This is the first meta-analysis that evaluated the potential effects of the cooling methods on the outcome in patients undergoing TTM after cardiac arrest. Our results can be summarized as follows: core cooling devices are associated with a lower probability of unfavorable neurological outcome, but not of survival, when compared to surface cooling devices; similarly, invasive cooling devices and TFD methods were associated with a higher occurrence of favorable outcome and survival when compared to other methods. In particular, endovascular catheter devices were associated with better outcomes when compared to air- or water-circulating blankets, even when blankets were TFD, and blankets had a better outcome than other surface cooling methods. However, most of the available data came from non-RCTs, potentially leading to high risk of bias.
Method of cooling: which is the best TTM device?
The initial studies dealing with the use of TTM after cardiac arrest used external surface cooling devices, either with TFD or without temperature control. Since then, several TTM methods to induce, maintain, or rewarm patients have been developed; these methods have been schematically divided into “core” or “surface” methods [
11], although other classifications have been proposed, i.e., “advanced” methods (using a retro-control according to the patient’s core temperature) vs. “basic” methods (such as cold fluids, ice packs without temperature feedback) [
12,
17,
38]. Core and TFD methods enable a more accurate control of patients’ temperature during the cooling phase when compared with surface techniques [
12,
17,
19]; nevertheless, current guidelines stated that no recommendation could be given on the optimal method, as there were no data indicating any potential benefits on survival or neurological outcome from one specific TTM device [
2]. The use of TFD to better optimize TTM was also recently suggested by a panel of French experts [
39], in both adult and pediatric CA, despite the lack of studies clearly demonstrating an effect on the patients’ outcome. Moreover, more recent invasive TTM devices, such as cold liquid ventilation and esophageal or peritoneal devices, were not included in this consensus.
A major strength of our study is that we demonstrated that core, invasive, and/or TFD methods to provide TTM to CA survivors were associated with an increased probability of favorable neurological outcome. These findings were consistent even in the subgroup analyses, when EC were compared to blanket systems or air- or water-circulating blankets to other surface methods. Moreover, the analyses showed a very low heterogeneity. Unfortunately, findings from RCTs were less convincing. In the largest multicenter RCT available to date, which compared EC to basic external methods (i.e., non-invasive, without TFD,
n = 400), favorable neurological outcome at day 28 was not significantly different between the groups [
12], although a strong trend towards a higher occurrence of intact neurological recovery at day 90 was observed in the EC group (odds ratio 1.51; 95% CIs 0.96–2.35;
p = 0.07). In another study (
n = 64), TTM using a TFD implementing water-circulating blankets showed a similar proportion of patients with favorable neurological outcome than cooling blankets and ice without TFD (46% vs. 38%); however, considering the total number of patients included, the study was probably underpowered to demonstrate any difference on the patients’ outcome [
33]. Two other small RCTs, including a total of 125 patients, also showed a non-significant trend for a better outcome in patients treated with EC when compared to TFD blankets [
13,
24].
How to explain these results? The limited data provided by the selected studies restricted our ability to explore the underlying mechanisms of our findings. Time to target temperature was significantly shorter in core and invasive TTM methods than others [
12,
33], although this was not observed in all studies [
14,
19]. Moreover, the early initiation of TTM in patients suffering from OHCA, either intra-arrest or immediately after ROSC in the pre-hospital setting, did not show any beneficial effects on survival or neurological outcome when compared to TTM initiated few hours following CA, after hospital admission [
8,
40]. Analysis of the rewarming time showed controversial results, with some studies suggesting a shorter time for EC when compared to non-TFD blankets and other showing similar findings for EC and TFD surface methods [
19,
25]. Also, the occurrence of post-TTM fever was similar between EC and surface methods [
17,
19]. As such, the main difference between the core and invasive methods, in particular EC, was associated with a more strict maintenance of the target temperature during the cooling phase, fewer periods of over-cooling or unexpected rewarming and less temperature variability [
14,
19,
25]. Importantly, temperature variability after CA has not been associated with poor neurological outcome in two retrospective studies [
41,
42]. Considering also the higher risk of side effects (i.e., infections, thrombosis, hemorrhage) associated with the use of core and invasive TTM systems, in particular EC [
12,
24,
43], further studies evaluating the mechanisms involved in potential neuroprotection for such methods are necessary.
Major weaknesses
The results of this meta-analysis should be considered as a step forward a future trial evaluating the effects of cooling methods on the patients’ outcome, in order to better answer the question on the optimal method to provide TTM after CA. However, it remains unclear which methods should be compared in this study. Deye et al. [
12] compared EC (i.e., core, invasive, TFD) with cooling blankets and ice packs (i.e., surface, non-invasive, and without TFD) and showed a non-significant but clinically relevant difference between the two groups. These findings are reinforced by this systematic review that observed a non-significant but large difference in the outcome when the two available RCTs comparing devices with TFD vs. those without TFD were considered. Whether it would be ethical to expose CA patients to TTM methods that are less effective in inducing hypothermia and maintaining a target temperature in such a trial, this should be further considered. The most adequate trial should compare EC with water-circulating blankets using TFD, as in the study from Pittl et al. [
24]. Nevertheless, to reproduce the same differences in the neurological outcome (i.e., 53% vs. 61%), more than 1200 patients would be necessary. In the meantime, considering the cost and invasiveness of some of these devices, the selection of the best TTM strategy remains challenging; if one could argue that core and invasive TFD methods should be implemented in those patients with the best prognosis (i.e., young patient with a shockable initial rhythm), another could also suggest these methods on patients with the most severe reperfusion injuries (i.e., prolonged resuscitation with poor clinical presentation) in order to have more chance to prevent them. Also, it could also be considered unethical to use other methods than those with TFD as this would expose patients to a “poor-quality TTM.” Other relevant aspects on the selection of TTM methods, such the reduced workload of the nursing team and the feasibility of skin counter warming in case of shivering for EC systems when compared to others, should also be assessed in future studies.
Another major issue of this study is the inclusion of different methods (i.e., EC, peritoneal lavage, dialysis techniques) in the same group (i.e., “core”). Also, in some studies, specific TTM methods were combined, in a variable proportion of patients, with cold fluids or iced packs; the role of such additional interventions on the measured outcome remains unknown. However, this allowed the selection of all available studies in the literature comparing at least two different methods of TTM, with a more complete assessment of the study hypothesis. Also, some additional data, such as side effects or speed and precision of cooling, were not collected. However, the time from arrest to target temperature was not further analyzed as this information would be largely biased by the retrospective data collection of most of the studies included in this report. Similarly, the issue of the adverse events has already been discussed in another study [
5]. Also, the performance for each TTM method was not routinely reported in all studies. Finally, we could not calculate the minimal number of patients to be included in the meta-analysis, and most of the studies had a high risk of bias, which would reduce the robustness of our findings.