Abstract
Objective:
Evaluate the relationship between heat generation during rewarming in post-cardiac arrest patients receiving targeted temperature management (TTM) as a surrogate of thermoregulatory ability and clinical outcomes.
Methods:
This is a prospective observational single-centre study conducted at an urban tertiary-care hospital. We included post-cardiac arrest adults who received TTM via surface cooling device between April 2018 and June 2019.
Results:
Patient heat generation was calculated by multiplying the inverse of the average machine water temperature with time to rewarm to 37 °C and standardized in two ways to account for target temperature variation: (1) divided by number of degrees between target temperature and 37 °C, and (2) limited to when patient was rewarmed from 36 °C to 37 °C. The primary outcome was poor neurologic status, defined as Cerebral Performance Category (CPC) score 3–5, and the secondary outcome was 30-day survival. Sixty-six patients were included: 45 (68%) had a CPC-score of 3–5 and 23 (35%) were alive at 30 days. Besides initial rhythm and arrest downtime, baseline characteristics were similar between outcomes. Heat generation was not associated with poor neurological outcome (CPC 3–5: 6.6 [IQR: 6.1, 7.4] versus CPC 1–2: 6.6 [IQR: 5.7, 7.6], p = 0.89) or survival at 30 days (non-survivors: 6.6 [IQR: 6.6, 7.4] vs. survivors: 6.6 [IQR: 5.7, 8.0, p = 0.78]).
Conclusion:
Heat generation during rewarming was not associated with neurologic outcomes. However, there was a relationship between poor neurological outcome and higher median water temperatures. Time to rewarm was prolonged in patients with poor neurological outcome.
Keywords: Heart arrest, Body temperature regulation, Rewarming, Brain injury, Prognosis
Introduction
Sudden cardiac arrest is a highly lethal condition which affects approximately 650,000 adults each year in the United States, of which 350,000 occur outside of the hospital.1 Only around 10–26% survive to hospital discharge1,2 in part due to the high incidence of hypoxia-induced injury to vital organs. Neurological injury is one of the primary reasons for death in those who survive to admission to an intensive care unit after an out-of-hospital cardiac arrest3,4 and, in one study, was the reason for death in over a quarter of in-hospital cardiac arrests.4
Targeted temperature management (TTM), introduced two decades ago as a means to mitigate ischaemia-reperfusion injury after cardiac arrest, is now a standard therapy in comatose patients who have achieved return of spontaneous circulation (ROSC).5 Due to TTM’s neuroprotective effect,6,7 many researchers have hypothesized that quicker time to target temperature following initiation of TTM would yield better outcomes. Prior studies in animals have supported this hypothesis8-10 but studies in humans have provided mixed results.11-13 One potential explanation for the inconclusive findings in humans is the heterogeneity of the patients included in the studies. Some studies may include patients with such severe neurological injury that their ability to thermoregulate is compromised; these patients theoretically would reach target temperature more quickly than those with lesser injury but be less likely to have a good outcome given the extent of their injury. If patients who are unable to benefit from treatment are included, particularly if they are included in different proportions in different studies, this could potentially cause bias and inconsistent results.14,15
Murnin et al.15 quantified a post-arrest patient’s ability to generate heat as a “heat index” (HI), defined as the inverse average water temperature on the surface device during TTM, and found an association between increased HI and improved neurological outcome during the induction phase of TTM. Increased HI in patients with good neurological outcome indicates that the patient needed a lower water temperature from the surface device to stay at target temperature, which could reflect resistance to cooling and ability to generate body heat, both of which could indicate less severe neurologic injury.
Uber et al. found a similar relationship between surface device water temperature, time between induction of TTM and arrival at target temperature, and neurologic outcomes in a recent study.14 Both studies were based on data from the induction phase of TTM, which, especially in out-of-hospital cardiac arrest, can be confounded by variability in the time between return of spontaneous circulation and TTM initiation.
The present prospective cohort study focused on the rewarming phase of TTM in order to reduce variability in the induction phase of TTM (such as in time from ROSC to induction of TTM). We hypothesized that patients with poor neurological outcomes would require more heat from the surface device (represented by a higher device water temperature) and/or a prolonged time to rewarm to normal body temperature. To test this hypothesis, we investigated the relationship between outcomes and the amount of heat, measured as a composite of water temperature and time, required to rewarm a post-cardiac arrest patient during TTM. Secondarily, we also explored the relationship between water temperatures and time to rewarm and outcomes individually to assess the relative contribution of each component.
Methods
Design, setting, and population
This was a prospective observational study of post-cardiac arrest patients treated at Beth Israel Deaconess Medical Centre, an urban tertiary-care centre in Boston, Massachusetts, USA. We included all comatose adult patients (≥18 years of age) with in-hospital or out-of-hospital cardiac arrest who achieved ROSC and underwent TTM. We excluded patients who were passively rewarmed (not rewarmed using a surface device), those rewarmed with assistance from the Bair Hugger Warmer (3M Medical, Saint Paul, Minnesota), those patients for whom a target temperature above 36 °C was selected, and those with an arrest as the result of trauma. We also excluded patients in whom TTM was discontinued prior to protocol completion, those who did not reach their target temperature, those who were never rewarmed to 37 °C (rounded to the nearest 0.1 °C) as documented on the surface cooling device’s downloaded data, those who were following commands shortly after arrest, and those who were transferred to an extracorporeal membrane oxygenation circuit shortly after arrest. We enrolled subjects from April 2018 through June 2019. The study was approved by the local Institutional Review Board prior to data collection.
TTM protocol
According to local protocol, unless there was a contraindication such as profound haemodynamic instability or active haemorrhage, all comatose post-cardiac arrest patients underwent TTM using a surface cooling device (Arctic Sun 5000; Bard Medical, Covington, Georgia). The patient’s temperature was monitored continuously by at least two sources (rectal, oesophageal, and/or bladder temperature probe) connected to the surface device. Per protocol, the target temperature was set between 32 °C and 36 °C at the discretion of the treating physician. Continuous monitoring by electroencephalogram was performed for each patient during TTM. Patients were maintained at their target temperature for 24 h, followed by active rewarming at a rate of 0.25 °C per hour to normothermia (37 °C). Treatment of shivering involved the use of sedation (propofol, midazolam, or fentanyl) and refractory shivering was treated using administration of neuromuscular blocking agents (vecuronium, rocuronium, or cisatracurium). Five patients received continuous neuromuscular blockade for 24 h as a result of being enrolled in a randomized interventional clinical trial (NCT02260258). For patients in that trial, neuromuscular blockade was initiated prior to the target temperature maintenance phase.
Data collection
Serial data on body, water, and target temperatures were collected by the surface cooling device and logged every minute. After the patient had completed the TTM protocol and was no longer using the surface device, the de-identified data were downloaded to a flash drive. These data were matched to a post-arrest patient via an internal cardiac arrest screening log using the date and time of the cardiac arrest and confirmed via electronic medical records. The patient’s demographics, cardiac arrest information, and outcomes were collected according to Utstein criteria16 by a trained research assistant.
Definitions and outcomes
Time to rewarming (Trewarm) was defined as minutes from initiation of the rewarming phase to the first time the patient’s temperature reached 37 °C (rounded to one decimal) on the surface device. In cases where target temperature changed during the maintenance phase, the most frequently used target temperature was used as the study target temperature. To ensure data quality, we excluded any temperature <30 °C and those that had a difference >1 °C in two consecutive minutes prior to analysis, which we a priori determined to be physiologically implausible.
Patient heat generation was calculated as the inverse of the average machine water temperature × Trewarm. Our primary clinical endpoint was neurologic status at hospital discharge. This was measured by Cerebral Performance Category (CPC) score, where CPC of 1 represents no to mild neurological disability, 2 represents moderate disability, 3 represents an inability to independently perform activities of daily living, 4 represents coma/vegetative state, and 5 is death.17 A CPC score of 1 or 2 was defined as a good neurological outcome, whereas a score of 3 to 5 was considered a poor neurological outcome. Our secondary endpoint was survival at 30 days post-arrest.18
Statistical analysis
Categorical data were presented as counts with relative frequencies. Continuous data were presented as medians with first and third quartiles due to non-normal distribution of data. Univariate analyses were performed using Fisher’s exact test for categorical data and Wilcoxon rank-sum tests for continuous variables. All analyses were two sided with a significance level of p-value <0.05. Statistical analyses were conducted using Stata, Version 14.2 (StataCorp LP, College Station, TX).
A power calculation performed prior to data collection used a two-sample t-test with an alpha of 0.05 to determine a sample size of 65 patients to achieve 80% power, assuming that approximately one third of patients would have a good neurological outcome and two-thirds would have a poor neurological outcome with pilot data used to determine hypothesized means.
In order to standardize heat generation between patients with different target temperatures, the total heat required to bring the patient to 37 °C from target temperature was divided by the difference between the target temperature and 37 °C. Since this calculation assumes that the amount of heat it takes to rewarm a patient 1 °C is independent of the patient’s starting temperature, we performed a sensitivity analysis restricting our measure of heat generation only to the period in which the patient’s temperature increased from 36 °C to 37 °C during rewarming. We additionally performed a post hoc analysis using the outcome of post-cardiac arrest brain death, as determined by the clinical team in accordance with published standards.19
Results
Patient characteristics
During the study period, 122 post-cardiac arrest patients received TTM; 66 met the inclusion and did not meet the exclusion criteria for this study and were included (see Fig. 1). Of the 66 included patients, 21 (32%) had a good neurological outcome at hospital discharge and 23 (35%) were alive at 30 days. Except for initial rhythm and arrest downtime, baseline characteristics were similar between patients with good and poor neurological outcome (see Table 1).
Fig. 1. TTM denotes targeted temperature management, AS denotes Arctic Sun, ROSC denotes Return of Spontaneous Circulation, ECMO denotes Extracorporeal membrane oxygenation circuit.
Flow-chart of cardiac arrest patients admitted for post-cardiac care during April 2018–June 2019.
Table 1.
Patients characteristics dichotomized into good and poor neurological outcome.
| Baseline characteristics | Total n=66 | CPC 1–2 n = 21 | CPC 3–5 n = 45 | p-Value |
|---|---|---|---|---|
| Age, yr, median (IQR) | 69.5 (58, 79) | 65 (57, 75) | 71 (60, 79) | 0.38 |
| Male, n (%) | 46 (70) | 17(81) | 29 (64) | 0.25 |
| Out-of-hospital cardiac arrest (%) | 48 (73) | 14 (67) | 34 (76) | 0.56 |
| Past medical history | ||||
| CAD | 14 (21) | 3(14) | 11 (24) | 0.52 |
| Cancer | 9(14) | 3(14) | 6(13) | >0.99 |
| CHF | 12 (18) | 3(14) | 9 (20) | 0.74 |
| Arrhythmia | 10 (15) | 2(10) | 8(18) | 0.48 |
| Hyperlipidemia | 19 (29) | 6 (29) | 13 (29) | >0.99 |
| Hypertension | 30 (45) | 9 (43) | 21 (47) | 0.80 |
| Thyroid disease | 5(8) | 1 (5) | 4 (9) | >0.99 |
| COPD | 13 (20) | 2(10) | 12 (26) | 0.20 |
| Diabetes | 18 (27) | 7(33) | 11 (24) | 0.56 |
| Liver disease | 3(5) | 0 (0) | 3 (7) | 0.55 |
| Renal disease | 16 (24) | 5 (25) | 11 (24) | >0.99 |
| Stroke | 8(12) | 3(15) | 5(11) | 0.70 |
| Initial shockable rhythm, n (%) | 15 (23) | 9 (45) | 6(13) | 0.01 |
| Arrest duration, min, median (IQR) | 14.5 (8, 22) | 10 (7, 15) | 17.5 (9, 30) | 0.01 |
| Witnessed arrest, n (%) | 52 (79) | 19 (90) | 33 (74) | 0.20 |
| Neuromuscular blockade use, n (%) | 18 (27) | 8 (40) | 10 (22) | 0.14 |
| Use of sedative, n (%) | 63 (95) | 21 (100) | 42 (93) | 0.55 |
| BMI, kg/m2, median (IQR)a | 28.9 (25.1,33.4) | 28 (25, 32.6) | 29.3 (25.6, 33.4) | 0.85 |
| Target temperature <36 °C, n (%) | 34 (52) | 7 (33) | 27 (60) | 0.06 |
CPC = Cerebral Performance Category, IQR = Interquartile range, CAD = Coronary artery disease, CHF = Chronic heart failure, COPD = Chronic obstructive pulmonary disease, BMI = Body mass index. a Missing data from one patient.
Between April 2018 and June 2019 there were a total of 357 cardiac arrests of which 122 received TTM, but only 66 met the inclusion criteria for this study. a A total of 68 patients did not receive therapeutic hypothermia for unknown reasons, b Two of the patients received additionally assistance by Bair Hugger (3 M Medical, Saint Paul, Minnesota) to achieve normothermia during the rewarming phase, c Discontinuation of TTM include patients who follow commands, expired, or were transferred to ECMO.
Heat generation during rewarming
There was no difference in heat generation during the rewarming phase between patients with poor versus good neurological outcome: unadjusted median 6.6 [IQR: 6.1, 7.4] versus 6.6 [IQR: 5.7, 7.6] respectively, p = 0.89. The result was similar in the sensitivity analysis (see Table 2). Survival at 30 days was not associated with heat generation during the rewarming phase in either the primary or the sensitivity analysis (see Table 2).
Table 2.
Analysis model of neurological outcome and survival at 30 days.
| Unadjusted models, median (IQR) | CPC 1–2 n = 21 | CPC 3–5 n = 45 | p-value | Survivors n = 23 | Non-survivors n = 43 | p-Value |
|---|---|---|---|---|---|---|
| Primary analysis | ||||||
| Heat generated to rewarm 1 °C | 6.6 (5.7, 7.6) | 6.6 (6.1,7.4) | 0.89 | 6.6 (5.7, 8.0) | 6.6 (6.1,7.4) | 0.78 |
| Water tp. rewarm, °C | 34.0 (31.7, 35.0) | 35.0 (33.6, 36.2) | 0.10 | 34.1 (32.4, 36.0) | 35.0 (33.6, 36.2) | 0.23 |
| Sensitivity analysis | ||||||
| Heat generated to change 1 °C | 6.6 (5.3, 7.5) | 6.2 (5.8, 7.1) | 0.64 | 6.6 (5.3, 8.7) | 6.2 (5.6, 7.1) | 0.40 |
| Water tp. rewarm, °C | 34.1 (32.4, 36.4) | 35.8 (34.5, 36.8) | 0.04 | 34.8 (32.5, 36.8) | 35.8 (34.2, 36.8) | 0.14 |
CPC denotes cerebral performance category score. IQR denotes interquartile range, heat generation denotes heat units, tp. denotes temperature. Unadjusted model between good (CPC1-2) and poor (CPC 3–5) neurological outcome (right) and survival at 30 days (right) analyzed in two different models: 1) primary analysis based on all target temperatures 2) sensitivity analysis based on calculation from rewarming a patient from 36 °C to 37 °C.
Median water temperature during rewarming
There was a non-significant trend towards higher median water temperatures during rewarming in patients good versus poor neurological outcome (34.0 °C [IQR: 31.7, 35.0] versus 35.0 °C [IQR: 33.6, 36.2], p = 0.1). The sensitivity analysis, analysing the time period of rewarming between 36 °C and 37 °C, found significantly higher median water temperature for patients with good versus poor neurological outcome (34.1 °C [IQR: 32.4, 36.4] versus 35.8 °C [IQR: 34.5, 36.8], p = 0.04, Fig. 2). Survival at 30 days was not associated with median water temperature during the rewarming phase (see Table 2).
Fig. 2. CPC denotes cerebral performance category score. IQR denotes interquartile range.
The figure illustrates a boxplot of unadjusted median machine water temperature during rewarming from 36 °C to 37 °C between poor (CPC 3–5) and good neurological outcome (CPC 1–2): unadjusted median 35.8 °C [IQR: 34.5, 36.8] versus 34.1 °C [IQR: 32.4, 36.4], respectively, p = 0.04.
Time to rewarm and outcomes
There was a significantly longer rewarming phase among patients with poor neurological outcome compared to those with a good neurological outcome: unadjusted median 431 min [IQR 249, 503] versus 240 min [IQR 199, 434], respectively, p = 0.03. The sensitivity analysis from 36 °C to 37 °C showed no difference in duration of rewarming between the two groups: unadjusted median 223 min [IQR 206, 249] in poor neurological outcome versus 234 min [IQR 198, 262] in good neurological outcome, p = 0.81.
There was a non-significant trend towards longer rewarming in non-survivors at thirty days compared to survivors (unadjusted median 431 min [IQR 238, 505] versus 249 min [IQR 199, 454], p = 0.06). The sensitivity analysis did not show a difference (median 223 min [IQR 200, 249] in non-survivors versus 237 min [IQR 198, 280] in survivors, p = 0.48).
Heat generation in patients with brain death
Eight patients (12%) were declared brain dead. There was no difference in heat generation between those who were declared brain dead compared to those who were not (unadjusted median 6.2 [IQR: 5.5, 6.9] versus 6.7 [IQR: 6.1, 7.6] respectively, p = 0.21). In addition, neither water temperature nor time to rewarming were associated with outcomes. However, patients who were declared brain dead showed non-significant trend towards higher water temperatures and a longer rewarming phase when compared to patients with a good neurological outcome (see Table 3).
Table 3.
Heat generation, water temperature, and time to rewarming by whether the patient met brain death criteria.
| Unadjusted models, median (IQR) | Brain death n = 8 | No brain death n = 58 | p-value | Brain death n = 8 | CPC 1–2 n = 21 | p-Value |
|---|---|---|---|---|---|---|
| Primary analysis | ||||||
| Heat generation to rewarm 1 °C | 6.2 (5.5, 6.9) | 6.7 (6.1,7.6) | 0.21 | 6.2 (5.5, 6.9) | 6.6 (5.7, 7.6) | 0.38 |
| Water tp. rewarm | 35.5 (33.6, 35.8) | 34.6 (32.8, 36.2) | 0.65 | 35.5 (33.6, 35.8) | 34.0 (31.7, 35.0) | 0.33 |
| Time to rewarm, min | 360 (252, 582) | 388 (224, 487) | 0.60 | 360 (252, 582) | 240 (199, 434) | 0.14 |
| Sensitivity analysis | ||||||
| Heat generation to change 1 °C | 5.9 (5.6, 6.8) | 6.5 (5.7, 7.5) | 0.40 | 5.9 (5.6, 6.8) | 6.6 (5.3, 7.5) | 0.41 |
| Water tp. rewarm, °C | 35.8 (35.1,36.1) | 35.3 (33.3, 36.8) | 0.61 | 35.8 (35.1,36.1) | 34.1 (32.4, 36.4) | 0.17 |
| Time to rewarm, min | 214 (197, 242) | 228 (199, 255) | 0.47 | 214 (197, 242) | 234 (198, 262) | 0.57 |
CPC denotes Cerebral Performance Category score, IQR denotes interquartile range, heat generation denotes heat units, tp. denotes temperature. Unadjusted analysis between patients who were declared brain dead and those who were not declared brain dead post-cardiac arrest (right) and post hoc analysis (left) between brain dead and patients with a good neurological outcome. Both comparisons are divided into two models: (1) primary analysis based on all target temperatures and (2) sensitivity analysis based on calculation from rewarming a patient from 36 °C to 37 °C.
Discussion
In this prospective study, we analyzed the relationship between heat generation during the rewarming process and clinical outcomes. We did not find any association between heat generation and clinical outcomes; however, we did find a relationship between neurological outcome at hospital discharge and median water temperature during rewarming from 36 °C to 37 °C. This could indicate that patients with poor neurological outcomes are generating less heat on their own, possibly due to loss of thermoregulatory ability, than those with good neurological outcomes, and therefore require more heat from the surface device. In addition, we found a relationship between neurological outcome and time to rewarm, however this did not hold up in the sensitivity analysis and may be because patients with poor neurological outcome were predominantly cooled to a lower target temperature.
To our knowledge, this is the first study to examine thermoregulatory ability during the rewarming phase of TTM. Even though this study was not able to support the theory regarding heat generation, our findings contribute to the evolving understanding of thermoregulatory ability and the potential of this variable to inform neuroprognostication after cardiac arrest, as suggested by two previous studies.14,15
Murnin et al.15 was the first to quantify post-arrest thermoregulatory ability during TTM using data from a surface cooling device. They found an association between greater heat generation during the time between initiation of TTM and reaching target temperature and improved neurologic function at hospital discharge. According to our hypothesis, patients who have lost the ability to thermoregulate would require less heat to reach target temperature (because they are not generating heat to counter the cooling) and would reach target temperature more quickly, which is what Murnin et al. found. This suggests that the ability to thermoregulate could confound the relationship between time to target temperature and outcomes and may help to explain why the results from previous similar human trials are conflicting.11,13,20-23
Only a few studies had reported the time to attain normothermia in patients with good versus poor clinical outcomes prior to the publication by Murnin et al.13,24,25 Benz-Woerner et al. reported that patients who survived to hospital discharge took less time to rewarm passively than non-survivors in accordance with the theory of thermoregulatory ability.24 They also found that non-survivors presented with spontaneously lower body temperatures. Another study reported no differences in time to rewarm with regard to neurological outcome.13 Similar findings were found in a recent registry-based study from Japan.25 The conflicting results may be influenced by the difference in method of rewarming (passive versus active) and the definition of when a patient is rewarmed. All three studies13,24,25 used different definitions, which makes direct comparisons of the results challenging and emphasizes the importance of using standardized definitions in order to explore the variable of time during rewarming.
This study has several limitations. First, patients were cooled to different target temperatures, which may affect the water temperatures used by the surface device and the time it takes for the patient to rewarm. Please see supplementary Table 1 for additional information on different target temperatures between patients with good and poor neurological outcome. This assumes that the amount of heat ittakes to rewarm a patient 1 °C is independent of the patient’s starting temperature. However, we tried to account for this by performing sensitivity analyses limiting patients to rewarming only between 36 °C to 37 °C. Second, the patients in our study were actively rewarmed targeting a rate at 0.25 °C per hour and time to rewarm between 36 °C to 37 °C was similar in patients with poor and good outcomes. This likely means that heat generation is more dependent on the machine water temperature than time. Third, the majority of patients with a poor outcome were cooled to a target temperature below 36 °C, whereas this was only the case in seven patients with good neurological outcome. This makes interpretation of heat generation challenging, given the contribution of the time to rewarming in that calculation. Fourth, 36 patients (55%) were enrolled in one of three interventional randomized trials (NCT02934555, NCT03450707, NCT02260258) of which we were blinded to the outcome at the time of analysis except for nine patients who were enrolled in an open-label interventional trial involving neuromuscular blockade versus placebo (NCT02260258). Five of the patients received continuous neuromuscular blockade, and there was no difference in outcomes based on randomization. The effect of the interventions (thiamine and coenzyme Q10) in these double-blinded trials on outcomes remains unknown. Fifth, we included patients with both in-hospital and out-of-hospital cardiac arrest. These two groups are generally considered different in terms of arrest aetiology and comorbidities, and may have different post-arrest injuries.3,26 Sixth, other factors that we were not able to account for, such as post-arrest fever, may have affected results.
Conclusion
In conclusion, this study found that heat generation was not associated with clinical outcomes during the rewarming phase of TTM. However, a poor neurological outcome was associated with a higher median water temperature during rewarming from 36 °C to 37 °C. In addition, we also found an association between a poor neurological outcome and a longer rewarming phase although the sensitivity analysis did not confirm this. This study adds to previous evidence regarding thermoregulatory ability and may be an important confounder to consider when designing clinical trials. Further research is warranted to explore the underlying mechanism of this phenomenon.
Supplementary Material
Acknowledgement
We would like to thank Stanley Heydrick Ph.D. for his contribution on the manuscript and the Centre for Resuscitation Science research assistants for their work in data collection including Varun Konanki B. S., Jacob M. Boise B.S., Thomas B. Leith B.S., Deanna Lee B.S., Ying Loo B.S., Garrett Thompson M.P.H., and Lethu Akhona Ntshinga B.S.
Funding
National Heart, Lung, and Blood Institute, USA, 1R01HL136705-01; K24HL127101; Director Ib Henriksens Foundation, Denmark; Danish Women Society, Denmark; Confederation of Danish Industry, Denmark; Torben & Alice Frimoundt Foundation, Denmark; Holger & Ruth Hesse’s Memorial Foundation, Denmark; A.P. Møller Medical Foundation, Denmark.
Footnotes
Conflict of interest statement
Dr. Hoeyer-Nielsen was supported by the Tryg Foundation. Dr. Donnino reported receiving grants from the National Institutes of Health (RO1HL136705 and K24HL127101).
Dr. Grossestreuer received support from Harvard Catalyst ∣ The Harvard Clinical and Translational Science Centre (National Centre for Advancing Translational Sciences, National Institutes of Health Award UL 1TR002541) and financial contributions from Harvard University and its affiliated academic healthcare centres. The remaining authors have disclosed that they do not have any conflicts of interest.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.resuscitation.2021.02.005.
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