Extracorporeal cardiopulmonary resuscitation with temperature management could improve the neurological outcomes of out-of-hospital cardiac arrest: a retrospective analysis of a nationwide multicenter observational study in Japan

In the present study, the primary outcome of propensity score analysis of all eligible patients revealed that ECPR combined with TTM was associated with better neurological outcomes after OHCA compared with ECPR without TTM. In this study population, about 70% of cases underwent TTM shown as therapeutic hypothermia (32–340C TTM). Although prior studies of CCPR cases have shown the effectiveness of therapeutic hypothermia [13, 14], these earlier studies used control groups without fever treatment, and controversially stated that the worse outcome was due to the onset of fever after ROSC, a topic that has been discussed recently [1, 2]. By comparison, ECMO during ECPR could prevent fever due to the heat dissipation effect of the extracorporeal circulation; thus, the control group of patients who did not receive TTM were unlikely to have developed high fever in this study, although the JAAM-OHCA registry did not record body temperatures during ECPR. Therefore, present study results might reveal the advantage of therapeutic hypothermia (70% of TTM group) compared to normothermia (fever treatment by heat dissipation).

We presume one of the advantages of ECPR with TTM is that it quickly lowers the body temperature constantly by directly lowering the blood temperature in the extracorporeal circulation instead of relying on spontaneous circulation. In this study, the median ICTT in patients who underwent TTM was 249 min. This rapid cooling may help improve the neurological outcome, as previously suggested (therapeutic hypothermia with within 3.5 h [4], around 200 min [5] of cooling period showed advantages). Furthermore, in subgroup analyses, patients with an ICPS of < 60 min, had better neurological outcomes than patients with a longer ICPS. In an analysis of cases with a cardiogenic cause, the effectiveness of TTM was also observed patients with an ICPS of > 60 min. Therefore, these results might suggest a benefit of TTM during ECPR in some ICPS conditions.

To confirm these possibilities of TTM benefits, and although ECPR with TTM still showed only 16% of favorable outcome, the indication for ECPR should be considered. Although one recent meta-analysis did not show positive outcomes of ECPR with TTM, this may be related to the heterogeneity of the study populations due to the broad use of ECPR [15]. To investigate the appropriate indications, a systematic review reported that the current standard indications of ECPR were age, witnessed OHCA, no flow (within 5–10 min), initial SR, and refractory cardiac arrest (10–30 min). In particular, patients with refractory cardiac arrest, defined as > 10 min, was associated with good neurological outcomes, which extended to those with refractory cardiac arrest of 15–30 min [16]. Most Japanese departments have similar protocols for starting ECPR, and our data showed positive neurological outcomes of ECPR with TTM. However, our data do not show the effectiveness of TTM in patients who undergo ECPR using other countries’ ECPR protocols, only showing outcome of ECPR in Japanese departments.

Overall, in this population of adult patients with witnessed OHCA, of whom about 90% had a cardiogenic cause, we have demonstrated the effectiveness of ECPR with TTM, which comprised therapeutic hypothermia in about 70% of patients, compared with ECPR in which heat was dissipated via extracorporeal circulation using VA-ECMO to prevent fever at least. In the majority of cases, the ICPS was less than 50 min and the median time to reach the target temperature was approximately 4 h. In previous studies of CCPR, there was no difference in positive outcomes between therapeutic hypothermia and normothermia [1, 2], despite positive effects of fever control versus uncontrolled fever [13, 14]. Our data suggest that therapeutic hypothermia with ECPR could improve the neurological outcomes of patients with OHCA. There are some possible reasons for our observations that should be discussed. First, the eligible population were generally not elderly, had an initial SR, and a cardiogenic cause, and early reperfusion was achieved by ECPR. Second, the time to reach the target temperature by ECPR with VA-ECMO was relatively short. Among cases of CCPR, rapid achievement of therapeutic hypothermia was a controversial finding [4, 5]. Third, the quick reperfusion and cooling of organs, not only the brain, might be beneficial. In CCPR, organ reperfusion started after ROSC, and relied on spontaneous circulation. By comparison, ECPR ensures early reperfusion and can help cool the body more quickly than CCPR can. This theory is supported by the results of animal studies in which quick cooling improved organ function after CCPR [17, 18]. However, an animal model of ECPR reported inconclusive effects of early reperfusion and quick cooling for organ preservation [19]. Whereas, although ECPR with TTM showed significant improvement of outcome, favorable neurological was unsatisfied result (16%), then, usage criteria should be continued to brush up for reducing overuse of ECPR with TTM, which needs more cost and effort. The present study could reveal possibility of improving neurological outcome in ECPR with TTM, however, which could not reach our satisfaction enough.

This study has several limitations. First, although the registry comprises a nationwide cohort, the study was performed retrospectively, which may introduce some bias. Second, the neurological outcomes were assessed in terms of the CPC at 1 month after resuscitation. It is possible that the neurological outcomes might have changed after 6 months or 1 year. Third, while the propensity score analysis demonstrated the efficacy of TTM, other factors might confound the results and introduce some bias. Fourth, the actual body temperatures were not recorded in patients who did not undergo TTM, and it is unknown whether their body temperatures differed from patients who underwent TTM. Fifth, implementation time of ECMO was not shown in database, might have potential to affect the outcome. Sixth, the database did not have the data of interval from collapse to ECMO initiation (inserting catheters), and ECMO initiation to ECMO pump start, these were no considered.

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