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

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.

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. 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. 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. 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.^,  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). 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).

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.