Anticoagulation practices associated with bleeding and thrombosis in pediatric extracorporeal membrane oxygenation; a multi-center secondary analysis.

To determine associations between anticoagulation practices and bleeding and thrombosis during pediatric extracorporeal membrane oxygenation (ECMO), we performed a secondary analysis of prospectively collected data which included 481 children (<19 years), between January 2012 and September 2014. The primary outcome was bleeding or thrombotic events. Bleeding events included a blood product transfusion >80 ml/kg on any day, pulmonary hemorrhage, or intracranial bleeding, Thrombotic events included pulmonary emboli, intracranial clot, limb ischemia, cardiac clot, and arterial cannula or entire circuit change. Bleeding occurred in 42% of patients. Five percent of subjects thrombosed, of which 89% also bled. Daily bleeding odds were independently associated with day prior activated clotting time (ACT) (OR 1.03, 95% CI= 1.00, 1.05, p=0.047) and fibrinogen levels (OR 0.90, 95% CI 0.84, 0.96, p <0.001). Thrombosis odds decreased with increased day prior heparin dose (OR 0.88, 95% CI 0.81, 0.97, p=0.006). Lower ACT values and increased fibrinogen levels may be considered to decrease the odds of bleeding. Use of this single measure, however, may not be sufficient alone to guide optimal anticoagulation practice during ECMO.

Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children.

BACKGROUND: Targeted temperature management is recommended for comatose adults and children after out-of-hospital cardiac arrest; however, data on temperature management after in-hospital cardiac arrest are limited. METHODS: In a trial conducted at 37 children's hospitals, we compared two temperature interventions in children who had had in-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose children older than 48 hours and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a score of 70 or higher on the Vineland Adaptive Behavior Scales, second edition (VABS-II, on which scores range from 20 to 160, with higher scores indicating better function), was evaluated among patients who had had a VABS-II score of at least 70 before the cardiac arrest. RESULTS: The trial was terminated because of futility after 329 patients had undergone randomization. Among the 257 patients who had a VABS-II score of at least 70 before cardiac arrest and who could be evaluated, the rate of the primary efficacy outcome did not differ significantly between the hypothermia group and the normothermia group (36% [48 of 133 patients] and 39% [48 of 124 patients], respectively; relative risk, 0.92; 95% confidence interval [CI], 0.67 to 1.27; P=0.63). Among 317 patients who could be evaluated for change in neurobehavioral function, the change in VABS-II score from baseline to 12 months did not differ significantly between the groups (P=0.70). Among 327 patients who could be evaluated for 1-year survival, the rate of 1-year survival did not differ significantly between the hypothermia group and the normothermia group (49% [81 of 166 patients] and 46% [74 of 161 patients], respectively; relative risk, 1.07; 95% CI, 0.85 to 1.34; P=0.56). The incidences of blood-product use, infection, and serious adverse events, as well as 28-day mortality, did not differ significantly between groups. CONCLUSIONS: Among comatose children who survived in-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a favorable functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute; THAPCA-IH ClinicalTrials.gov number, NCT00880087 .).

Survival and Hemodynamics During Pediatric Cardiopulmonary Resuscitation for Bradycardia and Poor Perfusion Versus Pulseless Cardiac Arrest.

OBJECTIVES: The objective of this study was to compare survival outcomes and intra-arrest arterial blood pressures between children receiving cardiopulmonary resuscitation for bradycardia and poor perfusion and those with pulseless cardiac arrests. DESIGN: Prospective, multicenter observational study. SETTING: PICUs and cardiac ICUs of the Collaborative Pediatric Critical Care Research Network. PATIENTS: Children (< 19 yr old) who received greater than or equal to 1 minute of cardiopulmonary resuscitation with invasive arterial blood pressure monitoring in place. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 164 patients, 96 (59%) had bradycardia and poor perfusion as the initial cardiopulmonary resuscitation rhythm. Compared to those with initial pulseless rhythms, these children were younger (0.4 vs 1.4 yr; p = 0.005) and more likely to have a respiratory etiology of arrest (p < 0.001). Children with bradycardia and poor perfusion were more likely to survive to hospital discharge (adjusted odds ratio, 2.31; 95% CI, 1.10-4.83; p = 0.025) and survive with favorable neurologic outcome (adjusted odds ratio, 2.21; 95% CI, 1.04-4.67; p = 0.036). There were no differences in diastolic or systolic blood pressures or event survival (return of spontaneous circulation or return of circulation via extracorporeal cardiopulmonary resuscitation). Among patients with bradycardia and poor perfusion, 49 of 96 (51%) had subsequent pulselessness during the cardiopulmonary resuscitation event. During cardiopulmonary resuscitation, these patients had lower diastolic blood pressure (point estimate, -6.68 mm Hg [-10.92 to -2.44 mm Hg]; p = 0.003) and systolic blood pressure (point estimate, -12.36 mm Hg [-23.52 to -1.21 mm Hg]; p = 0.032) and lower rates of return of spontaneous circulation (26/49 vs 42/47; p < 0.001) than those who were never pulseless. CONCLUSIONS: Most children receiving cardiopulmonary resuscitation in ICUs had an initial rhythm of bradycardia and poor perfusion. They were more likely to survive to hospital discharge and survive with favorable neurologic outcomes than patients with pulseless arrests, although there were no differences in immediate event outcomes or intra-arrest hemodynamics. Patients who progressed to pulselessness after cardiopulmonary resuscitation initiation had lower intra-arrest hemodynamics and worse event outcomes than those who were never pulseless.

Methods Used to Maximize Follow-Up: Lessons Learned From the Therapeutic Hypothermia After Pediatric Cardiac Arrest Trials.

OBJECTIVES: To describe telephone interview completion rates among 12-month cardiac arrest survivors enrolled in the Therapeutic Hypothermia after Pediatric Cardiac Arrest In-Hospital and Out-of-Hospital trials, identify key characteristics of the completed follow-up interviews at both 3- and 12-month postcardiac arrest, and describe strategies implemented to promote follow-up. SETTING: Centralized telephone follow-up interviews. DESIGN: Retrospective report of data collected for Therapeutic Hypothermia after Pediatric Cardiac Arrest trials, and summary of strategies used to maximize follow-up completion. PATIENTS: Twelve-month survivors (n = 251) from 39 Therapeutic Hypothermia after Pediatric Cardiac Arrest PICU sites in the United States, Canada, and United Kingdom. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: The 3- and 12-month telephone interviews included completion of the Vineland Adaptive Behavior Scales, Second Edition. Vineland Adaptive Behavior Scales, Second Edition data were available on 96% of 3-month survivors (242/251) and 95% of 12-month survivors (239/251) with no differences in demographics between those with and without completed Vineland Adaptive Behavior Scales, Second Edition. At 12 months, a substantial minority of interviews were completed with caregivers other than parents (10%), after calls attempts were made on 6 or more days (18%), and during evenings/weekends (17%). Strategies included emphasizing the relationship between study teams and participants, ongoing communication between study team members across sites, promoting site engagement during the study's final year, and withholding payment for work associated with the primary outcome until work had been completed. CONCLUSIONS: It is feasible to use telephone follow-up interviews to successfully collect detailed neurobehavioral outcome about children following pediatric cardiac arrest. Future studies should consider availability of the telephone interviewer to conduct calls at times convenient for families, using a range of respondents, ongoing engagement with site teams, and site payment related to primary outcome completion.

Association Between Diastolic Blood Pressure During Pediatric In-Hospital Cardiopulmonary Resuscitation and Survival.

BACKGROUND: On the basis of laboratory cardiopulmonary resuscitation (CPR) investigations and limited adult data demonstrating that survival depends on attaining adequate arterial diastolic blood pressure (DBP) during CPR, the American Heart Association recommends using blood pressure to guide pediatric CPR. However, evidence-based blood pressure targets during pediatric CPR remain an important knowledge gap for CPR guidelines. METHODS: All children ≥37 weeks' gestation and <19 years old in Collaborative Pediatric Critical Care Research Network intensive care units with chest compressions for ≥1 minute and invasive arterial blood pressure monitoring before and during CPR between July 1, 2013, and June 31, 2016, were included. Mean DBP during CPR and Utstein-style standardized cardiac arrest data were collected. The hypothesis was that DBP ≥25 mm Hg during CPR in infants and ≥30 mm Hg in children ≥1 year old would be associated with survival. Primary outcome was survival to hospital discharge. Secondary outcome was survival to hospital discharge with favorable neurological outcome, defined as Pediatric Cerebral Performance Categories 1 to 3 or no worse than prearrest baseline. Multivariable Poisson regression models with robust error estimates were used to estimate the relative risk of outcomes. RESULTS: Blinded investigators analyzed blood pressure waveforms during CPR from 164 children, including 60% <1 year old, 60% with congenital heart disease, and 54% after cardiac surgery. The immediate cause of arrest was hypotension in 67%, respiratory decompensation in 44%, and arrhythmia in 19%. Median duration of CPR was 8 minutes (quartiles, 3 and 27 minutes). Ninety percent survived the event, 68% with return of spontaneous circulation and 22% by extracorporeal life support. Forty-seven percent survived to hospital discharge, and 43% survived to discharge with favorable neurological outcome. Maintaining mean DBP ≥25 mm Hg in infants and ≥30 mm Hg in children ≥1 year old occurred in 101 of 164 children (62%) and was associated with survival (adjusted relative risk, 1.7; 95% confidence interval, 1.2-2.6; P=0.007) and survival with favorable neurological outcome (adjusted relative risk, 1.6; 95% confidence interval, 1.1-2.5; P=0.02). CONCLUSIONS: These data demonstrate that mean DBP ≥25 mm Hg during CPR in infants and ≥30 mm Hg in children ≥1 year old was associated with greater likelihood of survival to hospital discharge and survival with favorable neurological outcome.

Extracorporeal Cardiopulmonary Resuscitation: One-Year Survival and Neurobehavioral Outcome Among Infants and Children With In-Hospital Cardiac Arrest.

OBJECTIVE: To describe neurobehavioral outcomes and investigate factors associated with survival and survival with good neurobehavioral outcome 1 year after in-hospital cardiac arrest for children who received extracorporeal cardiopulmonary resuscitation. DESIGN: Secondary analysis of the Therapeutic Hypothermia after Pediatric Cardiac Arrest In-Hospital trial. SETTING: Thirty-seven PICUs in the United States, Canada, and the United Kingdom. PATIENTS: Children (n = 147) resuscitated with extracorporeal cardiopulmonary resuscitation following in-hospital cardiac arrest. INTERVENTIONS: Neurobehavioral status was assessed using the Vineland Adaptive Behavior Scales, Second Edition, at prearrest baseline and 12 months postarrest. Norms for Vineland Adaptive Behavior Scales, Second Edition, are 100 (mean) ± 15 (SD). Higher scores indicate better functioning. Outcomes included 12-month survival, 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points from baseline, and 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. MEASUREMENTS AND MAIN RESULTS: Of 147 children receiving extracorporeal cardiopulmonary resuscitation, 125 (85.0%) had a preexisting cardiac condition, 75 (51.0%) were postcardiac surgery, and 84 (57.1%) were less than 1 year old. Duration of chest compressions was greater than 30 minutes for 114 (77.5%). Sixty-one (41.5%) survived to 12 months, 32 (22.1%) survived to 12 months with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points from baseline, and 39 (30.5%) survived to 12 months with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. On multivariable analyses, open-chest cardiac massage was independently associated with greater 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points and greater 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. Higher minimum postarrest lactate and preexisting gastrointestinal conditions were independently associated with lower 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points and lower 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. CONCLUSIONS: About one third of children survived with good neurobehavioral outcome 1 year after receiving extracorporeal cardiopulmonary resuscitation for in-hospital arrest. Open-chest cardiac massage and minimum postarrest lactate were associated with survival with good neurobehavioral outcome at 1 year.

Ventilation Rates and Pediatric In-Hospital Cardiac Arrest Survival Outcomes.

OBJECTIVES: The objective of this study was to associate ventilation rates during in-hospital cardiopulmonary resuscitation with 1) arterial blood pressure during cardiopulmonary resuscitation and 2) survival outcomes. DESIGN: Prospective, multicenter observational study. SETTING: Pediatric and pediatric cardiac ICUs of the Collaborative Pediatric Critical Care Research Network. PATIENTS: Intubated children (≥ 37 wk gestation and < 19 yr old) who received at least 1 minute of cardiopulmonary resuscitation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Arterial blood pressure and ventilation rate (breaths/min) were manually extracted from arterial line and capnogram waveforms. Guideline rate was defined as 10 ± 2 breaths/min; high ventilation rate as greater than or equal to 30 breaths/min in children less than 1 year old, and greater than or equal to 25 breaths/min in older children. The primary outcome was survival to hospital discharge. Regression models using Firth penalized likelihood assessed the association between ventilation rates and outcomes. Ventilation rates were available for 52 events (47 patients). More than half of patients (30/47; 64%) were less than 1 year old. Eighteen patients (38%) survived to discharge. Median event-level average ventilation rate was 29.8 breaths/min (interquartile range, 23.8-35.7). No event-level average ventilation rate was within guidelines; 30 events (58%) had high ventilation rates. The only significant association between ventilation rate and arterial blood pressure occurred in children 1 year old or older and was present for systolic blood pressure only (-17.8 mm Hg/10 breaths/min; 95% CI, -27.6 to -8.1; p < 0.01). High ventilation rates were associated with a higher odds of survival to discharge (odds ratio, 4.73; p = 0.029). This association was stable after individually controlling for location (adjusted odds ratio, 5.97; p = 0.022), initial rhythm (adjusted odds ratio, 3.87; p = 0.066), and time of day (adjusted odds ratio, 4.12; p = 0.049). CONCLUSIONS: In this multicenter cohort, ventilation rates exceeding guidelines were common. Among the range of rates delivered, higher rates were associated with improved survival to hospital discharge.

Cardiac Arrest Outcomes in Children With Preexisting Neurobehavioral Impairment.

OBJECTIVES: To describe survival and 3-month and 12-month neurobehavioral outcomes in children with preexisting neurobehavioral impairment enrolled in one of two parallel randomized clinical trials of targeted temperature management. DESIGN: Secondary analysis of Therapeutic Hypothermia after Pediatric Cardiac Arrest In-Hospital and Out-of-Hospital trials data. SETTING: Forty-one PICUs in the United States, Canada, and United Kingdom. PATIENTS: Eighty-four participants (59 in-hospital cardiac arrest and 25 out-of-hospital cardiac arrest), 49 males, 35 females, mean age 4.6 years (SD, 5.36 yr), with precardiac arrest neurobehavioral impairment (Vineland Adaptive Behavior Scales, Second Edition composite score < 70). All required chest compressions for greater than or equal to 2 minutes, were comatose and required mechanical ventilation after return of circulation. INTERVENTIONS: Neurobehavioral function was assessed using the Vineland Adaptive Behavior Scales, Second Edition at baseline (reflecting precardiac arrest status), and at 3 and 12 months postcardiac arrest, followed by on-site cognitive evaluation. Vineland Adaptive Behavior Scales, Second Edition norms are 100 (mean) ± 15 (SD); higher scores indicate better function. Analyses evaluated survival, changes in Vineland Adaptive Behavior Scales, Second Edition, and cognitive functioning. MEASUREMENTS AND MAIN RESULTS: Twenty-eight of 84 (33%) survived to 12 months (in-hospital cardiac arrest, 19/59 (32%); out-of-hospital cardiac arrest, 9/25 [36%]). In-hospital cardiac arrest (but not out-of-hospital cardiac arrest) survival rate was significantly lower compared with the Therapeutic Hypothermia after Pediatric Cardiac Arrest group without precardiac arrest neurobehavioral impairment. Twenty-five survived with decrease in Vineland Adaptive Behavior Scales, Second Edition less than or equal to 15 (in-hospital cardiac arrest, 18/59 (31%); out-of-hospital cardiac arrest, 7/25 [28%]). At 3-months postcardiac arrest, mean Vineland Adaptive Behavior Scales, Second Edition scores declined significantly (-5; SD, 14; p < 0.05). At 12 months, Vineland Adaptive Behavior Scales, Second Edition declined after out-of-hospital cardiac arrest (-10; SD, 12; p < 0.05), but not in-hospital cardiac arrest (0; SD, 15); 43% (12/28) had unchanged or improved scores. CONCLUSIONS: This study demonstrates the feasibility, utility, and challenge of including this population in clinical neuroprotection trials. In children with preexisting neurobehavioral impairment, one-third survived to 12 months and their neurobehavioral outcomes varied broadly.

Development of the Pediatric Extracorporeal Membrane Oxygenation Prediction Model for Risk-Adjusting Mortality.

OBJECTIVES: To develop a prognostic model for predicting mortality at time of extracorporeal membrane oxygenation initiation for children which is important for determining center-specific risk-adjusted outcomes. DESIGN: Multivariable logistic regression using a large national cohort of pediatric extracorporeal membrane oxygenation patients. SETTING: The ICUs of the eight tertiary care children's hospitals of the Collaborative Pediatric Critical Care Research Network. PATIENTS: Five-hundred fourteen children (< 19 yr old), enrolled with an initial extracorporeal membrane oxygenation run for any indication between January 2012 and September 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 514 first extracorporeal membrane oxygenation runs were analyzed with an overall mortality of 45% (n = 232). Weighted logistic regression was used for model selection and internal validation was performed using cross validation. The variables included in the Pediatric Extracorporeal Membrane Oxygenation Prediction model were age (pre-term neonate, full-term neonate, infant, child, and adolescent), indication for extracorporeal membrane oxygenation (extracorporeal cardiopulmonary resuscitation, cardiac, or respiratory), meconium aspiration, congenital diaphragmatic hernia, documented blood stream infection, arterial blood pH, partial thromboplastin time, and international normalized ratio. The highest risk of mortality was associated with the presence of a documented blood stream infection (odds ratio, 5.26; CI, 1.90-14.57) followed by extracorporeal cardiopulmonary resuscitation (odds ratio, 4.36; CI, 2.23-8.51). The C-statistic was 0.75 (95% CI, 0.70-0.80). CONCLUSIONS: The Pediatric Extracorporeal Membrane Oxygenation Prediction model represents a model for predicting in-hospital mortality among children receiving extracorporeal membrane oxygenation support for any indication. Consequently, it holds promise as the first comprehensive pediatric extracorporeal membrane oxygenation risk stratification model which is important for benchmarking extracorporeal membrane oxygenation outcomes across many centers.

Survival and Cardiopulmonary Resuscitation Hemodynamics Following Cardiac Arrest in Children With Surgical Compared to Medical Heart Disease.

OBJECTIVES: To assess the association of diastolic blood pressure cutoffs (≥ 25 mm Hg in infants and ≥ 30 mm Hg in children) during cardiopulmonary resuscitation with return of spontaneous circulation and survival in surgical cardiac versus medical cardiac patients. Secondarily, we assessed whether these diastolic blood pressure targets were feasible to achieve and associated with outcome in physiology unique to congenital heart disease (single ventricle infants, open chest), and influenced outcomes when extracorporeal cardiopulmonary resuscitation was deployed. DESIGN: Multicenter, prospective, observational cohort analysis. SETTING: Tertiary PICU and cardiac ICUs within the Collaborative Pediatric Critical Care Research Network. PATIENTS: Patients with invasive arterial catheters during cardiopulmonary resuscitation and surgical cardiac or medical cardiac illness category. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hemodynamic waveforms during cardiopulmonary resuscitation were analyzed on 113 patients, 88 surgical cardiac and 25 medical cardiac. A similar percent of surgical cardiac (51/88; 58%) and medical cardiac (17/25; 68%) patients reached the diastolic blood pressure targets (p = 0.488). Achievement of diastolic blood pressure target was associated with improved survival to hospital discharge in surgical cardiac patients (p = 0.018), but not medical cardiac patients (p = 0.359). Fifty-three percent (16/30) of patients with single ventricles attained the target diastolic blood pressure. In patients with an open chest at the start of chest compressions, 11 of 20 (55%) attained the target diastolic blood pressure. In the 33 extracorporeal cardiopulmonary resuscitation patients, 16 patients (48%) met the diastolic blood pressure target with no difference between survivors and nonsurvivors (p = 0.296). CONCLUSIONS: During resuscitation in an ICU, with invasive monitoring in place, diastolic blood pressure targets of greater than or equal to 25 mm Hg in infants and greater than or equal to 30 mm Hg in children can be achieved in patients with both surgical and medical heart disease. Achievement of diastolic blood pressure target was associated with improved survival to hospital discharge in surgical cardiac patients, but not medical cardiac patients. Diastolic blood pressure targets were feasible to achieve in 1) single ventricle patients, 2) open chest physiology, and 3) extracorporeal cardiopulmonary resuscitation patients.

Therapeutic hypothermia after out-of-hospital cardiac arrest in children.

BACKGROUND: Therapeutic hypothermia is recommended for comatose adults after witnessed out-of-hospital cardiac arrest, but data about this intervention in children are limited. METHODS: We conducted this trial of two targeted temperature interventions at 38 children's hospitals involving children who remained unconscious after out-of-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose patients who were older than 2 days and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a Vineland Adaptive Behavior Scales, second edition (VABS-II), score of 70 or higher (on a scale from 20 to 160, with higher scores indicating better function), was evaluated among patients with a VABS-II score of at least 70 before cardiac arrest. RESULTS: A total of 295 patients underwent randomization. Among the 260 patients with data that could be evaluated and who had a VABS-II score of at least 70 before cardiac arrest, there was no significant difference in the primary outcome between the hypothermia group and the normothermia group (20% vs. 12%; relative likelihood, 1.54; 95% confidence interval [CI], 0.86 to 2.76; P=0.14). Among all the patients with data that could be evaluated, the change in the VABS-II score from baseline to 12 months was not significantly different (P=0.13) and 1-year survival was similar (38% in the hypothermia group vs. 29% in the normothermia group; relative likelihood, 1.29; 95% CI, 0.93 to 1.79; P=0.13). The groups had similar incidences of infection and serious arrhythmias, as well as similar use of blood products and 28-day mortality. CONCLUSIONS: In comatose children who survived out-of-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a good functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute and others; THAPCA-OH ClinicalTrials.gov number, NCT00878644.).

Factors Associated with Bleeding and Thrombosis in Children Receiving Extracorporeal Membrane Oxygenation.

RATIONALE: Extracorporeal membrane oxygenation (ECMO) is used for respiratory and cardiac failure in children but is complicated by bleeding and thrombosis. OBJECTIVES: (1) To measure the incidence of bleeding (blood loss requiring transfusion or intracranial hemorrhage) and thrombosis during ECMO support; (2) to identify factors associated with these complications; and (3) to determine the impact of these complications on patient outcome. METHODS: This was a prospective, observational cohort study in pediatric, cardiac, and neonatal intensive care units in eight hospitals, carried out from December 2012 to September 2014. MEASUREMENTS AND MAIN RESULTS: ECMO was used on 514 consecutive patients under age 19 years. Demographics, anticoagulation practices, severity of illness, circuitry components, bleeding, thrombotic events, and outcome were recorded. Survival was 54.9%. Bleeding occurred in 70.2%, including intracranial hemorrhage in 16%, and was independently associated with higher daily risk of mortality. Circuit component changes were required in 31.1%, and patient-related clots occurred in 12.8%. Laboratory sampling contributed to transfusion requirement in 56.6%, and was the sole reason for at least one transfusion in 42.2% of patients. Pump type was not associated with bleeding, thrombosis, hemolysis, or mortality. Hemolysis was predictive of subsequent thrombotic events. Neither hemolysis nor thrombotic events increased the risk of mortality. CONCLUSIONS: The incidences of bleeding and thrombosis are high during ECMO support. Laboratory sampling is a major contributor to transfusion during ECMO. Strategies to reduce the daily risk of bleeding and thrombosis, and different thresholds for transfusion, may be appropriate subjects of future trials to improve outcomes of children requiring this supportive therapy.

Identifying Risk for Acute Kidney Injury in Infants and Children Following Cardiac Arrest.

OBJECTIVES: Our goal was to identify risk factors for acute kidney injury in children surviving cardiac arrest. DESIGN: Retrospective analysis of a public access dataset. SETTING: Fifteen children's hospitals associated with the Pediatric Emergency Care Applied Research Network. PATIENTS: Two hundred ninety-six subjects between 1 day and 18 years old who experienced in-hospital or out-of-hospital cardiac arrest between July 1, 2003, and December 31, 2004. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Our primary outcome was development of acute kidney injury as defined by the Acute Kidney Injury Network criteria. An ordinal probit model was developed. We found six critical explanatory variables, including total number of epinephrine doses, postcardiac arrest blood pressure, arrest location, presence of a chronic lung condition, pH, and presence of an abnormal baseline creatinine. Total number of epinephrine doses received as well as rate of epinephrine dosing impacted acute kidney injury risk and severity of acute kidney injury. CONCLUSIONS: This study is the first to identify risk factors for acute kidney injury in children after cardiac arrest. Our findings regarding the impact of epinephrine dosing are of particular interest and suggest potential for epinephrine toxicity with regard to acute kidney injury. The ability to identify and potentially modify risk factors for acute kidney injury after cardiac arrest may lead to improved morbidity and mortality in this population.

Variability in Usual Care Mechanical Ventilation for Pediatric Acute Respiratory Distress Syndrome: Time for a Decision Support Protocol?

OBJECTIVES: Although pediatric intensivists philosophically embrace lung protective ventilation for acute lung injury and acute respiratory distress syndrome, we hypothesized that ventilator management varies. We assessed ventilator management by evaluating changes to ventilator settings in response to blood gases, pulse oximetry, or end-tidal CO2. We also assessed the potential impact that a pediatric mechanical ventilation protocol adapted from National Heart Lung and Blood Institute acute respiratory distress syndrome network protocols could have on reducing variability by comparing actual changes in ventilator settings to those recommended by the protocol. DESIGN: Prospective observational study. SETTING: Eight tertiary care U.S. PICUs, October 2011 to April 2012. PATIENTS: One hundred twenty patients (age range 17 d to 18 yr) with acute lung injury/acute respiratory distress syndrome. MEASUREMENTS AND MAIN RESULTS: Two thousand hundred arterial and capillary blood gases, 3,964 oxygen saturation by pulse oximetry, and 2,757 end-tidal CO2 values were associated with 3,983 ventilator settings. Ventilation mode at study onset was pressure control 60%, volume control 19%, pressure-regulated volume control 18%, and high-frequency oscillatory ventilation 3%. Clinicians changed FIO2 by ±5 or ±10% increments every 8 hours. Positive end-expiratory pressure was limited at ~10 cm H2O as oxygenation worsened, lower than would have been recommended by the protocol. In the first 72 hours of mechanical ventilation, maximum tidal volume/kg using predicted versus actual body weight was 10.3 (8.5-12.9) (median [interquartile range]) versus 9.2 mL/kg (7.6-12.0) (p < 0.001). Intensivists made changes similar to protocol recommendations 29% of the time, opposite to the protocol's recommendation 12% of the time and no changes 56% of the time. CONCLUSIONS: Ventilator management varies substantially in children with acute respiratory distress syndrome. Opportunities exist to minimize variability and potentially injurious ventilator settings by using a pediatric mechanical ventilation protocol offering adequately explicit instructions for given clinical situations. An accepted protocol could also reduce confounding by mechanical ventilation management in a clinical trial.

Potential Acceptability of a Pediatric Ventilator Management Computer Protocol.

OBJECTIVES: To examine issues regarding the granularity (size/scale) and potential acceptability of recommendations in a ventilator management protocol for children with pediatric acute respiratory distress syndrome. DESIGN: Survey/questionnaire. SETTING: The eight PICUs in the Collaborative Pediatric Critical Care Research Network. PARTICIPANTS: One hundred twenty-two physicians (attendings and fellows). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used an online questionnaire to examine attitudes and assessed recommendations with 50 clinical scenarios. Overall 80% of scenario recommendations were accepted. Acceptance did not vary by provider characteristics but did vary by ventilator mode (high-frequency oscillatory ventilation 83%, pressure-regulated volume control 82%, pressure control 75%; p = 0.002) and variable adjusted (ranging from 88% for peak inspiratory pressure and 86% for FIO2 changes to 69% for positive end-expiratory pressure changes). Acceptance did not vary based on child size/age. There was a preference for smaller positive end-expiratory pressure changes but no clear granularity preference for other variables. CONCLUSIONS: Although overall acceptance rate for scenarios was good, there was little consensus regarding the size/scale of ventilator setting changes for children with pediatric acute respiratory distress syndrome. An acceptable protocol could support robust evaluation of ventilator management strategies. Further studies are needed to determine if adherence to an explicit protocol leads to better outcomes.

Hospital-level variation in inpatient cost among children receiving extracorporeal membrane oxygenation.

OBJECTIVE: Pediatric extracorporeal membrane oxygenation (ECMO) varies in the way care is provided from hospital to hospital. This variability in hospital ECMO care can be represented by the variation in ECMO costs. We hypothesized that hospitals will demonstrate large variations in case-mix-adjusted ECMO inpatient costs for children requiring ECMO and higher volume hospitals will have lower associated costs. METHODS: We retrospectively analyzed the inpatient cost of children receiving ECMO in 2006, 2009 and 2012, using the Healthcare Cost and Utilization Project Kids' Inpatient Database. We used a hierarchical linear regression model and the intraclass correlation coefficient to quantify how much of the difference in ECMO inpatient costs was associated with the hospital where a child received care. To do this, we adjusted for patient factors, hospital factors and potentially modifiable factors such as complications, procedures and length of stay. RESULTS: The median inflation-adjusted inpatient costs for children requiring ECMO were $183,000, $240,000 and $241,000 in years 2006, 2009 and 2012, respectively. The largest median cost for ECMO cases in a given hospital in a given year ($690,000) was more than 11 times that of the smallest median cost ($60,000). After case-mix adjustment, 27% of the variation in inpatient costs was associated with the hospital where ECMO care was provided. Average hospital costs were not associated with hospital ECMO volume. CONCLUSIONS: The large variation in ECMO inpatient costs between hospitals suggests great variation in care between hospitals, which is important because hospitals have a co-existing variation in ECMO survival rates.

Functional Outcome Trajectories After Out-of-Hospital Pediatric Cardiac Arrest.

OBJECTIVES: To analyze functional performance measures collected prospectively during the conduct of a clinical trial that enrolled children (up to age 18 yr old), resuscitated after out-of-hospital cardiac arrest, who were at high risk of poor outcomes. DESIGN: Children with Glasgow Motor Scale score less than 5, within 6 hours of resuscitation, were enrolled in a clinical trial that compared two targeted temperature management interventions (THAPCA-OH, NCT00878644). The primary outcome, 12-month survival with Vineland Adaptive Behavior Scale, second edition, score greater or equal to 70, did not differ between groups. SETTING: Thirty-eight North American PICUs. PARTICIPANTS: Two hundred ninety-five children were enrolled; 270 of 295 had baseline Vineland Adaptive Behavior Scale, second edition, scores greater or equal to 70; 87 of 270 survived 1 year. INTERVENTIONS: Targeted temperatures were 33.0°C and 36.8°C for hypothermia and normothermia groups. MEASUREMENTS AND MAIN RESULTS: Baseline measures included Vineland Adaptive Behavior Scale, second edition, Pediatric Cerebral Performance Category, and Pediatric Overall Performance Category. Pediatric Cerebral Performance Category and Pediatric Overall Performance Category were rescored at hospital discharges; all three were scored at 3 and 12 months. In survivors with baseline Vineland Adaptive Behavior Scale, second edition scores greater or equal to 70, we evaluated relationships of hospital discharge Pediatric Cerebral Performance Category with 3- and 12-month scores and between 3- and 12-month Vineland Adaptive Behavior Scale, second edition, scores. Hospital discharge Pediatric Cerebral Performance Category scores strongly predicted 3- and 12-month Pediatric Cerebral Performance Category (r = 0.82 and 0.79; p < 0.0001) and Vineland Adaptive Behavior Scale, second edition, scores (r = -0.81 and -0.77; p < 0.0001). Three-month Vineland Adaptive Behavior Scale, second edition, scores strongly predicted 12-month performance (r = 0.95; p < 0.0001). Hypothermia treatment did not alter these relationships. CONCLUSIONS: In comatose children, with Glasgow Motor Scale score less than 5 in the initial hours after out-of-hospital cardiac arrest resuscitation, function scores at hospital discharge and at 3 months predicted 12-month performance well in the majority of survivors.

Pediatric Out-of-Hospital Cardiac Arrest Characteristics and Their Association With Survival and Neurobehavioral Outcome.

OBJECTIVE: To investigate relationships between cardiac arrest characteristics and survival and neurobehavioral outcome among children recruited to the Therapeutic Hypothermia after Pediatric Cardiac Arrest Out-of-Hospital trial. DESIGN: Secondary analysis of Therapeutic Hypothermia after Pediatric Cardiac Arrest Out-of-Hospital trial data. SETTING: Thirty-six PICUs in the United States and Canada. PATIENTS: All children (n = 295) had chest compressions for greater than or equal to 2 minutes, were comatose, and required mechanical ventilation after return of circulation. INTERVENTIONS: Neurobehavioral function was assessed using the Vineland Adaptive Behavior Scales, Second Edition at baseline (reflecting prearrest status) and 12 months postarrest. U.S. norms for Vineland Adaptive Behavior Scales, Second Edition scores are 100 (mean) ± 15 (SD). Higher scores indicate better functioning. Outcomes included 12-month survival and 12-month survival with Vineland Adaptive Behavior Scales, Second Edition greater than or equal to 70. MEASUREMENT AND MAIN RESULTS: Cardiac etiology of arrest, initial arrest rhythm of ventricular fibrillation/tachycardia, shorter duration of chest compressions, compressions not required at hospital arrival, fewer epinephrine doses, and witnessed arrest were associated with greater 12-month survival and 12-month survival with Vineland Adaptive Behavior Scales, Second Edition greater than or equal to 70. Weekend arrest was associated with lower 12-month survival. Body habitus was associated with 12-month survival with Vineland Adaptive Behavior Scales, Second Edition greater than or equal to 70; underweight children had better outcomes, and obese children had worse outcomes. On multivariate analysis, acute life threatening event/sudden unexpected infant death, chest compressions more than 30 minutes, and weekend arrest were associated with lower 12-month survival; witnessed arrest was associated with greater 12-month survival. Acute life threatening event/sudden unexpected infant death, other respiratory causes of arrest except drowning, other/unknown causes of arrest, and compressions more than 30 minutes were associated with lower 12-month survival with Vineland Adaptive Behavior Scales, Second Edition greater than or equal to 70. CONCLUSIONS: Many factors are associated with survival and neurobehavioral outcome among children who are comatose and require mechanical ventilation after out-of-hospital cardiac arrest. These factors may be useful for identifying children at risk for poor outcomes, and for improving prevention and resuscitation strategies.

Family Burden After Out-of-Hospital Cardiac Arrest in Children.

OBJECTIVES: To describe family burden among caregivers of children who survived out-of-hospital cardiac arrest and who were at high risk for neurologic disability and examine relationships between family burden, child functioning, and other factors during the first year post arrest. DESIGN: Secondary analysis of data from the Therapeutic Hypothermia after Pediatric Cardiac Arrest Out-of-Hospital trial. SETTING: Thirty-six PICUs in the United States and Canada. PATIENTS: Seventy-seven children recruited to the Therapeutic Hypothermia after Pediatric Cardiac Arrest Out-of-Hospital trial who had normal prearrest neurologic functioning and were alive 1 year post arrest. INTERVENTIONS: Family burden was assessed using the Infant Toddler Quality of Life Questionnaire for children less than 5 years old and the Child Health Questionnaire for children 5 years old or older at baseline (reflecting prearrest status), 3 months, and 12 months post arrest. Child functioning was assessed using the Vineland Adaptive Behavior Scale II, the Pediatric Overall Performance Category, and Pediatric Cerebral Performance Category scales and caregiver perception of global functioning. MEASUREMENTS AND MAIN RESULTS: Fifty-six children (72.7%) were boys, 48 (62.3%) were whites, and 50 (64.9%) were less than 5 years old prior to out-of-hospital cardiac arrest. Family burden at baseline was not significantly different from reference values. Family burden was increased at 3 and 12 months post arrest compared with reference values (p < 0.001). Worse Pediatric Overall Performance Category and Pediatric Cerebral Performance Category, lower adaptive behavior, lower global functioning, and higher family burden all measured 3 months post arrest were associated with higher family burden 12 months post arrest (p < 0.05). Sociodemographics and prearrest child functioning were not associated with family burden 12 months post arrest. CONCLUSIONS: Families of children who survive out-of-hospital cardiac arrest and have high risk for neurologic disability often experience substantial burden during the first year post arrest. The extent of child dysfunction 3 months post arrest is associated with family burden at 12 months.

Nurses' Attitudes Toward Clinical Research: Experience of the Therapeutic Hypothermia After Pediatric Cardiac Arrest Trials.

OBJECTIVES: To understand factors affecting nurses' attitudes toward the Therapeutic Hypothermia After Pediatric Cardiac Arrest trials and association with approach/consent rates. DESIGN: Cross-sectional survey of pediatric/cardiac intensive care nurses' perceptions of the trials. SETTING: Study was conducted at 16 of 38 self-selected study sites. SUBJECTS: Pediatric and cardiac intensive care nurses. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the proportion of nurses with positive perceptions, as defined by agree or strongly agree with the statement "I am happy to take care of a Therapeutic Hypothermia after Pediatric Cardiac Arrest patient". Associations between perceptions and study approach/consent rates were also explored. Of 2,241 nurses invited, 1,387 (62%) completed the survey and 77% reported positive perceptions of the trials. Nurses, who felt positively about the scientific question, the study team, and training received, were more likely to have positive perceptions of the trials (p < 0.001). Nurses who had previously cared for a research patient had significantly more positive perceptions of Therapeutic Hypothermia After Pediatric Cardiac Arrest compared with those who had not (79% vs 54%; p < 0.001). Of the 754 nurses who cared for a Therapeutic Hypothermia After Pediatric Cardiac Arrest patient, 82% had positive perceptions, despite 86% reporting it required more work. Sixty-nine percent believed that hypothermia reduces brain injury and mortality; sites had lower consent rates when their nurses believed that hypothermia was beneficial. Institution-specific approach rates were positively correlated with nurses' perceptions of institutional support for the trial (r = 0.54; p = 0.04), ICU support (r = 0.61; p = 0.02), and the importance of conducting the trial in children (r = 0.61; p = 0.01). CONCLUSIONS: The majority of nurses had positive perceptions of the Therapeutic Hypothermia After Pediatric Cardiac Arrest trials. Institutional, colleague, and study team support and training were contributing factors. Despite increased work, nurses remained enthusiastic demonstrating that studies with intensive bedside nursing procedures are feasible. Institutions whose nurses believed hypothermia was beneficial had lower consent rates, suggesting that educating nurses on study rationale and equipoise may enhance study participation.