Is 48-hour targeted temperature management not superior to 24-hour targeted temperature management after out-of-hospital cardiac arrest in adults? Feasible but still inconclusive

Since positive results of a quasi-randomized controlled trial and a randomized controlled trial were reported in 2002, mild therapeutic hypothermia (TH) has been accepted as an intervention to improve both survival and neurological outcomes following out-of-hospital cardiac arrest (OHCA) with shockable rhythm and has been actively implemented for all cardiac arrest patients around the world over the past decade (1,2). However, many questions for the optimal use of mild TH remain unresolved. Some researchers asserted that the scientific evidence is not sufficient to use mild TH for comatose survivors after cardiac arrest and have undertaken well-designed randomized controlled trials (RCTs) to demonstrate the efficacy and to determine an optimal dose for this intervention (3,4). In 2013, the largest trial including 939 patients after OHCA that compared a target temperature of 33 vs. 36 °C found no difference in 6-month mortality between the two temperatures (4). The results of the trial cast doubt on the efficacy of mild TH, and a following trial comparing targeted temperature management (TTM) at 33 °C with standard normothermia care (<37.5 °C) will be just started by the same investigators (5). One of the important knowledge gaps for dose of TTM is the optimal duration of treatment.

Neuronal injury mechanisms following brain ischemia after cardiac arrest were affected by hypothermia in multifaceted ways for several days after reperfusion (6). In an animal study, a short duration of hypothermia (1–2 hours) had no neuroprotective effects unless it was started just after global ischemia (7). However, a longer duration (6–36 hours) of hypothermia was beneficial, although the cooling was slightly delayed, even after reperfusion (8). Twenty-four-hour hypothermia resulted in better neurological outcome than 4-hour hypothermia in an animal study using an 8-minute asphyxial cardiac arrest rat model (9). Unlike animal studies, hypothermia tends to be delayed by many reasons in clinical situations, and prolonged hypothermia will inevitably have multifaceted effects on delayed neuronal injury mechanisms. In three landmark trials, 12- or 24-hour durations were used, with the 24-hour duration applied in the two largest trials (1,2,4). On the basis of the available evidence, current guidelines recommended TTM at 32 to 36 °C for at least 24 hours (10). However, some animal studies using different arrest models have suggested that 48-hour hypothermia could have additional neuroprotective effects compared with 24-hour hypothermia, and a small prospective observational study suggested that prolonged hypothermia may blunt the inflammatory response after rewarming in patients following cardiac arrest (11-13). Although the prolonged hypothermia could have potential benefits, a longer duration of hypothermia may increase the risk for adverse events. Some observational studies suggested that the cooling duration of the infection group was longer than that in the non-infection group, and prolonged duration of cooling and rewarming ≥28 hours may increase complications, such as pneumonia and bleeding (14,15). To provide an answer regarding the relative efficacies and the concern about adverse events, a RCT for the prolonged TTM duration is necessary.

In a recent issue of JAMA, Kirkegaard et al. (16) reported the results of the Time-differentiated Therapeutic Hypothermia 48 (TTH48) trial—a pragmatic, international, multicenter RCT that compared the 6-month favorable neurological outcome (defined as Cerebral Performance Category scores of 1 or 2) of 24 vs. 48 hours of TTM with 33 °C among unconscious adult survivors treated in ten intensive care units (ICUs) in six European countries.

Based on data from 335 patients, the rates for 6-month favorable neurological outcomes were 69% (120/175) in the 48-hour group and 64% (112/176) in the 24-hour group. The risk ratio for the primary outcome was 1.08 (95% CI, 0.93–1.25) and the risk difference was 4.9% (95% CI, −5–14.8%). The investigators carefully analyzed unadjusted and adjusted 6-month survival rates in both modified intention-to-treat and per-protocol analyses but showed similar results. Secondary outcomes, including mortality during ICU and ward hospitalization or at 6 months, also did not show meaningful differences between the two groups. Based on these results, the investigators concluded that TTM at 33 °C for 48 hours did not significantly improve 6-month neurologic outcome compared with TTM at 33 °C for 24 hours.

The internal validity of this trial was strong. Among 907 patients registered, 355 patients were randomized into two groups. A total of 351 patients (99%) completed the trial, and only 1 patient was lost to follow-up. Randomization was performed individually within strata defined by age and initial rhythm using a web-based central procedure, and allocation was concealed until randomization. TTM initiation and induction time were relatively short (<2 and <6 hours in the two groups, respectively), and rates of immediate coronary angiography were high (>80% in both groups). Neurologic prognostication was delayed and used a multimodal approach, and decisions to withdraw life-supporting treatment were made by a multidisciplinary team independently and according to established protocols. All of the study protocols and a statistical analysis plans were published in advance (17,18).

The TTH48 trial was the first RCT comparing different durations of TTM after adult OHCA and has many methodological strengths, as mentioned above. Additionally, the trial added to our knowledges of TTM dose after cardiac arrest. Although the incidence of overall adverse events and ICU length of stay were significantly different between the two duration groups, there were no significant differences in the incidence rates of the known major adverse events of prolonged TTM after OHCA, such as pneumonia, bleeding, or severe arrhythmias, as reported in previous studies (14,19,20). The authors reported that most of the adverse events were mild and did not affect the neurological outcomes. These findings suggest that the 48-hour duration could be considered clinically feasible for TTM after OHCA.

However, the superiority of the 48-hour TTM for improving 6-month neurological outcomes in adult OHCA to 24-hour TTM is inconclusive due to the limited statistical power of the trial. The 15% absolute difference in the primary outcome between two different TTM duration groups might be too large considering the study subjects and study settings in this trial. In spite of the pragmatic trial design, the enrolled study subjects had many favorable prognostic characteristics, such as witnessed OHCA (91% in the 48-hour group vs. 92% in the 24-hour group) and shockable initial rhythm (91% in the 48-hour group vs. 86% in the 24-hour group). Furthermore, the study settings were good systems with a high bystander cardiopulmonary resuscitation rate (87% in the 48-hour group vs. 84% in the 24-hour group), short basic life support starting time (median 1 min in both groups), short emergency medical system response time (median 8 min in both groups), and active coronary angiography (83% in the 48-hour group vs. 82% in the 24-hour group). Due to the characteristics, the overall outcomes of this study were higher than in previous landmark RCTs (2,4). This particular patient sample may not represent the diverse range of illness severity of post-cardiac arrest patients. Although there is no definitive clinical evidence in adult cardiac arrest, theoretically, prolonged duration of TTM intervention could also be more helpful for patients with moderate-to-severe brain injury (11,13). Thus, the results of this trial do not exclude the possibility that prolonged TTM duration might be beneficial for an individual with moderate-to-severe brain injury. For these reasons, the generalizability of the findings in this trial could be limited to other settings in which patients with moderate-to-severe brain injury are more common.Therefore, further TTM duration trials including patients with moderate-to-severe brain injury and sample sizes estimated from more realistic clinical differences between the two duration groups (if 10%, the estimated sample size is approximately 800) in different systems are needed to answer to the research question. Although a universal illness severity model for the TTM indicated OHCA patients is not currently recommended, some early prediction models for the patients have suggested it as a triage tool (21,22). Thus, further studies must use an available and reliable model for developing an enrollment criteria or patient stratification. Recently, some experts have requested more sophisticated trial designs for future clinical trials to overcome the limitations due to the diversity of the patients with post-cardiac arrest syndrome and the complexity of post-cardiac arrest care (23,24). In his editorial, Dr. Callaway suggested the necessity of dose-finding trials using appropriate targets or monitors to guide the titration of post-cardiac arrest care to individual responses rather than optimum fixed-dose interventions (23). Recently, individualized and tailored brain resuscitation strategies using various multimodal cerebral monitoring methods have begun to be actively studied in the post-cardiac arrest field (25). Therefore, a trial comparing fixed vs. titrated TTM dose according to the illness or brain injury severity and individual responses to the intervention using multimodal brain monitoring is also expected in the future.

In summary, the trial by Kirkegaard et al. (16) demonstrated the clinical feasibility of 48-hour TTM as an additional target duration for adult OHCA patients. However, it is still inconclusive whether this prolonged duration is more effective than the 24-hour duration recommended in current guidelines and which subgroups benefit more from the intervention. Therefore, additional multicenter clinical trials with more sophisticated designs using various multimodal cerebral monitoring methods are needed.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

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