Optimal Timing of Targeted Temperature Management for Post-Cardiac Arrest Syndrome: Is Sooner Better?

Targeted temperature management (TTM) is often considered to improve post-cardiac arrest patients’ outcomes. However, the optimal timing to initiate cooling remained uncertain. This retrospective analysis enrolled all non-traumatic post-cardiac arrest adult patients with either out-of-hospital cardiac arrest (OHCA) or in-hospital cardiac arrest (IHCA) who received TTM from July 2015 to July 2021 at our hospital. The values of time delay before TTM and time to target temperature were divided into three periods according to optimal cut-off values identified using receiver operating characteristic curve analysis. A total of 177 patients were enrolled. A shorter time delay before TTM (pre-induction time) was associated with a lower survival chance at 28 days (32.00% vs. 54.00%, p = 0.0279). Patients with a longer cooling induction time (>440 minis) had better neurological outcomes (1.58% vs. 1.05%; p = 0.001) and survival at 28 days (58.06% vs. 29.25%; p = 0.006). After COX regression analysis, the influence of pre-induction time on survival became insignificant, but patients who cooled slowest still had a better chance of survival at 28 days. In conclusion, a shorter delay before TTM was not associated with better clinical outcomes. However, patients who took longer to reach the target temperature had better hospital survival and neurological outcomes than those who were cooled more rapidly. A further prospective study was warranted to evaluate the appropriate time window of TTM.


Introduction
Targeted temperature management (TTM) has been the standard approach to improve postcardiac arrest outcomes for years [1,2]. However, several issues have yet to be clarified, including the optimal time to initiate cooling and the speed of reaching the target temperature. Almost all animal studies suggest that early interventions can improve survival and neurological outcomes [3]. However, human studies have shown that "the sooner the better" is not always the correct approach, especially if TTM is initiated during the arrest [4,5]. In addition, whether a shorter time delay between the return of spontaneous circulation (ROSC) and initiation of TTM is preferable also remains controversial, although most studies suggest that a shorter delay may be better [6][7][8][9]. In addition, some studies have reported that a faster cooling rate during TTM may be beneficial [7][8][9][10] for postcardiac arrest patients because of theoretical reasons [11] and variable cooling device efficiency [12]. However, other 2 of 14 studies [13][14][15] have reported opposite results. Furthermore, some studies have shown that maintenance of afebrile instead of aggressive cooling does not lead to worse outcomes in these patients [16,17]. Our institution has adopted TTM for a number of years and previously reported the outcomes of TTM for out-of-hospital cardiac arrest (OHCA) [18] and in-hospital cardiac arrest (IHCA) [19] patients. The aim of this study was to analyze whether the timing and rate of TTM would modify the outcome of these patient groups.

Study Design
In this retrospective analysis, we enrolled all nontraumatic adult ROSC patients with either OHCA or IHCA who received TTM at Mackay Memorial Hospital (MMH) Taipei and Tamsui branches, Taiwan, from July 2015 to July 2021. The exclusion criteria were as follows: (1) those aged < 18 years; (2) those who died within 24 h after ROSC; (3) those who suffered from traumatic cardiac arrest; and (4) those who didn't receive TTM. The study plan was reviewed and approved by the Institutional Review Board of MMH (approval reference No. 21MMHIS012e). The requirement for informed consent was waived because of the retrospective nature of the study.

Protocol Description
At MMH, every comatose ROSC patient admitted to the intensive care unit is considered a potential candidate for TTM. Permission for TTM is obtained from the patient's next of kin. TTM was performed in accordance with the standard protocol at MMH (Supplement S1). Briefly, TTM was initiated with 4 • C Ringer's lactate solution (30 mL/kg) given through an intravenous route, followed by wrapping the patient's body in a surface cooling blanket (Arctic Sun Model 2000/5000, Medivance, Louisville, CO, USA) for 24 or 48 h. The targeted temperature is set at 33 • C. After the preset hypothermia phase was completed, the patients received controlled rewarming at a rate of 0.15 • C/h until 36.5 • C was reached. Active temperature management with medications to prevent fever (>37.2 • C) is allowed for another 24 h. Magnesium sulfate is routinely given to prevent shivering during the hypothermia phase. Propofol, fentanyl, and cisatracurium can be given according to the preference of the physician in charge.

Data Collection and Outcome Assessment
Data includes the patient's age, sex, arrest type (IHCA or OHCA), whether or not the arrest was witnessed, presence of bystander chest compression, rhythm type when the emergency medical service staff arrived, epinephrine administration before ROSC, defibrillation, first available body temperature during cardiac arrest, and body temperature at the time of initiating cooling and end of cooling. The timing of the entire TTM course was recorded, including no-flow time (the time from cardiac arrest to initiation of cardiopulmonary resuscitation), low-flow time (the time from CPR to ROSC), pre-induction time (time from ROSC to initiation of cooling), and induction time (time from initiation of cooling to the achievement of the target temperature) ( Figure 1A).
Two clinical outcomes were used in this study, namely, 28-day survival and neurological outcomes. Associations of induction time and rate of cooling with the two clinical outcomes were the secondary outcomes. Neurological outcomes were evaluated using the Cerebral Performance Category (CPC) scale as follows: category 1, good cerebral performance; category 2, moderate cerebral disability; category 3, severe cerebral disability; category 4, coma or vegetative state; and category 5, death/brain death. A CPC score of 3-5 was defined as a poor neurological outcome [20,21]. Two clinical outcomes were used in this study, namely, 28-day survival and neurological outcomes. Associations of induction time and rate of cooling with the two clinical outcomes were the secondary outcomes. Neurological outcomes were evaluated using the Cerebral Performance Category (CPC) scale as follows: category 1, good cerebral performance; category 2, moderate cerebral disability; category 3, severe cerebral disability; category 4, coma or vegetative state; and category 5, death/brain death. A CPC score of 3-5 was defined as a poor neurological outcome. [20,21]

Statistical Analysis
Differences in baseline demographics between the survivors and non-survivors were analyzed using Pearson's chi-squared test for categorical variables (presented as n (%)) and the t-test for continuous variables (presented as the mean ± SD). The Mann-Whitney U test was used for nonnormally distributed variables (presented as the median (interquartile range)). The pre-induction time and induction time were divided into three periods according to two optimal cut-off values identified using receiver operating characteristic (ROC) curve analysis. [22][23][24] The rate of cooling was calculated by dividing the

Statistical Analysis
Differences in baseline demographics between the survivors and non-survivors were analyzed using Pearson's chi-squared test for categorical variables (presented as n (%)) and the t-test for continuous variables (presented as the mean ± SD). The Mann-Whitney U test was used for nonnormally distributed variables (presented as the median (interquartile range)). The pre-induction time and induction time were divided into three periods according to two optimal cut-off values identified using receiver operating characteristic (ROC) curve analysis [22][23][24]. The rate of cooling was calculated by dividing the difference between the temperature at ROSC and 33 • C by the time interval. The log-rank test was used for time-to-event analysis to compare differences in the survival probability between three groups of pre-induction and induction time. We also performed univariant and multivariant Cox regression models. All variables with p < 0.05 in the univariate Cox regression model were considered confounders and were included in the multivariant Cox regression model. All statistical tests were two-tailed, and p-values < 0.05 were considered statistically significant. Data extraction and processing were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).

Discussion
In this retrospective study of postcardiac arrest patients, we found that a faster drop in body temperature during TTM was associated with worse outcomes, whereas a shorter resuscitation time, slower cooling rate and lower APACHE II score at admission were associated with better hospital survival. In contrast to previous reports, we found that a shorter time delay before TTM and a faster rate of achieving the target temperature after TTM did not lead to better clinical outcomes. Moreover, we found that a slower initiation of TTM and a slower rate of reaching the temperature goal were associated with better outcomes, at least until the 28th day after cardiac arrest.
Timing is a critical part of resuscitation, and delays in treatment, including patient delay and prehospital system delay, have been shown to be major determinants of the outcomes of ST-elevation myocardial infarction patients [25]. Reducing the time delay to primary percutaneous coronary interventions among patients with ST-elevation myocardial infarction, even by <60 to 90 min, has been shown to significantly improve outcomes [26]. TTM has been widely used for postcardiac arrest patients to improve hospital survival and neurological outcomes in the last decade [1,2]. However, the optimal timing remains uncertain. The mechanisms of hypothermia can mitigate brain injury at multiple levels, including the ability to reduce cerebral metabolism by 6-10% for each 1 • C reduction in body temperature [11,27]. This is thought to be the main protective effect since oxygen deprivation, and the accumulation of excitatory neurotransmitters play a significant role in cell death after cerebral ischemia. Another important effect is the suppression of inflammatory responses and associated free radical production during ischemia and repercussion injury [11]. Some experimental studies have suggested that hypothermia can mitigate the activation of apoptosis [28,29]. White et al. reported increased levels of arterial neuroprotection D1 in animal cardiac arrest models after 3 h of resuscitation, [30] and the level was three times higher in hypothermic animals. Accordingly, the early implementation of TTM after cardiac arrest, and even during arrest, has been shown to be beneficial, at least in animal studies [9,31]. Sendelbach et al. reported that the odds of a poor neurological outcome increased with each 5-min delay in initiating TTM (OR = 1.06, 95% CI 1.02-1.10) [9]. In a post hoc analysis of nontraumatic OHCA patients, Stanger et al. found better neurological outcomes in the early door-to-TTM group (<122 min, 48% and 38%, respectively) [32]. However, early TTM in human trials has not always shown positive results. The PRINCESS trial reported that intra-arrest cooling initiated <20 min from the collapse was not associated with better neurological outcomes compared to cooling initiated at the hospital [33]. Moreover, Bernard et al. found that patients with prehospital cold fluid infusion tended to have worse outcomes [6]. In the present study, we found that the delayed initiation of TTM was associated with a higher short-term survival rate than a shorter pre-induction time, but there were no significant differences in good/poor neurological outcomes between the groups. Further studies are warranted to investigate these conflicting results.
Some animal studies have suggested that a pre-induction delay did not significantly influence the outcomes of TTM [34,35]. Apoptosis can develop later during the postperfusion phase and continue for at least 48 h, [29,36] which suggests a wide window of opportunity to mitigate this pathway. Lawrence et al. reported that the neuroprotective effect of hypothermia is both optimal and equivalent when initiated between 1 and 8 h after reoxygenation [37]. Che et al. also reported that a delay of up to 4 h did not significantly influence outcomes [38]. In a human study, Perman et al. reported no significant difference in pre-induction time between patients with good versus poor outcomes [14]. Our results showed that patients with a shorter pre-induction delay (<276 min) had a nearly two-fold higher risk of death than those with a delay > 390 min. This suggests that while hypothermia has a wide spectrum of pathophysiologic protective mechanisms, there may also be deleterious effects. Singh et al. reported that hypothermia might protect against conditions that generate reactive oxygen and nitrogen species and that this may decrease the activity of cellular antioxidant defenses to attenuate the benefits of TTM [39]. A previous observational study also suggested that if TTM was started within 2 h of cardiac arrest, the mortality rate was higher than if TTM was started later [40]. Since TTM may have limited benefits after 12 h due to irreversible damage to nerve cells, [41] there may be an optimal time frame to initiate TTM after ROSC. Our results suggest this possibility; however, further investigations are needed for verification.
Several studies have suggested that the clinical benefits of TTM in postcardiac arrest patients depended on whether the temperature target was achieved rapidly [7][8][9][10]. However, other studies have reported opposite results. In a retrospective study, Haugk et al. found that cooling to 34 • C or below was slower (median time: 209 min) in patients with favorable neurological outcomes than in those with unfavorable outcomes (158 min) [13]. In addition, Perman et al. reported that patients with a longer induction time (>300 min to reach 33 • C) were associated with better neurological outcomes than those with an induction time of <120 min [14]. Lin et al. also observed that a slower rate of cooling was associated with improved neurological outcomes (OR, 0.73 • C/h) and survival [15]. Our study results are consistent with these findings, and patients with a longer induction time, especially >440 min, had a better survival rate (AOR, 3.10) than those with an induction time < 260 min on the 28th day after cardiac arrest. The survival benefit of this group of patients remained significant until 180 days after cardiac arrest. Moreover, they were more likely to have good neurological outcomes compared with those who were cooled rapidly. The cooling rate was 0.2 • C/h in this group, almost half that of the rate in the <260 min group (0.48 • C/h). One possible explanation may be compromised thermoregulation after cerebral insult [13,14,42,43]. Among our patients, those who were cooled more rapidly had significantly higher APACHE II scores than those who were cooled more slowly. These characteristics are consistent with the aforementioned hypothesis. Besides, Benz-Woerner et al. found that patients with poor neurological outcomes had a lower core temperature upon ROSC [44]. Our results are in line with those of Lin et al. [15], and the patients with good neurological outcomes had a higher core temperature upon ROSC. An intact thermoregulatory center allows the body to exhibit a normal response to temperature differences. This may explain why shivering [45] and bradycardia [46] are more common in patients with improved neurological outcomes during TTM. In summary, our patients with good neurological outcomes were younger, had a lower APACHE II score, higher temperature upon ROSC, and shorter no/low flow time, which are in line with the findings of Perman et al. [14]. Thus, we hypothesize that a TTM target at <34 • C might be a 'stress test' to recognize the integrity of the patient's thermoregulatory center and that the cerebral insult severity after cardiac arrest itself is the main prognostic factor. This speculation was in line with the finding of the TTM-2 trial [17]. In the sub-group analysis of the TTM-2 trial, [47] Simpson et al. divided included sites into six groups according to the speed of hypothermia, which was surrogated as the average temperature at four hours from ROSC in the hypothermia group. Of the patients enrolled in the fastest sites, whose average temperature was ≤34 • C at four hours, 49% of the patients died at six months in the hypothermia group compared with 46% in the normothermia group. Compared to the patients enrolled in the slowest sites, whose average temperature was 35.3, the mortality rate was 45% in the hypothermia group and 56% in the normothermia group. The patients with faster speed to target temperature didn't show better survival compared to those with slower speed. Our study also found that the non-survivors had a faster rate of cooling compared to survivors (0.42 ± 0.28 vs. 0.33 ± 0.18 • C/h, p = 0.0097). However, there are inherent limitations because both studies were post-hoc analyses or retrospective, and the number may be too small to be underpowered. Further investigations are warranted to investigate whether a lower temperature target in TTM is necessary for postcardiac arrest patients.
This study has some limitations. First, it is a retrospective study, and thus missing data are inevitable. It was especially difficult to estimate no/low flow time as we did not have access to the emergency medical service database. Second, the average pre-induction time delay in our patient groups was approximately 6 h, even in the IHCA group. The most common causes of delay were emergency room-hospital ward-ICU preparation for patient transfer, surrogate availability to make decisions, and overcrowding. However, our institution has long-term experience in TTM and has used the same protocol for a decade [18,19]. The performance was not inferior to other similar studies of the same period. We were surprised to find that delays in pre-induction and induction times of TTM may be associated with better survival, albeit short-term. However, most experts believe that "the sooner the better", [41,[48][49][50] the temperature target, devices used for TTM, patient arrest location, no/low flow time limits and exclusion criteria have varied between studies [1,2,4,[6][7][8][9][10][11]14,15,18,19,22,32,33,40,51,52]. However, the length of the delay of pre-induction time becomes statistically insignificant after multiple Cox regression analysis. There might be a 'time window' in the timeline of patient management, which suggests that an adequate delay may be able to attenuate the side effects of early cooling without compromising the protective effects of hypothermia. But too much delay can be detrimental again. An international registration network to record timing issues with TTM would help to elucidate this issue. Third, 61 (36.5%) of our patients received 48 h instead of 24 h TTM which may interfere with clinical outcomes [53][54][55]. However, our results were consistent with the results of the latest randomized clinical trial; [56] target temperature management for 48 h did not significantly improve clinical outcomes compared with those received TTM for 24 h.

Conclusions
Among the enrolled patients with OHCA/IHCA who received TTM in this retrospective study with a limited sample size, we found that a shorter pre-induction delay was not associated with improved survival outcomes. Patient outcomes were primarily determined by disease severity and no/low flow time. The patients with a longer time delay before TTM initiation had a higher hospital survival rate, but their neurological outcomes were not different from those with a shorter delay. Patients with a longer induction time had a higher hospital survival rate and better neurological outcomes. However, our results were not suggesting clinicians delay or abandon TTM, and further prospective study was warranted to evaluate the appropriate time window of TTM.

Institutional Review Board Statement:
This study was carried out in accordance with the principles of the Declaration of Helsinki and approved by the Institutional Review Board of Mackay Memorial Hospital (approval reference No. 21MMHIS012e). The IRB of Mackay Memorial Hospital Foundation waived the need to obtain consent for participation because of the retrospective nature of this study. All procedures followed were in accordance with the ethical standards of the IRB of Mackay Memorial Hospital Foundation and with the Helsinki Declaration. All personal information was encrypted in a database, and patient data were anonymized. No identifiable information, such as personal ID or birthday, was reported in this manuscript. There was no breach of privacy.
Informed Consent Statement: Patient consent was waived due to the retrospective nature of the study.

Data Availability Statement:
The data sets analyzed during the current study are available from the corresponding author upon reasonable request.