Time to intra-arrest therapeutic hypothermia in out-of-hospital cardiac arrest patients and its association with neurologic outcome: a propensity matched sub-analysis of the PRINCESS trial

Severe brain injury remains the primary cause of death in resuscitated cardiac arrest patients, while the strategies currently available to improve neurologic outcome are limited [1‐5]. Therapeutic hypothermia reduces ischemia–reperfusion brain injury after cardiac arrest by a number of mechanisms in experimental models [6]. This is especially true when early intra-arrest hypothermia [i.e., cooling initiated during cardiopulmonary resuscitation (CPR)] is compared to delayed cooling initiated after return of spontaneous circulation (ROSC) [7‐12]. Despite these laboratory findings, the vast majority of clinical studies have assessed the effect of delayed therapeutic hypothermia when cooling has been initiated after hospital arrival, often several hours after the cardiac arrest [13‐15]. The delayed timing of hypothermia in recent clinical studies may not have adequately addressed the underlying pathophysiology of ischemia and reperfusion, and thus, there is a risk that the optimal time window for the greatest effectiveness of hypothermia will be missed [13].

To induce therapeutic hypothermia during CPR is challenging in real-world clinical practice. While rapid infusion with cold intravenous fluids is feasible for most emergency medical services (EMS), this approach has been associated with increased rate of hemodynamic adverse events [16‐18], most likely due to the volume load to the heart and reduction in coronary perfusion pressure [19, 20]. In particular, these adverse events have been observed in patients with initial shockable rhythm (i.e., ventricular fibrillation or pulseless ventricular tachycardia [17].

In the recent PRINCESS trial, 677 bystander-witnessed out-of-hospital cardiac arrest (OHCA) patients were randomized to intra-arrest transnasal evaporative cooling or cooling started after hospital arrival. Transnasal evaporative cooling is a method to induce hypothermia without adding a volume load to the heart, primarily targeting rapid cooling of the brain [21‐23]. In the study, time to reach target core body temperature of < 34°C was significantly shortened in the intra-arrest cooling group. The difference in survival with favorable neurologic outcome, Cerebral Performance Category (CPC) 1–2, was 16.6% vs 13.5% (p = 0.25) in favor of the intra-arrest cooling group. In patients with shockable rhythms, CPC 1–2 survival was 34.8% in the intra-arrest cooling group vs 25.9% in controls (p = 0.11). [24].

Although early intra-arrest therapeutic hypothermia was targeted in the PRINCESS trial, the median time from collapse to start of intra-arrest cooling was 19 min which may have been too long for optimal neurologic outcome. Thus, the fact that about 50% of the patients in the intervention group had intra-arrest cooling initiated later than 20 min from the collapse may have influenced the overall results. The main hypothesis of this study was that the earlier intra-arrest therapeutic hypothermia could be initiated, the better effect on mitigating ischemia and reperfusion injuries and thereby improving neurologic outcome among survivors.

The aim of this secondary analysis of the PRINCESS trial data was to investigate the association between the group of OHCA patients who received earlier initiation (i.e., < 20 min from collapse) of intra-arrest therapeutic hypothermia and survival with favorable neurologic outcome.

Among the 343 patients randomized to intra-arrest cooling in the PRINCESS trial, 156 patients with complete study variables had cooling initiated < 20 min from the arrest. Out of these, propensity score matching (1:1) could be performed in 150 patients with corresponding patients in the control group, and thus, 300 patients were included in the primary analysis (see Fig. 1). Baseline characteristics before and after propensity score matching in patients (all patients and patients with initial shockable and non-shockable rhythm) are presented in Table 1. The time to target temperature (< 34 °C) was significantly shorter in patients receiving intra-arrest cooling (Table 1). The rate of ROSC was similar between groups (STable 1). Additional patient characteristics are presented in STable 1.

In this secondary analysis of the PRINCESS trial where patients were randomized at the scene of the arrest to intra-arrest cooling versus standard ALS and subsequent initiation of systemic cooling at hospital, we assessed a potential association between time to initiate intra-arrest cooling before 20 min from the collapse and survival with favorable neurologic outcome (CPC1-2) at 90 days. There are several potentially important findings of the study. First, the difference observed in favorable neurologic outcome at 90 days was not statistically significant in the whole patient cohort. Second, in the subgroup of patients with initial shockable rhythms, early intra-arrest cooling is associated with improved favorable neurologic outcome, whereas no difference is seen in patients with non-shockable rhythms. Third, there are significant differences in complete neurologic outcome in the whole patient cohort, but with the most apparent differences in patients with initial shockable rhythm. Fourth, intra-arrest transnasal evaporative cooling was not associated with decreased rate of ROSC which has been the case of earlier intra-arrest studies when cooling has been performed with cold fluids. Thus, early, intra-arrest cooling per se does not seem convey hemodynamic side effects if you use a method that does not add volume load to the heart.

Crucial knowledge gaps remain regarding how to attenuate reperfusion brain injury after cardiac arrests. The pathophysiologic mechanisms following ROSC are triggered promptly; in clinical practice, this means prior to hospital arrival. The immediate injuries caused by ischemia will deplete intracellular ATP within minutes inducing several pathophysiologic pathways [6]. Within 15 min of reperfusion, formation of free oxygen radicals and dysfunctional calcium regulation promote subsequent damage to cellular membranes and alterations in cerebral blood flow [6]. Thus, therapeutic strategies to mitigate brain injury in this population may be more effective if established during resuscitation itself or immediately following ROSC.

A key question for clinicians is whether there is a time window for best effectiveness of therapeutic hypothermia in cardiac arrest as suggested in prior experimental studies [8‐10, 12]. The approach to assess the effect of therapeutic hypothermia was different in PRINCESS compared to most previous studies. In the pragmatic TTM trial, there was a four-hour window allowed from ROSC (not collapse) to randomization (not initiation of treatment) [13]. This could be an important methodological issue when trying to reduce the highly time-sensitive ischemic and reperfusion brain injury after cardiac arrest. In this earlier cooling subgroup analysis with bystander-witnessed OHCA, we observed a signal toward a higher rate of favorable neurologic outcome and complete recovery in patients where intra-arrest cooling had been initiated < 20 min from collapse compared to standard care where cooling was initiated after hospital arrival. Although 20 min must be seen as an explorative time stamp, the results suggest that an earlier initiation of intra-arrest cooling in refractory cardiac arrest may improve the chance to influence neurologic outcome compared to cooling started after hospital arrival. The time to initiate cooling is different than the time required to reach the target temperature. In this population, the initiation of intra-arrest cooling reduced the time to reach target temperature significantly. We believe that this strategy of fast cooling is important even if the time interval to reach target temperature may vary for several reasons and could be confounded by the severity of the brain injury. Thus, patients with more extensive brain injuries may be easier to cool rapidly because they no longer have the compensatory physiology to defend core body temperature [27, 28].

Consistent with prior cardiac arrest trials, the vast majority of survivors in the current investigation were within the patient subgroup with initial shockable rhythms. It is also in this subgroup that a potential benefit in neurologic outcomes with an earlier cooling initiation was observed. In a recent study [29] of OHCA and in-hospital cardiac arrest patients with non-shockable rhythms, a benefit of therapeutic hypothermia initiated during intensive care was seen also in these patients compared to normothermia. We did not see any signal toward improved outcome in these patients. However, this population with non-shockable rhythms in the PRINCESS trial was randomized prior to ROSC which make direct comparisons difficult. When patients with non-shockable rhythms, especially asystole, are included in randomized cardiac arrest trials, the potential benefit of a specific intervention may be masked due to the extreme poor chances of survival in that specific group [30]. Based on our data, further studies of intra-arrest cooling should focus primarily on the patients with initial shockable rhythms.

While many prior studies have grouped CPC 1 and 2 outcomes, more granular analysis suggests potential differences in outcome in the current cohort. When evaluating CPC scores in the PRINCESS trial itself, there was a post hoc finding with a higher proportion of patients with CPC 1 in the intra-arrest cooling group among patients with initial shockable rhythms. The current sub-analysis suggests that this potential benefit is more pronounced in the patients that receive start of intra-arrest cooling within 20 min from collapse. Future studies should preferably include more subtle neurological and cognitive end points such as the modified Rankin Scale and Glasgow Coma Outcome Scale extended [31].

In the whole study population, intra-arrest cooling initiated < 20 min from collapse compared to cooling initiated at hospital was not associated with improved favorable neurologic outcome. In the subgroup with shockable rhythms, early cooling was associated with improved favorable outcome and complete recovery. No outcome differences were seen in patients with initial non-shockable rhythms. The findings should be seen as hypothesis generating and warranting future intra-arrest cooling studies.