Abstract
Aim:
Although recent out-of-hospital cardiac arrest (CA) trials found no benefits of hypothermia versus normothermia targeted temperature management, preclinical models suggest earlier timing of hypothermia improves neuroprotective efficacy. This study investigated whether shorter time to goal temperature was associated with better one-year outcomes in the Therapeutic Hypothermia After Pediatric Cardiac Arrest Out-of-Hospital Trial
Methods:
Patients were classified by tertiles of time to attain assigned goal temperature range (32–34°C or 36–37.5°C) following ROSC. Outcomes in the first tertile (“earlier”) Group 1 were compared with second and third tertiles (“later”) Group 2. Separate analyses were, additionally, completed for hypothermia and normothermia intervention groups. Three one-year outcomes were examined: survival; Vineland Adaptive Behavior Scale (VABS-II) score ≥70; and decrease in VABS-II ≤15 points from baseline.
Results:
In the entire cohort (n=281), median time from ROSC to goal temperature was 7.4 [IQR 6.2–9.7] hours: Group 1, 5.8 [IQR 5.2, 6.2] and Group 2, 8.8 [IQR 7.4, 10.4] hours. Outcomes did not differ between these groups. For hypothermia subgroup, survival was lower in Group 1 than 2, [10/49(20%) versus 47/99(47%), p<0.002], with a trend towards fewer with VABS-II scores ≥70 and change in VABS-II ≤15 points (p=0.07–0.08). For normothermia subgroup, there was a trend toward higher survival in Group 1 than 2 [18/42(43%) versus 21/83(25%), p=0.065], but no differences in VABS-II-related measures. In multivariable logistic regression models, no difference in earlier and later groups or temperature intervention was observed.
Conclusion:
We found no evidence that earlier time to goal temperature was associated with better outcomes.
Introduction
In animal models of CA, therapeutic hypothermia (TH) improves survival and functional outcome when administered within 1 hour of return of spontaneous circulation (ROSC)[1]. In a rat model, Jia et al showed that the efficacy of TH was optimal if treatment was implemented immediately after ROSC, rather than after a one-hour delay[2]. A subsequent study found that in a rat model, delayed onset of TH (33°C ± 1°C) up to 4 hours after ROSC, coupled with sustained temperature interventions for 24 or 48 hours, improved survival and rates of good neurological outcome, compared with normothermia controls; these benefits were lost if TH onset was delayed to 8 hours after ROSC[3]. These pre-clinical studies illustrated that timing to begin hypothermia and to attain target temperature, as well as duration of TH, are potent variables that influence efficacy of this intervention.
One of the initial clinical trials that evaluated adults who were comatose after ROSC and were treated with hypothermia reported benefit, despite the long time interval (median 8 hours) required to achieve the goal temperature and inclusion of 14% of cases who never achieved the goal temperature range[4]. Another trial in adults, reported that early initiation of cooling in the field versus in-hospital resulted in shorter time to goal temperature range of 34 C [4.2 vs 5.5 hours] but found no survival or neurological outcome benefit[5]. In contrast, shorter time to target temperature has been reported in an adult observational registry study with a cut off of less than 300 minutes to be associated with worse outcome[6]. In humans resuscitated after CA, the timing for onset and duration for targeted temperature management to attain optimal outcomes are unknown.
The Therapeutic Hypothermia After Pediatric Cardiac Arrest Out-of-Hospital Trial (THAPCA-OH) was the first large multicenter trial that was completed in children who remained comatose after ROSC; the study examined 12 month outcomes with two different target temperatures to prevent fever, TH (32–340C) and TN (36.0–37.50C)[7]. Analysis of THAPCA-OH data revealed no statistically significant differences in mortality or neurobehavioral outcomes between the two target temperature management interventions; median time interval from ROSC to goal temperature range was approximately 7.4 hours, IQR 6.2–9.7 hours.
The current study is an exploratory analysis to compare one year outcomes in patients enrolled in THAPCA-OH who achieved target temperature range earlier versus later in the initial intervention period. We examined one year outcomes for the following groups: 1) earlier versus later time to achieve goal temperature for all subjects; 2) earlier versus later times to achieve goal temperature separately for TH and TN cohorts; 3) earlier time to achieve goal temperature, comparing TH and TN groups, and later time to achieve goal temperatures comparing TH and TN groups. We hypothesized that 1) earlier times to goal temperature would be associated with better outcomes than later time to goal temperature and 2) temperature intervention group assignment (TH or TN) would not be associated with outcome.
Methods
Study Design
The THAPCA-OH trial was supported by the National Heart Lung and Blood Institute (NHLBI) and results were published in 2015[7]. The rationale, study design, outcome selection process, protocol summary, and 12-month pilot vanguard phase were previously described[8–10]. Briefly, this was a randomized clinical trial conducted in pediatric intensive-care units at 38 children’s hospitals in the United States and Canada.
Authors (VN, SS, FM) defined, by consensus, two levels of time to goal temperature from ROSC to investigate. (1) Group 1 was defined as the earlier 33% (first tertile) of cases achieving the goal temperature range for each of the TH and TN interventions. (2) Group 2 was defined as the remaining later 67% of cases achieving the goal temperature range for each intervention.
Patient Population
The study population has been previously described in detail[7]. Briefly, children older than 48 hours and less than 18 years who sustained CA, required chest compressions for at least two minutes, and remained dependent on mechanical ventilation after ROSC, met the inclusion criteria. Subjects who never reached the goal temperature range were excluded from this analysis. A full listing of exclusion criteria is provided in the Supplementary Appendix of the original trial report[7].
Randomization and Intervention
Eligible subjects were randomized to either TH or TN in a 1:1 ratio. Targeted temperature management was actively maintained for 120 hours in both groups using the Blanketrol III. Children assigned to TH were maintained at 33°C (range 32–34°C) core temperature for 48 hours. They were then rewarmed over 16 hours or longer to a target temperature range of 36.8°C (range 36–37.5°C); this temperature was actively maintained throughout the remainder of the 120-hour intervention period. Children randomized to TN received identical care except core temperature was actively maintained at 36.8°C (range 36–37.5°C) for 120 hours. Additional details of targeted temperature management are described in the original trial publication[7].
Outcomes
Two outcomes from the original trial and one modified outcome were examined. The primary outcome in the THAPCA-OH trial was survival with favorable neurobehavioral outcome at twelve-month follow-up, defined as an age-corrected standard score of ≥70 on the VABS-II composite score[11]. The VABS-II has an age-corrected mean of 100 and a standard deviation of 15; higher scores indicate better performance. The VABS-II data were collected centrally (Kennedy-Krieger Institute, Baltimore, MD) via telephone by a trained interviewer blinded to treatment assignment. As pre-specified in the trial protocol, enrolled children whose reported pre-arrest VABS-II scores were <70 (based on data from formal caregiver report at each site within 24 hours of randomization) were not included in the primary efficacy analysis. Subjects with no baseline VABS-II available were considered eligible for the primary analysis if the baseline Pediatric Overall Performance Category (POPC) and Pediatric Cerebral Performance Category (PCPC) scores were in the normal or mild disability category[10,12,13]. Scores for both scales range from 1 to 6, with lower scores representing less disability; patients with scores of either 1 or 2 on both scales were eligible for the primary analysis.
Secondary outcomes were survival twelve months after CA and VABS-II score at 12 months reduced no more than 15 points from baseline (measured as the difference from pre-arrest baseline to twelve-month measurement on the VABS-II). For the latter, deceased patients and those with the lowest possible VABS-II score were assigned the worst possible outcomes, regardless of baseline function. We dichotomized the change in VABS-II score measured at one year as ≤15-point decline (good outcome) or >15-point decline from baseline (poor outcome).
Statistical Analyses
The analysis for the primary outcome in this study was performed using a pre-specified modified intention-to-treat approach, excluding children with pre-arrest neurobehavioral impairment (VABS-II <70) and other criteria described in the methods above. Secondary efficacy outcomes were analyzed among all children. The primary outcome, twelve-month survival and twelve-month change in VABS-II ≤15 points were compared between time-to-goal temperature range groups using Fisher’s exact test. An alpha level of 0.05 was considered significant with two-sided tests used in all instances. No adjustment for multiple p-values was performed in this exploratory study. Logistic regression models were used to examine relationships between the three defined 12-month outcomes adjusting for other variables associated with outcome. Independent variables having a univariate p-value < 0.10 were considered in multivariable models. Stepwise selection was used to select the final models; assigned treatment group and time to goal temperature range group were controlled for and kept in the final models while only other characteristics with a p value less than 0.05 were retained. All analyses were performed using SAS software, version 9.4 (SAS Institute, Inc., Cary, NC).
Results
As originally reported, a total of 295 cases were randomized in the THAPCA-OH trial with 155 assigned to TH and 140 assigned to TN[7]. Fourteen patients (4.7%), four in the TH group and ten in the TN group, were excluded from the current study because they did not reach the goal temperature range. Two hundred and eighty-one (281) patients were included in this analysis. For the entire cohort, the medians and interquartile ranges of time for TH cases were 7.6 (6.2, 9.6) hours; for TN cases were 7.4 (6.2, 9.8) hours; and all cases were 7.4 (6.2, 9.7) hours. Overall, Group 1 patients attained their target temperature at a median time of 5.8 hours (IQR 5.2, 6.2) after ROSC; for the TH intervention and TN intervention subgroups the median with IQR values were 5.8 (5.2, 6.2) and 5.8 (5.0, 6.3) hours respectively. In contrast, Group 2 patients achieved their target temperature range at a median of 8.8 hours (IQR 7.4, 10.4) after ROSC; for the TH and TN intervention subgroups the corresponding median with IQR values were 8.8 (7.6, 10.0) and 8.6 (7.4, 11.4) hours respectfully. See Figure 1 for time from ROSC to the goal temperature range for all patients and the two intervention subgroups.
Figure 1. Time from ROSC to goal temperature range in THAPCA out of hospital trial.
First and second tertiles of the time in hours from ROSC to goal temperature range, by treatment group, were Hypothermia 6.7, 8.8; Normothermia 6.5, 8.6; Overall 6.6, 8.8.
Overall, patients in the earlier compared to later time to goal temperature range (Group 1 versus Group 2) were similar by age, gender, aetiology of arrest, first rhythm asystole, estimated duration of chest compressions, and number of adrenaline (epinephrine) doses. Patients in Group 1 (earlier time) had significantly lower body weight, were more likely to have a study hospital as first hospital, had higher first lactate reported, and had lower temperature at the time of onset of the study intervention (See Table 1). Among patients randomized to TH, the following characteristics differed between the earlier (Group 1) compared to later (Group 2) time to goal temperature groups: younger age, lower body weight, more likely to have apparent life threatening event/sudden infant death syndrome (ALTE/SIDS) and less likely to have drowning aetiology, longer estimated duration of chest compressions, more frequent requirement for chest compressions on first hospital arrival, receipt of more epinephrine doses, unwitnessed CA, higher first measured lactate level, and lower first temperature at onset of study intervention. In patients randomized to TN, the only differences between the earlier Group 1 compared to later Group 2 were lower first reported lactate and higher first reported temperature at time of the temperature intervention (See Table 1).
Table 1.
THAPCA-OH characteristics by time to goal temperature and temperature intervention
| Overall | Hypothermia | Normothermia | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Group 1 First 33% (N = 95) |
Group 2 Last 67% (N = 186) |
P-value | Group 1 First 33% (N = 51) |
Group 2 Last 67% (N = 101) |
P-value | Group 1 First 33% (N = 44) |
Group 2 Last 67% (N = 85) |
P-value | |
| Age at Randomization (years): Median (Q1, Q3) | 1.5 (0.3, 7.4) | 2.3 (0.6, 9.0) | 0.1051 | 0.8 (0.3, 2.3) | 3.5 (1.0, 12.0) | <.0011 | 3.2 (0.4, 10.8) | 1.4 (0.3, 4.6) | 0.0691 |
| Age in years | 0.3672 | 0.0022 | 0.2222 | ||||||
| <1 year | 43 (45%) | 64 (34%) | 28 (55%) | 25 (25%) | 15 (34%) | 39 (46%) | |||
| 1–4 years | 26 (27%) | 60 (32%) | 14 (27%) | 33 (33%) | 12 (27%) | 27 (32%) | |||
| 5–12 years | 12 (13%) | 31 (17%) | 4 (8%) | 20 (20%) | 8 (18%) | 11 (13%) | |||
| > 13 years | 14 (15%) | 31 (17%) | 5 (10%) | 23 (23%) | 9 (20%) | 8 (9%) | |||
| Male | 65 (68%) | 120 (65%) | 0.5952 | 36 (71%) | 64 (63%) | 0.4692 | 29 (66%) | 56 (66%) | 1.0002 |
|
Weight (Kg) Median (Q1, Q3) |
10.7 (5.9, 20.0) | 13.2 (8.1, 32.0) | 0.0411 | 10.0 (5.9, 15.0) | 16.0 (10.0, 40.5) | <.0011 | 14.6 (5.9, 34.7) | 11.0 (7.0, 18.8) | 0.2891 |
| Pre-existing condition | 46 (48%) | 91 (49%) | 1.0002 | 20 (39%) | 54 (53%) | 0.1222 | 26 (59%) | 37 (44%) | 0.0992 |
| Primary aetiology of cardiac arrest | 0.0992 | 0.0042 | 0.6162 | ||||||
| Cardiac | 9 (9%) | 27 (15%) | 2 (4%) | 14 (14%) | 7 (16%) | 13 (15%) | |||
| ALTE/SUID | 21 (22%) | 23 (12%) | 14 (27%) | 7 (7%) | 7 (16%) | 16 (19%) | |||
| Drowning | 18 (19%) | 51 (27%) | 11 (22%) | 34 (34%) | 7 (16%) | 17 (20%) | |||
| Other Respiratory | 35 (37%) | 55 (30%) | 16 (31%) | 27 (27%) | 19 (43%) | 28 (33%) | |||
| Other | 3 (3%) | 7 (4%) | 2 (4%) | 7 (7%) | 1 (2%) | 0 (0%) | |||
| Unknown | 9 (9%) | 23 (12%) | 6 (12%) | 12 (12%) | 3 (7%) | 11 (13%) | |||
| Initial rhythm asystole | 51 (54%) | 114 (61%) | 0.2502 | 29 (57%) | 56 (55%) | 1.0002 | 22 (50%) | 58 (68%) | 0.0562 |
| Estimated duration chest compressions: Median (Q1, Q3) | 25.0 (17.5, 41.0) | 25.0 (15.0, 35.0) | 0.4771 | 27.0 (18.5, 43.5) | 21.0 (14.0, 33.0) | 0.0111 | 25.0 (14.0, 35.0) | 28.0 (17.5, 45.0) | 0.1261 |
| Chest compressions required on arrival at the first hospital | 68 (72%) | 115 (62%) | 0.1072 | 38 (75%) | 56 (55%) | 0.0122 | 30 (68%) | 59 (69%) | 0.6852 |
| Total doses of Epinephrine (EMS And hospital) Median (Q1, Q3) |
3.0 (2.0, 5.0) | 3.0 (2.0, 5.0) | 0.8431 | 4.0 (2.0, 6.0) | 3.0 (1.0, 4.0) | 0.0412 | 2.0 (1.0, 4.0) | 3.0 (2.0, 6.0) | 0.0622 |
| Cardiac arrest witnessed | 32 (34%) | 73 (39%) | 0.5942 | 12 (24%) | 45 (45%) | 0.0282 | 20 (45%) | 28 (33%) | 0.1802 |
| First hospital was study hospital | 38 (40%) | 48 (26%) | 0.0202 | 20 (39%) | 25 (25%) | 0.0902 | 18 (41%) | 23 (27%) | 0.1162 |
| Baseline Lactate3 Median (Q1, Q3) |
7.5 (3.5, 11.1) | 4.7 (2.9, 9.0) | 0.0261 | 8.8 (6.0, 13.3) | 3.8 (2.6, 6.9) | <.0011 | 4.4 (3.3, 8.7) | 7.6 (4.0, 11.9) | 0.0341 |
| First reported temperature Median (Q1, Q3) |
35.6 (33.5, 36.6) | 36.2 (34.4, 37.5) | 0.0021 | 33.8 (32.8, 35.3) | 36.9 (35.7, 37.7) | <.0011 | 36.6 (36.0, 37.5) | 35.1 (33.6, 37.3) | <.0011 |
Wilcoxon rank-sum test.
Fisher’s exact test.
First lactate measurement up to 8 hours after randomization (mmol/L)
In Table 2, 12 month outcomes for Group 1 and Group 2 time to goal temperature are described overall and separately for the TH and TN groups. For the entire cohort, there were no differences in survival with a VABS-II ≥70 at 12 months, survival, or VABS-II decrease by no more than 15 points for early versus later time to goal temperature. For the subgroup receiving TH, survival was higher in those achieving a goal temperature later compared to earlier (p=0.002). There were similar trends that did not achieve statistical significance for survival with VABS-II ≥70 at 12 months and VABS-II decrease by no more than 15 points from baseline (p value 0.07–0.08). For TN, there was no difference by earlier Group 1 versus later Group 2 time to goal temperature groups for any of these three outcomes, although there was a trend for higher survival at 12 months for TN cases achieving the goal range earlier (p=0.065).
Table 2.
THAPCA-OH outcomes by treatment received and time to goal temperature
| Group 1 Earlier 33% |
Group 2 Later 67% |
P-value | |
|---|---|---|---|
| Overall | |||
| Survival at 12 months with VABS-II ≥70 | 10/85 (12%) | 32/164 (20%) | 0.1541 |
| Survival at 12 months | 28/91 (31%) | 68/182 (37%) | 0.3471 |
| VABS-II decreased no more than 15 points or improved | 9/91 (10%) | 29/180 (16%) | 0.1971 |
| Hypothermia | |||
| Survival at 12 months with VABS-II ≥70 | 5/46 (11%) | 22/89 (25%) | 0.0701 |
| Survival at 12 months | 10/49 (20%) | 47/99 (47%) | 0.0021 |
| VABS-II decreased no more than 15 points or improved | 3/49 (6%) | 18/99 (18%) | 0.0771 |
| Normothermia | |||
| Survival at 12 months with VABS-II ≥70 | 5/39 (13%) | 10/75 (13%) | 1.0001 |
| Survival at 12 months | 18/42 (43%) | 21/83 (25%) | 0.0651 |
| VABS-II decreased no more than 15 points or improved | 6/42 (14%) | 11/81 (14%) | 1.0001 |
Fisher’s exact test.
Denominators reflect the number of subjects with available outcomes at 12 months. Additionally, subjects with poor pre-arrest neurobehavioral function were excluded from analysis of the primary outcome, survival at 12 months with VABS-II ≥ 70.
Table 3 examines outcomes separately for the TH and TN treated cases in Groups 1 and 2. For the earlier time to goal temperature (Group 1), survival was higher in the TN group (p=0.02). For the later time to goal temperature (Group 2), survival was higher for those assigned to TH (p=0.002).
Table 3.
THAPCA-OH outcomes by time to goal temperature and treatment received
| Hypothermia | Normothermia | P-value | |
|---|---|---|---|
| Group 1 (Earlier 33%) | |||
| Survival at 12 months with VABS-II ≥70 | 5/46 (11%) | 5/39 (13%) | 1.0001 |
| Survival at 12 months | 10/49 (20%) | 18/42 (43%) | 0.0251 |
| VABS-II decreased no more than 15 points or improved | 3/49 (6%) | 6/42 (14%) | 0.2931 |
| Group 2 (Later 67%) | |||
| Survival at 12 months with VABS-II ≥70 | 22/89 (25%) | 10/75 (13%) | 0.0771 |
| Survival at 12 months | 47/99 (47%) | 21/83 (25%) | 0.0021 |
| VABS-II decreased no more than 15 points or improved | 18/99 (18%) | 11/81 (14%) | 0.4241 |
Fisher’s exact test.
Denominators reflect the number of subjects with available outcomes at 12 months. Additionally, subjects with poor pre-arrest neurobehavioral function were excluded from analysis of the primary outcome, survival at 12 months with VABS-II ≥ 70.
Table 4 presents multivariate models for the three 12-month outcomes. For both survival with VABS-II ≥ 70 at one year and survival at one year, time to goal temperature and temperature intervention group were not associated with outcome, while primary aetiology of CA and first measured lactate were significantly associated with outcome. For survival at 12 months with VABS-II decrease no more than 15 points from baseline, neither time to goal temperature or temperature intervention group were associated with outcome, while initial cardiac rhythm asystole and first measured lactate were significantly associated with outcome.
Table 4.
Multivariable Logistic Regression Models of One Year Outcomes
| Characteristic | Odds ratio (95% CI) | P-value |
|---|---|---|
| Survival at 12 months with VABS-II >70 | ||
| Out-of-Hospital Tertile Group | 0.767 | |
| First 33 Percent | 0.87 (0.35, 2.19) | |
| Last 67 Percent | Reference | |
| Treatment Group | 0.648 | |
| Normothermia | Reference | |
| Hypothermia | 1.22 (0.53, 2.80) | |
| Primary aetiology of cardiac arrest | 0.003 | |
| Cardiac | Reference | |
| ALTE/SUID | 0.23 (0.05, 1.06) | |
| Drowning | 0.50 (0.17, 1.46) | |
| Other Respiratory | 0.10 (0.03, 0.35) | |
| Other/Unknown | 0.20 (0.05, 0.84) | |
| Baseline Lactate (up to 8 hours after randomization) (mmol/L) | 0.67 (0.56, 0.80) | <.001 |
| Survival at 12 months | ||
| Out-of-Hospital Tertile Group | 0.805 | |
| First 33 Percent | 1.08 (0.57, 2.05) | |
| Last 67 Percent | Reference | |
| Treatment Group | 0.652 | |
| Normothermia | Reference | |
| Hypothermia | 1.15 (0.63. 2.08) | |
| Primary aetiology of cardiac arrest | 0.016 | |
| Cardiac | Reference | |
| ALTE/SUID | 0.24 (0.07, 0.79) | |
| Drowning | 1.00 (0.39, 2.57) | |
| Other Respiratory | 0.45 (0.18, 1.10) | |
| Other/Unknown | 0.34 (0.12, 1.01) | |
| Baseline Lactate (up to 8 hours after randomization) (mmol/L) | 0.80 (0.74, 0.87) | <.001 |
| VABS-II decreased no more than 15 points or improved | ||
| Out-of-Hospital Tertile Group | 0.282 | |
| First 33 Percent | 0.62 (0.26, 1.49) | |
| Last 67 Percent | Reference | |
| Treatment Group | 0.275 | |
| Normothermia | Reference | |
| Hypothermia | 0.65 (0.30, 1.41) | |
| Initial cardiac arrest rhythm was asystole | 0.007 | |
| No | Reference | |
| Yes | 0.34 (0.15, 0.74) | |
| Baseline Lactate (up to 8 hours after randomization) (mmol/L) | 0.81 (0.72, 0.92) | <.001 |
Discussion
This secondary cohort analysis of the THAPCA-OH trial found, in unadjusted analyses, that patients assigned to TH who achieved their goal temperature range earlier had worse outcomes, while patients who were assigned to TN who achieved their goal range earlier had better outcomes. These trends were likely primarily attributable to severity of illness and case-mix differences (i.e. confounding variables) in the cohorts for the earlier versus later time to goal temperature groups. In multivariate analyses, the associations of time to target temperature were no longer statistically significant after controlling for the primary aetiology of CA, baseline lactate, and first rhythm asystole. Therefore, controlling for CA severity of illness was key in this investigation.
The THAPCA–OH trial was the first large pediatric CA trial which examined outcomes of TH and TN targeted temperature management in comatose children. The current report is the first pediatric study to examine whether time to the goal temperature range is associated with survival and good functional outcomes in a targeted temperature management intervention trial. In the adjusted multivariate analyses, earlier versus later time to the goal temperature range (Group 1 versus Group 2) and target temperature group (TH versus TN) were not associated with any of the three outcomes assessed, while aetiology of CA and baseline lactate measurement were associated with both survival and survival with VABS-II ≥70. For the outcome survival with VABS-II no more than 15 point less than baseline, initial CA rhythm asystole and higher baseline lactate were associated with worse outcome. Higher lactate has previously been associated with worse outcome after pediatric CA[14]. We previously reported from the THAPCA-OH trial database that aetiology of CA was associated with survival and survival with 12 month VABS-II ≥70[15]; in the current study we demonstrated that the association persisted even after adjusting for time to the goal temperature range.
In adults, lower temperature on hospital arrival has been associated with worse outcome following CA[16]. In an adult observational registry study shorter time to target temperature for TH with a cut off of less than 300 minutes (5 hours) was associated with worse outcome (6). In TH-treated patients from the THAPCA-OH trial, aetiology of CA, younger age, lower weight, longer estimated duration of chest compressions, higher number of epinephrine doses, higher first lactate measurement, and lower first reported temperature near time of intervention were associated with shorter time to goal temperature. Longer estimated duration of chest compressions, higher number of epinephrine doses and higher first lactate measurement have previously been reported to be associated with worse outcome for OH-CA[14,15,17]. Similarly, patients less than one year (younger, smaller) would more likely have the diagnosis of ALTE/SUID, which is known to have very poor outcomes[17,18–20]. It is likely that the first reported temperature at the start of the intervention for TH was lower in those with longer duration of chest compressions and in some etiologies of CA (e.g. ALTE/SUID). For TN, lower first lactate measurement and higher reported temperature at the start of the temperature intervention were associated with shorter time to the goal temperature range; these variables are associated with lower severity of illness and better outcomes.
Limitations of the THAPCA-OH Trial have been previously described[7]. In addition, for the current investigation practical considerations in the implementation of the THAPCA-OH trial influenced time to attain goal temperature. A large proportion of study patients (70%) required transfer from a non-study hospital to a study site. In addition, the availability of guardians for obtaining informed consent and the study protocol, which required central venous and arterial lines to be placed in patients prior to the initiation of any intervention, were factors that delayed the onset of temperature management. Time to the goal range after ROSC for the entire cohort was a median of 7.4 hours. This was longer than corresponding values in an adult trial that examined early initiation of cooling where time to goal temperature following ROSC was reported to be a mean of 4.2 hours when started in the field and 5.5 hours when initiated in the emergency room[5]. Nonetheless, in that trial outcomes were not improved with earlier initiation of cooling. It is also of note that the 2002 HACA trial had a time to the hypothermia goal temperature range (32–340C) of 8 hours (4–16 IQR), and 19 of 132 (14%) never achieved the goal range[4]. However, improved outcome was reported in the group treated with TH with 24 hours of cooling and rewarming of approximately 8 hours compared to a usual care comparison group, which did not uniformly prevent fever. In the THAPCA-OH trial, the median and IQR times to goal temperature were Hypothermia 7.6 (6.2, 9.6); Normothermia 7.4 (6.2, 9.8); Overall 7.4 (6.2, 9.7); the 120-hour duration of temperature control was much longer than previously studied in adult CA trials[4, 21, 22].
It remains challenging to compare time intervals to achieve hypothermia in clinical trials with findings in pre-clinical models, and to replicate the scenarios of experimental studies in a clinical context. In a fetal sheep cerebral ischaemia model, hypothermia onset up to 5.5 hours after the initiating insult remains neuroprotective, and efficacy is lost when initiated 7.5 hours after the event[23]. A recent report in a rat CA model further illustrated the potent role of timing of onset of hypothermia to attain benefit, and suggested a mechanism that contributed to the benefits of immediate post-resuscitation onset of hypothermia[24]. Specifically, they showed that early hypothermia resulted in rapid restoration of cerebral blood flow back to baseline levels, thereby limiting secondary injury, and contributing to improved neurological outcome. At this time for comatose adults and children following CA, optimal time to goal temperature has yet to be identified.
In conclusion, earlier time to attainment of the goal temperature range was not associated with better outcomes, for the whole population or for either the hypothermia or normothermia intervention subgroups, after adjusting for confounding factors related to cause of CA and severity of CA (lactate, asystole). In future clinical trials to evaluate temperature management, if more rapid attainment of goal temperature becomes feasible, it could be informative to re-evaluate whether earlier time to achieve goal temperature improves survival and functional outcomes.
Acknowledgements
Sites and research teams - contributors
We acknowledge the contributions of the following sites and individuals who made the THAPCA-OH Trial possible.
Site principal investigators (PI), Sub-investigators (Sub-I), Clinical research coordinators (CRC), Neurologists (Neurologist), Psychologists (Psychologist).
Underline indicates is coauthor.
The Children’s Hospital of Alabama, Birmingham, AL
J. Alten (PI), S. Borasino (Sub-I), C. Pruitt (Sub-I), R. Bush (CRC), K. Hock (CRC), L. Dure (Neurologist), D, Marullo (Psychologist)
Arkansas Children’s Hospital, Little Rock, AR
R. Sanders (PI), P. Prodhan (Sub-I), G. Hefley (CRC)
Phoenix Children’s Hospital, Phoenix, AZ
H. Dalton (PI), S. Buttram (Sub-I), K. Wai (Sub-I), A. La Bell (CRC), C. Bliss (CRC), D. Liss (CRC), A. Ortiz (CRC), C. Downhour (CRC), K. Williams (Neurologist), M. Lavoie (Psychologist), V. Bordes-Edgar (Psychologist)
Diamond Children’s Medical Center, Tucson, AZ
A. Theodorou (PI), K. Typpo (Sub-I), C. Wells (CRC), J. Deschenes (CRC), J. Teodori (Neurologist), C. Viscusi (Sub-I), J. Katsanis (Psychologist)
Children’s Hospital of Los Angeles, Los Angeles, CA
C. Newth (PI), S. Rubin (Sub-I), R. Bart (Sub-I), T, Deakers (Sub-I), A. Ghuman (Sub-I), R. Khemani (Sub-I), B. Markovitz (Sub-I), J. Dicarlo (Sub-I), P. Ross (Sub-I), V. Wang (Sub-I), M. Villa (CRC), F. Fajardo (CRC), J. Kwok (CRC), J. Serrano (CRC), J. Valentine (CRC), J. Terry (CRC), A. Yamakawa (CRC), S. Briones (CRC), S. Cauley (RN), A. Briseno (RN), C. Young (RN), M. Nyc (CRC), T. Rosser (Neurologist), J. Gold (Psychologist), R. Engilman (Psychometrician)
Children’s Hospital of Orange County, Orange, CA
A Schwarz (PI), J. Haykawa (Sub-I), T. Patterson (CRC), O. Vargas-Shiraishi (CRC), A. Galion (Neurologist), P. Armstrong (Psychologist)
Loma Linda University Children’s Hospital, Loma Linda, CA
M. Mathur (PI), G. Oei (Sub-I), B. Barcega (Sub-I), J. Newcombe (CRC), A. Pinto (CRC), S. Ashwal (Neurologist), D. Michelson (Neurologist), J. Pivonka-Jones (Neuropsychologist)
University of California Los Angeles, Los Angeles, CA
R. Harrison (PI), R. Kelly (Sub-I), A. Madikians (Sub-I), M. Federman (Sub-I), M. Morgan (Sub-I), A. Yamakawa (CRC), M. Nyc (CRC), S. Briones (CRC), M. Villa (CRC), J. Kwok (CRC), J. Serrano (CRC), J. Valentine (CRC), T. Rosser (Neurologist), R. Engilman (Psychometrician), J. Gold (Psychologist)
UCSF Benioff Children’s Hospital, San Francisco, CA
P. McQuillen (PI), S. Tabbutt (Sub-I), L. Haeusslein (CRC), S. Strong (CRC), H. Glass (Neurologist), B. Johnson (Psychologist), B. Loomis (Psychologist), D. Gano (Neurologist)
Hospital for Sick Children, Toronto, Toronto, ON, Canada
J. Hutchison (PI), S. Schwartz (Sub-I), A. Guerguerian (Sub-I), K. Boutis (Sub-I), D. Clark (CRC), J. Van Huyse (CRC), K. Fusco (CRC), K. McBain (CRC), A. Kravecevic (CRC), L. Toller (CRC), R. Gaiteiro (CRC), S. Furness (CRC), R. Askaland (Neurologist), C. Hahn (Neurologist), R. Sananes (Psychologist)
Children’s Hospital of Denver, Denver, CO
E. Dobyns (PI), L. Rappaport (Sub-I), E. Jewett (CRC), T. Wilson (CRC), B. Wathen (CRC), M. Dix (CRC), J. Allen (CRC), T. Garling (CRC), D. DiDomenico (CRC), D. Loyola (CRC), T. Bernard (Neurologist), J. Dise-Lewis (Psychologist)
All Children’s Hospital, Tampa, FL
A. Stock (PI), K. Battick (CRC), A. Fleming (CRC), J. Hanson (CRC), M. Macogay (CRC), K. Martin (CRC), K. Burger (CRC)
Children’s Healthcare of Atlanta, Atlanta, GA
N. Pham (PI), K. Walson (Sub-I), J. Sturm (Sub-I), C. Stone (CRC), A. Wellons (CRC), S. Meisner (CRC), B. Weissman (Neurologist), A. Alexander (Psychologist), A. Johnson (Psychologist)
Robert Lurie Children’s Hospital of Chicago, Chicago, IL
D. Goodman (PI), C. Smith (PI), E. Powell (Sub-I), S. Shah (CRC), J. Chiambrietti (CRC), C. Lutz (CRC), S. Shah (CRC), C. Vitt (CRC), L. Jackson-McCarthy (CRC), N. Leannais (CRC), M. Wainwright (Neurologist), J. Goldstein (Neurologist), C. Weil (Psychologist)
Kosair Charities Pediatric Clinical Research Unit, Department of Pediatrics, University of Louisville and the Kosair Children’s Hospital, Louisville, KY
M. Porter (PI), J. Sullivan (Sub-I), K. Orman (Sub-I), E. Owen (Sub-I), A. Hardin (Sub-I), K. Potter (Sub-I), E. Peterson (Sub-I), M. Ruppe (Sub – I), J. Berkenbosch (Sub-I), P. Padmanabhan (Sub-I), M. McDonald (Sub-I), V. Montgomery (Sub-I), A. Calhoun (Sub-I), M. Thomas (CRC), A. Michael (CRC), C. Schanie (CRC), L. Rayborn (CRC), K. Kernen (CRC), T. Bratton (CRC), L. Good (CRC), V. Puri (Neurologist), L. Sears (Psychologist)
John’s Hopkins Children’s Center, Baltimore, MD
U. Bhalala (PI), J. Lee Summers (PI), M. Bembea (PI), D. Shaffner (Sub-I), A. Walker (Sub-I), M. Shackelford (CRC), A. Larson (CRC), J. Jamrogowicz (CRC), J. Kim (CRC), R. Felling (Neurologist), B. Slomine (Psychologist)
Outcome Center, Kennedy Krieger Institute, Baltimore, MD
J.R. Christensen (Site PI), B.S. Slomine (Site Co-Investigator), E. DeMatt (Telephone Interviewer), M. Talley (Telephone Interviewer), C. Rodweller (Telephone Interviewer)
Children’s Hospital of Michigan, Detroit, MI
K. Meert (PI), S. Heidemann (Sub-I), J. Clark (Sub-I), A. Pawluszka (CRC), M. Lulic (RA), M. Frey (CRC), L. Sivaswamy (Neurologist), S. Horman (Psychometrician), L. Chiodo (Psychologist)
C.S. Mott Children’s Hospital, University of Michigan, Ann Arbor, MI
F. Moler (PI), R. Stanley (Sub-I), T. Cornell (Sub-I), M. Weber (CRC), J. Reske (CRC), L. Conlin (CRC), F. Silverstein (Neurologist), M. Carlson (Neurologist), S. Warschausky (Psychologist), C. Young (Psychologist), T. Behnke (Program Administrator), D. Poszywak (Procurement Subcontract Administrator)
“Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Numbers UL1 TR 000433 and UL1 TR 000433. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.”
Children’s Hospital and Clinics of Minnesota, Minneapolis, MN
J. Nowak (PI), H. Ortega (EM Sub-I), D. Milner (EM Sub-I), E. Zielinski (CRC), A. Doucette (CRC), A. Overman (CRC), C. Leonard (CRC), E. Gilles (Neurologist), P. Huszar (Neurologist), M. Troy (Psychologist), J. Alden (Psychologist)
Washington University, St. Louis, St, Louis, MO
J. Pineda (PI), P. Oren (Sub-I), M. Shoykhet (Sub-I), S. Friess (Sub-I), K. Guilliams (Sub-I), D. Jaffe (Sub-I), T. Day (CRC), T. Hicks (CRC), L. Barganier (CRC), E. Fish (CRC), L. Toennies (CRC), P. Thurst (CRC), S. Blankenship (CRC), M. Noetzel (Neurologist), K. Guilliams (Neurologist), D. White (Psychologist)
Children’s Hospital of New York/Columbia University Medical Center New York, NY
C. Schleien (PI), J. Cappell (PI), David Schnadower (Sub-I), N. Talathoti (CRC), N. Sidhu (Neurologist), V. Hinton (Psychologist)
University of Rochester Medical Center/Golisano Children’s Hospital, Rochester, NY
E. van der Jagt, (PI), E. R. Taillie (CRC), E. Nazarian (Sub-I), L. E. Daugherty (Sub-I), C.O. Davis (Sub-I), J. Mulbury (Neurologist), J. Kwon (Neurologist), H. Adams (Psychologist)
Duke Children’s Hospital, Durham, NC
G. Ofori-Amanfo (PI), W. Bordley (Sub-I), S. Wrenn (CRC), T. Uhl (CRC), C. Milleson (CRC), E. Smith (Neurologist), K. Gustafson (Psychologist), S. Asbeck (Psychologist), W. Gallentine (Neurologist)
Nationwide Children’s Hospital, Columbus, OH
E. Lloyd (PI), M. Hall (Sub-I), N. Khan (Sub-I), J. Frazier (Sub-I), Daniel Cohen (Sub-I), J. Haines (CRC), K. Carter (CRC), L. Bird (CRC), S. Hough (CRC), W. Lo (Neurologist), K. Yeates (Psychologist), K. Morfing (Psychologist), M. Ginn (Psychologist)
Cincinnati Children’s Hospital, Cincinnati, OH
D. Wheeler (PI), G. Geis (Sub-I), E. Beckman (CRC), S. Banschbach (CRC), M. Monaco (CRC), B. Hallinan (Neurologist), N. Walz (Psychologist)
Rainbow Babies and Children’s Hospital, Cleveland, OH
K. Lidsky (PI), S. Bergant (CRC), A. Browning (CRC), J. Haky (CRC), N. Bass (Neurologist), R. Tangen (Psychologist)
Penn State Children’s Hospital, Hershey, PA
N. Thomas (PI), A. Shelly (CRC), J. Vallati (CRC), P. Carper (CRC), D. Spear (CRC), A. McMonagle (CRC), J. Stokes (CRC), H. Watts (CRC), W. Trescher (Neurologist), C. Flaherty-Craig (Psychologist)
Children’s Hospital of Philadelphia, Philadelphia, PA
A. Topjian (PI), B. Berg (Sub-I), V, Nadkarni (Sub-I), S. Friess (Sub-I), J. Fitzgerald (Sub-I), P. Meaney (Sub-I), E. Alpern (EM Sub-I), M. DiLiberto (CRC), C. Twelves (CRC), S. McGowan (CRC), M. Sisko (CRC), B. Park (CRC), R. Ichord (Neurologist), J. Radcliffe (Psychologist), N. Hattiangadi Thomas (Psychologist), K. Friedman (Psychologist), A. Sullivan (Psychometrist)
“The project described was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR000003. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.”
University of Pittsburg Medical Center, Pittsburg, PA
E. Fink (PI), R. Hickey (Sub-I), R. Clark (Planning Committee), M. Bell (Sub-I), A. Abraham (CRC), R. Bell (CRC), R. Varma (Neurologist), S. Beers (Psychologist), H. Feldman (Psychologist), J. Walters (Psychologist), K. McIntyre (Psychologist)
University of Tennessee Health Science Center, Memphis, TN
S. Shah (PI), K. Anand (Sub-I), C. Woodward (Sub-I), A. Hickerson (CRC), B. Moore (CRC), A. Nico West (CRC), M. Grandberry (CRC), N. Shah (Neurologist), N. Clanton (Psychologist), L. Berkelhammer (Psychologist), O. King (Psychologist), A. Huling (Psychologist), L. White (Psychologist)
Children’s Medical Center Dallas, University of Texas Southwestern Medical School, Dallas, TX
J. Koch (PI), P. Okada (Sub-I), D. Miles (Sub-I), L. Raman (Sub-I), M. Green (Sub-I), E. Golson (CRC), A. Jones (CRC), D. Kelly (CRC), T. Plumb (CRC), K. Van de Bruinhorst (CRC), M. Dowling (Neurologist), P. Stavinoha (Psychologist), A. Hernandez (Psychometrician)
University of Texas Health Sciences Center at San Antonio, San Antonio, TX
T. Wu (PI), C. Bauerfeld (Sub-I), M. Rodkey (Sub-I), H. Dibrell (CRC), S. Atkinson (Neurologist), L. O’Donnell (Psychologist), J. Eubanks (Psychologist)
Texas Children’s Hospital, Houston, TX
L. Loftis (PI), L. Castillo (PI), J. Graf (Sub-I), N. Jaimon (CRC), U. Kyle (CRC), Y. Henry (CRC)
Data Coordinating Center (DCC), University of Utah, Salt Lake City, UT
J. M. Dean (PI), R. Holubkov (Biostatistician), B. Browning (Program Director), M. Gildea (Project Manager), R. Kuhn (Project Manager), K. Register (Project Manager), N. Tattersall (Project Manager), A. Vrem (Project Manager) A. Webster (Biostatistician), A. Clark (Biostatistician), K. Page (Biostatistician), J. Wang (Biostatistician), L. Herrera (Data Manager), J. Yearley (Director Data Management), R. Enriquez (Director Information Technology/Information Systems), D. Demarco (Data Center Manager), M. Virtosu (Senior Software Engineer), S. Su (Senior Software Engineer), J. Bell (Senior Database Developer), S. Zuspan (PECARN Program Director), J. Burr (CPCCRN Program Director), S. Simmons (Information Coordinator), V. McKean (Administrative Assistant), C. Traeden (Administrative Assistant), H. Nitsuma (Administrative Assistant)
Primary Children’s Medical Center, Salt Lake City, UT
K.S. Bennett (PI), R. Lane (Sub-I), J. Lilley (CRC), S. Bjerregaard (CRC), K. Jacobsen (CRC), A. Watson, (CRC), D. Stephen (CRC), M. DelaCruz (CRC), K. Cooley (CRC), N. Kwendakwema (CRC), B. Ameel (CRC), G. Jensen (CRC), M. Metcalf (CRC), R. Cole (CRC), R. Moore (CRC), D. Morita (Neurologist), R. Burr (Psychologist), T. Bennett (Sub-I), J. Henricksen (PICU MD), E. Hirshberg (Sub-I), A. Hubbard (Sub-I), G. Larsen (Sub-I), B. Poss (Sub-I), M. Schober (Sub-I), J. Sweney (Sub-I)
Seattle Children’s Hospital, Seattle, WA
J. Zimmerman (PI), J. McGuire (Sub-I), R. Farris (Sub-I), O. Yanay (Sub-I), J. Reid (Sub-I), L. Smith (Sub-I), T. Brogan (Sub-I), S. Hamilton (CRC), R. Barker (CRC), C. Greeley (CRC), M. Sadler Greever (CRC), S. Gospe (Neurologist), C. Amlie-Lefond (Neurologist), D. Breiger (Psychologist), A. Paolozzi (Psychologist)
Children’s National Medical Center, Washington, DC
J. Berger (PI), D. Wessel (Sub- I), M. Sharron (Sub-I), S. Basu (Sub-I), A. Wratney (Sub-I), N. Dean (Sub-I), K. Brown (Sub-I), J. Reardon (CRC), E. Tomanio (CRC), F. Ramos (RA), B. Tadesse (RA), M. Menicucci (CRC), J. Carpenter (Neurologist), S. Swanson (Psychologist), T. Brennan (Psychologist), P. Glass (Psychologist), B. Malek (Psychologist), M. Mintz (Psychologist)
Our follow ups were conducted in the Clinical Research Center which is supported by NIH P30HD040677.
Medical College of Wisconsin, Milwaukee, WI
M. Meyer (PI), M. Wakeham (Sub-I), S. Hanson (Sub-I), Marc Gorelick (Sub-I), M. Christensen (CRC), D. Triscari (CRC), B. Horn (CRC), K. Murkowski (CRC), K. Hecox (Neurologist), C. Brosig (Psychologist)
Support
Supported by the National Heart, Lung, and Blood Institute (NHLBI) grants HL094345 (to Dr. Moler) and HL094339 (to Dr. Dean).
Support in part from the following federal planning grants contributed to the planning of the THAPCA Trials: HD044955 (to Dr. Moler) and HD050531 (to Dr. Moler). Additional in part support from the following research networks: Pediatric Emergency Care Applied Research Network (PECARN) from cooperative agreements U03MC00001, U03MC00003, U03MC00006, U03MC00007, and U03MC00008; and the Collaborative Pediatric Critical Care Research Network (CPCCRN) from cooperative agreements U10HD500009, U10HD050096, U10HD049981, U10HD049945, U10HD049983, U10HD050012 and U01HD049934.
This work is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or National Institutes of Health.
The study sponsors listed had no role in the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.
Funded by the National Heart, Lung and Blood Institute; THAPCA-OH ClinicalTrials.gov number, NCT00878644.
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Declaration of Conflict of Interest Statement:
Faye S. Silverstein: ‘Conflicts of interest: none’
Kent Page: ‘Conflicts of interest: none’
Richard Holubkov: ‘Conflicts of interest: none’
Beth S. Slomine: ‘Conflicts of interest: none’
Kathleen L. Meert: ‘Conflicts of interest: none’
James R. Christensen: ‘Conflicts of interest: none’
Samir Shah: ‘Conflicts of interest: none’
Vinay M. Nadkarni: ‘Conflicts of interest: none’
J. Michael Dean: ‘Conflicts of interest: none’
Frank W. Moler: ‘Conflicts of interest: none’
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