Currently there exist inadequate data in the literature upon which to plan interventional clinical trials in children achieving ROC following cardiac arrest. Most U.S. reports in this population are limited by small numbers of cases in series reports and/or single geographic locations (1
). As such, the existing literature is inadequate for planning large multicenter interventional clinical trials aimed to improve neurobehavioral outcomes in this population. The current pre-clinical trial planning cohort study was conducted over a relatively short period of 18 months at 15 PECARN children’s hospitals and represents one of the largest experiences of OH cardiac arrest with ROC cases from a U.S. pediatric population. The participating sites were diversely located across eastern, northern and western regions of the US; the network has limited representation in the most southern states where submersion type events may be more common year round than in other regions. Despite this limitation, our report is likely more generalizable to the overall U.S. pediatric population than existing reports. We believe this is the first report in the literature to focus specifically on OH pediatric cardiac arrest with ROC in a broad based U.S. population.
New findings related to OH pediatric cardiac arrest with ROC were observed in this investigation. First, we observed age was not associated with survival when examined either as a continuous variable or as Utstein style age categories. Previous studies have reported age to be associated with survival; however, the largest prior report included cases without ROC (1
). This likely accounts for the different study findings, as cases without ROC constitute a larger proportion of the total than the subset of cases with ROC (1
). Second, we observed weekend arrests to be associated with better outcomes following pediatric cardiac arrest in the OH setting and to our knowledge this has not been reported previously. Possible explanations might be the greater availability of adult caregivers during weekends or less traffic and quicker response times by EMS. This is in contrast to observations in adults with in-hospital cardiac arrest, where higher mortality on weekends and night shifts has been demonstrated (25
Post-arrest factors occurring within 12 h of arrest were also observed to be associated with survival. Higher lowest temperature measured during the 0–12 hour period was associated with better survival. This may be explained by longer duration of CPR associated with lower body temperature. Biochemical measurements during the 0–12 hour period for lower pH, higher lactate and higher glucose were also associated with increased mortality. On clinical exam, the presence of bilateral reactive pupils in the immediate 12 hour period post ROC was associated with higher survival.
The only previous large US based report to describe both survival and neurological outcome in a pediatric OH arrest with ROC cohort was by Young et al (1
). This was a secondary analysis of a dataset from a clinical trial of OH airway management conducted between 1994 and 1997 from two counties in the Los Angeles area. After excluding cases that did not have ROC, 165 cases with OH cardiac arrest with ROC were described (1
). Overall, 51 (31%) cases were discharged home alive, while 114 (69%) died during hospitalization. Of those who survived to hospital discharge, good PCPC (1 or 2) occurred in 16/51 (31%), no change from previously abnormal neurologic status in 11/51 (22%), and poor outcome 3–5 occurred in 24/51 (47%). Nearly half (26
) of the 51 survivors did not receive epinephrine. In our cohort, 138 cases with cardiac arrest and ROC occurred over 18 months at 15 PECARN children’s hospitals. Overall, 62% (85/138) of cases died, while 38% (53/138) survived. Of survivors with available PCPC information (n=50), 27 (54%) had a PCPC of 1 or 2 at hospital discharge; 4 (8%) had no change from previously abnormal PCPC, and 19 (38%) had a poor outcome (score 3–5). Approximately 50% of survivors of OH cardiac arrest did not receive epinephrine, similar to the Young report.
Previous reports have attempted to describe a specific number of epinephrine doses in which outcome was universally poor so that futility of the resuscitation intervention could be assured. More than 2 or 3 doses of epinephrine have been reported as such cut points in the past (1
). In 1996, Schindler reported no survivors of pediatric cardiac arrest if more than 2 doses of epinephrine were required. Young more recently reported in 2004 greater than 3 epinephrine doses to be universally associated with poor survival outcome (1
). In our cohort, 46 patients had greater than three doses of epinephrine. Only 7 of these 46 children survived with live hospital discharge. Six of the 7 had normal PCPC reported prior to cardiac arrest; at hospital discharge one survivor was comatose, three had severe disability, one had an outcome of moderate disability, and one had normal outcome. One case had unknown baseline PCPC and had mild disability (PCPC=2) at discharge. Overall, 44/46 (96%) had poor outcome defined as death or PCPC > 2. Therefore, four or more doses of epinephrine cut point was usually, but not always, associated with poor outcome in our experience. Finally, we believe caution is required as future interventions (i.e. therapeutic hypothermia) may alter any arbitrary cut points (epinephrine doses, duration of cardiac arrest, biomarker measurements, etc), resulting in inaccurate prognostication.
We performed exploratory logistic regression analyses to determine which factors were most strongly associated with outcome at the time of ROC, while controlling for patient age, gender, race and cardiac rhythm asystole or ventricular fibrillation/ventricular tachycardia (VF/VT) anytime during the arrest. Similar analyses were also performed with additional information available up to 12 h after ROC. For variables available at the completion of the CPR (Model 1), only the use of epinephrine and atropine were independently associated with reduced survival (AUC 0.83). In a model with additional factors available out to 12 hours following arrest (Model 2), preexisting lung or airway disease, etiology of arrest drowning or asphyxia, higher pH, and reactive pupils were all associated with lower mortality (AUC 0.86).
A major limitation of the existing pediatric cardiac arrest literature concerns long-term neurological outcome of survivors. In our report, neurological outcome could only be ascertained at hospital discharge with the simple clinical score PCPC (20
). Optimally, outcome would be assessed at follow up periods of at least a year or more with more extensive neurobehavioral assessment tools. Limited reports have suggested that following cardiac arrest the status of children at hospital discharge is similar to that measured at 12 month follow up (26
). Detailed neurobehavioral testing on a large number of cases has not been reported at one year or longer follow-up after pediatric OH cardiac arrest. This may be needed to detect more subtle changes in long-term neurobehavioral outcome (27
). ‘Good’ outcome has been defined in some large reports as a PCPC score 1, 2, or 3 for in-hospital cardiac arrest (28
). For society and individual families, a decline in even one level is likely to represent a huge burden in terms of family adjustment, school performance and long term functioning in society. Long term follow up with age appropriate neurobehavioral testing may detect more subtle changes in brain function following ‘successful’ resuscitation than can be detected with gross measurement by PCPC or similar scales.
Another limitation of our study commonly observed in other cardiac arrest reports concerns missing data for some variables of interest. For example, initial cardiac arrest rhythm has often been missing information even in optimal settings of cardiac arrest. One study from the National Registry of Cardiopulmonary Resuscitation (NRCPR) database of pediatric inhospital cardiac arrests, reported missing first documented rhythm occurring in 22% of cases (28
). In spite of the fact that most in-hospital cardiac arrests occurred in monitored settings (PICU and ED) and records were abstracted by trained personnel, missing information is common. Therefore, it is not surprising that our OH cohort had missing information for initial rhythm in 24%, a rate similar to that in the NRCPR. An exception is the study of OH cardiac arrest by Young et al who reported arrest rhythms in 548/601 cases (91%). This was possibly due to real time contact of EMS paramedic personnel by study investigators. The authors described that they were able to complete data for rhythm classification even if it was not available in the EMS record. This was primarily the result of reclassification of the rhythms recorded on EMS forms as PEA (1
). An additional limitation of our retrospective cohort study was that we could not capture information on the training of the individuals performing resuscitation or whether standard PALS guidelines were followed. Because we only examined cases with ROC for at least 20 minutes, it is likely at least partially effective resuscitation was provided at some point to result in ROC.
Some notable population differences exist between our report and that of Young et al (1
). The latter report included newly born cardiac arrest cases (5%), while ours excluded these cases. This age group had a higher survival than older infants (36% vs 4%) (1
). The newborn group was a planned exclusion in our study since TH for newborns with hypoxic ischemic encephalopathy was being actively evaluated in several completed or ongoing trials (12
), and the NRCPR recommends newborns be analyzed separately. Additionally, in our cohort cases up to 18 years of age were included while Young et al did not report data on cases more than 40 kg or 12 yrs of age. Their population originated from two counties near Los Angeles and may not be generalizable to the rest of US. Our 15 centers were wide spread and well represented across the US, with the exception of southern sites. In spite of these distinct differences, our findings are relatively similar.
It should be emphasized that our report differs from others in the literature in several important respects. Since our primary goal was to collect feasibility information for interventional TH trials in children after cardiac arrest, we excluded cases that did not survive the initial resuscitation event to have ROC for at least 20 minutes. For this reason, comparison of our findings directly with other reports that often included cases without ROC would need to account for this difference. In a recent literature review of out of hospital cardiac arrest reported approximately 70% of out of hospital arrests in children not to have ROC (17
). Another difference is that we had study-specific inclusion and exclusion criteria. For example, since we were planning a clinical trial of TH after pediatric cardiac arrest, we were primarily interested in a population with at least some risk of mild to severe hypoxic-ischemic brain injury. Therefore, we excluded all cases that received less than a minute of chest compressions, regardless of whether epinephrine or defibrillation was administered. Finally, we excluded cases less than 24 hours of age (newborn) since TH studies have been and are being conducted in this population.
A simple requirement of a minimum of 1 minute of chest compressions was used for our definition of cardiac arrest as inclusion criteria in planning a future RCT of TH after cardiac arrest. We did not use the existing NRCPR definition of in-hospital cardiac arrest, which emphasizes documentation in the medical record of the absence of a palpable pulse or a rhythm not associated with a pulse. Pulse detection or absence of it is an extremely unreliable and problematic physical finding to accurately measure in adults under optimal conditions; trained pediatric caregivers perform poorly as well (29
); an expert group has ranked it as a high research priority (31
). An American Heart Association-affiliated expert group recently proposed a different ‘pragmatic definition’ for OH cardiac arrest to include ‘receives chest compressions by EMS personnel’ (32
In conclusion, this multicenter cohort study is one of the largest to date and reports new associations related to OH pediatric cardiac arrest with ROC outcomes. Weekend arrests (Saturday or Sunday) were associated with higher survival than those occurring on weekdays. We observed greater than 3 epinephrine doses to be associated with poor outcome (96%), although good outcome did occur infrequently (4%). In a multivariate model that used information available up to 12 hours after ROC and controlled for patient age, gender, race, and cardiac rhythm asystole or VF/VT at anytime during the arrest, we observed factors most strongly associated with lower mortality to be 1) a history of preexisting lung disease, 2) etiology of arrest drowning or asphyxia, 3) higher minimum pH, and 4) the presence of bilateral reactive pupils. Using information only available up to ROC, number of epinephrine doses and atropine use were most strongly associated with higher mortality. Finally, investigators should be aware that when planning clinical trials related to cardiac arrest, variables associated with outcome in prior reports that include cases with and without ROC may not be associated with outcome in the subset with ROC. Pre- clinical trial cohort studies may clarify such associations and assist in the planning of clinical trials.