the control group (n= 12,762). Survival to hospital discharge (OR 1.02, 95% CI 0.77 to 1.35; p= 0.89) and favorable neurological outcomes (OR 1.06, 95% CI 0.56 to 2.02, p= 0.85) did not show statistical difference between the two groups. To address the variable sample size and the large effect on the heterogeneity, subgroup analyses were performed which still demonstrated no significant effect on survival to hospital discharge; however, therapeutic hypothermia was associated with an increased risk of unfavorable neurological outcomes in the large sample size subgroup when compared to those with no hypothermia (OR 0.81, 95% CI 0.69 to 0.94; p= 0.006). Overall, the results may be limited due to significant heterogeneity across studies, potential confounding factors (e.g., specific cryotherapy method), and its retrospective observational study design. [6]
A 2021 review (N= 32 trials) was performed to evaluate multiple aspects of targeted temperature management including timing, temperature, duration, method of induction and maintenance, and rewarming. Adults patients with cardiac arrest in any setting (in- or out-of-hospital) were included. Nine trials compared TTM at 32-34 °C vs. normothermia. Most of these trials were pilot studies or limited to small sample size; six of these studies were included in the meta-analysis which found that a target of 32-34 °C did not result in improved survival (RR 1.08, 95% CI 0.89 to 1.30) or favorable neurologic outcome (RR 1.21, 95% CI 0.91 to 1.61) at 90 to 180 days after the cardiac arrest. No difference was found in any other outcomes measured including different hypothermic targets (no difference between 32 °C, 33 °C, 34 °C, or 36 °C), in prehospital vs. no prehospital cooling; there was no improvement in improved survival (RR 1.01, 95% CI 0.92 to 1.11) or favorable neurologic outcome at hospital discharge (RR 1.00; 95% CI 0.90 to 1.11). Overall, most comparisons were based on low to moderate certainty of evidence. The results suggested an overall lack of effectiveness associated with TTM based on the included data. [7]
Another 2021 systematic review and network meta-analysis included 10 RCTs (N= 4,218 patients) to evaluate the efficacy and safety of deep hypothermia (31–32 °C), moderate hypothermia (33–34 °C), mild hypothermia (35–36 °C), and normothermia (37–37.8 °C) during TTM in patients with out-of-hospital cardiac arrest (OHCA) and decreased level of consciousness. The analysis with low certainty revealed deep hypothermia (odds ratio [OR] 1.30, 95% confidence interval [CI] 0.73 to 2.30), moderate hypothermia (OR 1.34, 95% CI 0.92 to 1.94), and mild hypothermia (OR 1.44, 95% CI 0.74 to 2.80) may have no effect on survival with a good functional outcome compared to normothermia. Likewise, compared to moderate hypothermia, there may be no additional benefits of deep hypothermia on survival with a good functional outcome (OR 0.97, 95% CI 0.61 to 1.54). Additionally for overall survival, there may be no effect of 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) compared to normothermia (all low certainty). Compared to normothermia, moderate hypothermia and deep hypothermia were associated with an increased risk of arrhythmia (OR 1.45, 95% CI 1.08 to 1.94 and OR 3.58, 95% CI 1.77 to 7.26; both high certainty). Similarly, arrhythmia was reported more commonly in the deep hypothermia group versus the moderate hypothermia group (OR 2.47, 95% CI 1.25 to 4.88; high certainty). For the incidence of bleeding or pneumonia, no significant difference was revealed among the various temperature management groups (all low or very low certainty). Given the limitations of this network meta-analysis mainly due to clinical heterogeneity, various timing of outcome measurement, and unblinded target group allocation, the results should be interpreted with caution. As data are insufficient for subgroup analysis, future studies are warranted to identify patient populations likely to benefit from TTM with moderate to deep temperatures. [8]
A 2019 systematic review and meta-analysis compared the effects of different TTM methods on survival and neurological outcomes. A total of 22 studies (N= 8,027 patients) were included in the final analysis. Cooling methods evaluated include core (i.e., endovascular cooling devices [EC], intravenous cold fluids, automated peritoneal lavage, any dialysis technique, extracorporeal membrane oxygenation, esophageal or trans-nasal) or surface (i.e., skin exposure, cooling beds, iced packs, cooling pads, air-circulating or water-circulating blankets, water-filled blankets, air-filled blankets), as well as invasive (i.e., EC, automated peritoneal lavage, any dialysis technique, extracorporeal membrane oxygenation) and non-invasive (all others). Most included studies were retrospective with very low quality of evidence, but four high-quality randomized controlled trials (RCTs) were also included. Comparison of core vs. surface TTM revealed core methods were associated with a lower probability of unfavorable neurological outcomes (OR 0.85, 95% CI 0.75 to 0.96; p= 0.008) but not mortality (OR 0.88, 95% CI 0.62 to 1.25; p= 0.21). The comparison of invasive to noninvasive TTM methods indicated a significantly lower probability of unfavorable neurological outcomes (OR 0.70, 95% CI 0.61 to 0.81; p<0.001) and mortality (OR 0.84, 95% CI 0.74 to 0.94; p= 0.002) versus the invasive methods. Overall, the analyses were based on non-randomized controlled trials, but the reported randomized controlled trials revealed a similar trend. Based on non-randomized controlled trials, the use of temperature feedback devices (TFD) was associated with a significantly lower probability of unfavorable neurological outcomes and mortality than non-TFD methods. [9]
Finally, another systematic review and meta-analysis from 2018 included 11 RCTs (N= 4,782) to also evaluate the efficacy of TTM after cardiac arrest. Five trials (n= 1,389) compared hypothermia and normothermia strategies, finding no difference in mortality (RR 0.88, 95% CI 0.73 to 1.05) or neurological outcomes (RR 1.26, 95% CI 0.92 to 1.72), and six trials (n= 3,393) compared prehospital hypothermia and in-hospital hypothermia, again finding no difference in mortality (RR 1.00, 95% CI 0.97 to 1.03) or neurological outcome (RR 0.96, 95% CI 0.85 to 1.08). It was discussed that therapeutic hypothermia includes risks associated with the rewarming period; if similar outcomes can be achieved utilizing alternative means, these risks can be avoided. Overall, the authors concluded that TTM with therapeutic hypothermia may not improve mortality or neurological outcomes in post-arrest survivors, meriting reevaluation of this standard-of-care strategy. [10]
Two commentary statements provided expert opinions regarding the study conducted by Nielsen et al (summarized in Table 3). In one commentary, the authors emphasized that despite an insignificant difference in benefits between the two hypothermic temperature goals (33°C vs. 36°C), TTM improves outcomes in post-cardiac arrest patients. The other commentary specifies that the scene where the assessment of cardiac arrest takes place is important and will influence the patient demographic (e.g., out-of-hospital versus within the emergency department). In response to the commentaries, the study authors noted a 50% mortality rate, indicating that included patients were severely ill and appropriate for the study to detect a clinically satisfactory outcome. [11], [12], [13]