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Is there a protective effect of 48-h therapeutic hypothermia on acute kidney injury?

      Sir,
      I read the article by Strand et al. titled ‘The influence of prolonged temperature management on acute kidney injury after out-of-hospital cardiac arrest: A post-hoc analysis of the TTH48 trial’ with great interest.
      • Strand K.
      • Soreide E.
      • Kirkegaard H.
      • et al.
      The influence of prolonged temperature management on acute kidney injury after out-of-hospital cardiac arrest: a post-hoc analysis of the TTH48 trial.
      In the case that therapeutic hypothermia (TH) had a protective effect on acute kidney injury (AKI), there should have been a difference in the incidence of AKI between the 24-h and the 48-h group. Indeed, the incidence of AKI in the 48-h group was slightly lower than that in the 24-h group (44.3% vs. 46.8%). However, this difference failed to achieve statistical significance. Nonetheless, before ignoring these results, we should consider several important factors of the study. The TTH48 trial did not confirm whether there was a difference in the 6-month mortality between the 24-h and the 48-h groups.
      • Kirkegaard H.
      • Soreide E.
      • de Haas I.
      • et al.
      Targeted temperature management for 48 vs 24 hours and neurologic outcome after out-of-hospital cardiac arrest: a randomized clinical trial.
      Although the 6-month mortality in the 48-h group was lower than that in the 24-h group (27% vs. 34%), this difference also failed to achieve statistical significance.
      • Kirkegaard H.
      • Soreide E.
      • de Haas I.
      • et al.
      Targeted temperature management for 48 vs 24 hours and neurologic outcome after out-of-hospital cardiac arrest: a randomized clinical trial.
      Several factors account for this result. First, the TTH48 trial included only out-of-hospital cardiac arrest (OHCA) patients with a presumed cardiac origin. In addition, the authors excluded patients with unwitnessed asystole rhythm. As a result, the overall 6-month mortality was only 30.8%. A decreased overall mortality might have decreased the mortality gap between the two groups. Furthermore, the development of AKI after OHCA was a strong risk factor for 6-month mortality.
      • Oh J.H.
      • Lee D.H.
      • Cho I.S.
      • et al.
      Association between acute kidney injury and neurological outcome or death at 6months in out-of-hospital cardiac arrest: a prospective, multicenter, observational cohort study.
      Therefore, a similar trend between the 6-month mortality (34% [24-h group] vs. 27% [48-h group]) and the incidence of AKI (46.8% [24-h group] vs. 44.3% [48-h group]) suggests that there was a possibility of a protective effect in the 48-h group.
      • Strand K.
      • Soreide E.
      • Kirkegaard H.
      • et al.
      The influence of prolonged temperature management on acute kidney injury after out-of-hospital cardiac arrest: a post-hoc analysis of the TTH48 trial.
      • Kirkegaard H.
      • Soreide E.
      • de Haas I.
      • et al.
      Targeted temperature management for 48 vs 24 hours and neurologic outcome after out-of-hospital cardiac arrest: a randomized clinical trial.
      Second, the sample size calculated in the TTH48 trial (n = 338) was too small as the authors overestimated the protective effect of TH in the 48-h group (absolute difference of 15%). If they had set the absolute difference as 7% (34% vs. 27%), 1352 participants should have been enrolled. Hence, the difference in the incidence of AKI between the 24-h and the 48-h TH group failed to reach statistical significance
      Moreover, there were no differences in the risk of death between the patients with Stage 1 AKI and patients without AKI. Had the authors extended the inclusion criteria, different results might have been obtained. We conducted a Cox regression analysis using the dataset of the Korean Hypothermia Network prospective registry (KORHN-PRO) which included all adult patients with OHCA regardless of the cause of arrest (n = 729).
      • Oh J.H.
      • Lee D.H.
      • Cho I.S.
      • et al.
      Association between acute kidney injury and neurological outcome or death at 6months in out-of-hospital cardiac arrest: a prospective, multicenter, observational cohort study.
      The results showed that there was a significant difference in the risk of death between the patients with Stage 1 AKI and the patients without AKI (HR of Stage 1 AKI: 2.102 [95% CI: 1.459–3.028], P < 0.001) (Fig. 1).
      Fig. 1
      Fig. 1Cumulative survival according to the acute kidney injury stage.
      AKI, acute kidney injury; ROSC, return of spontaneous circulation.
      In conclusion, a new randomized trial with an expanded inclusion criteria and a larger sample size will be necessary to confirm the protective effect of a 48-h TH on AKI. If we can confirm the benefit of prolonged TH, tailoring targeted temperature management for patients with OHCA will become feasible.

      Conflict of interest

      The authors have no potential conflicts of interest to disclose.

      References

        • Strand K.
        • Soreide E.
        • Kirkegaard H.
        • et al.
        The influence of prolonged temperature management on acute kidney injury after out-of-hospital cardiac arrest: a post-hoc analysis of the TTH48 trial.
        Resuscitation. 2020; 151: 10-17https://doi.org/10.1016/j.resuscitation.2020.01.039
        • Kirkegaard H.
        • Soreide E.
        • de Haas I.
        • et al.
        Targeted temperature management for 48 vs 24 hours and neurologic outcome after out-of-hospital cardiac arrest: a randomized clinical trial.
        JAMA. 2017; 318: 341-350
        • Oh J.H.
        • Lee D.H.
        • Cho I.S.
        • et al.
        Association between acute kidney injury and neurological outcome or death at 6months in out-of-hospital cardiac arrest: a prospective, multicenter, observational cohort study.
        J Crit Care. 2019; 54: 197-204