Assessing the impact of risk-based data monitoring on outcomes for a paediatric multicentre randomised controlled trial.

BACKGROUND/AIMS: Regulatory guidelines recommend that sponsors develop a risk-based approach to monitoring clinical trials. However, there is a lack of evidence to guide the effective implementation of monitoring activities encompassed in this approach. The aim of this study was to assess the efficiency and impact of the risk-based monitoring approach used for a multicentre randomised controlled trial comparing treatments in paediatric patients undergoing cardiac bypass surgery. METHODS: This is a secondary analysis of data from a randomised controlled trial that implemented targeted source data verification as part of the risk-based monitoring approach. Monitoring duration and source to database error rates were calculated across the monitored trial dataset. The monitored and unmonitored trial dataset, and simulated trial datasets with differing degrees of source data verification and cohort sizes were compared for their effect on trial outcomes. RESULTS: In total, 106,749 critical data points across 1,282 participants were verified from source data either remotely or on-site during the trial. The total time spent monitoring was 365 hours, with a median (interquartile range) of 10 (7, 16) minutes per participant. An overall source to database error rate of 3.1% was found, and this did not differ between treatment groups. A low rate of error was found for all outcomes undergoing 100% source data verification, with the exception of two secondary outcomes with error rates >10%. Minimal variation in trial outcomes were found between the unmonitored and monitored datasets. Reduced degrees of source data verification and reduced cohort sizes assessed using simulated trial datasets had minimal impact on trial outcomes. CONCLUSIONS: Targeted source data verification of data critical to trial outcomes, which carried with it a substantial time investment, did not have an impact on study outcomes in this trial. This evaluation of the cost-effectiveness of targeted source data verification contributes to the evidence-base regarding the context where reduced emphasis should be placed on source data verification as the foremost monitoring activity.

Pragmatic Randomized Trial of Corticosteroids and Inhaled Epinephrine for Bronchiolitis in Children in Intensive Care.

OBJECTIVE: To determine whether the combination of systemic corticosteroids and nebulized epinephrine, compared with standard care, reduces the duration of positive pressure support in children with bronchiolitis admitted to intensive care. STUDY DESIGN: We performed a pragmatic, multicenter, open-label, randomized trial between July 2013 and November 2019 in children younger than 18 months old with a clinical diagnosis of bronchiolitis. The intervention group received the equivalent of 13 mg/kg prednisolone over 3 days, then 1 mg/kg daily for 3 days, plus 0.05 mL/kg of nebulized 1% epinephrine made up to 6 ml with 0.9% saline via jet nebulizer and mask using oxygen at 12 l/min every 30 minutes for 5 doses, then 1-4 hourly for 3 days, then as required for 3 days. The primary outcome was clinician-managed duration of positive pressure support in intensive care defined as high-flow nasal-prong oxygen, nasopharyngeal continuous positive airway pressure, or mechanical ventilation. RESULTS: In total, 210 children received positive pressure support. In the corticosteroid-epinephrine group, 107 children received positive pressure support for a geometric mean of 26 (95% CI, 22-32) hours compared with 40 (95% CI 34-47) hours in 103 controls, adjusted ratio 0.66 (95% CI 0.51-0.84), P = .001. In the intervention group, 41 (38%) children experienced at least 1 adverse event, compared with 39 (38%) in the control group. CONCLUSIONS: In children with severe bronchiolitis, the duration of clinician-managed pressure support was reduced by regular treatment with systemic corticosteroids and inhaled epinephrine compared with standard care. CLINICAL TRIAL REGISTRATION: Australian Clinical Trials Research Network: ACTRN12613000316707.

Temperature Management and Health-Related Quality of Life in Children 3 Years After Cardiac Arrest.

OBJECTIVES: Therapeutic hypothermia minimizes neuronal injury in animal models of hypoxic-ischemic encephalopathy with greater effect when used sooner after the insult. Clinical trials generally showed limited benefit but are difficult to perform in a timely manner. In this clinical study, we evaluated the association between the use of hypothermia (or not) and health-related quality of life among survivors of pediatric cardiac arrest as well as overall mortality. DESIGN: Single-center, retrospectively identified cohort with prospective assessment of health-related quality of life. SETTING: PICU of a pediatric hospital. PATIENTS: Children with either out-of-hospital or in-hospital cardiac arrest from January 2012 to December 2017. INTERVENTIONS: Patients were assigned into two groups: those who received therapeutic hypothermia at less than or equal to 35°C and those who did not receive therapeutic hypothermia but who had normothermia targeted (36-36.5°C). The primary outcome was health-related quality of life assessment and the secondary outcome was PICU mortality. MEASUREMENTS AND MAIN RESULTS: We studied 239 children, 112 (47%) in the therapeutic hypothermia group. The median (interquartile range) of lowest temperature reached in the 48 hours post cardiac arrest in the therapeutic hypothermia group was 33°C (32.6-33.6°C) compared with 35.4°C (34.7-36.2°C) in the no therapeutic hypothermia group (p < 0.001). At follow-up, 152 (64%) were alive and health-related quality of life assessments were completed in 128. Use of therapeutic hypothermia was associated with higher lactate and lower pH at baseline. After regression adjustment, therapeutic hypothermia (as opposed to no therapeutic hypothermia) was associated with higher physical (mean difference, 15.8; 95% CI, 3.5-27.9) and psychosocial scores (13.6 [5.8-21.5]). These observations remained even when patients with a temperature greater than 37.5°C were excluded. We failed to find an association between therapeutic hypothermia and lower mortality. CONCLUSIONS: Out-of-hospital or in-hospital cardiac arrest treated with therapeutic hypothermia was associated with higher health-related quality of life scores despite having association with higher lactate and lower pH after resuscitation. We failed to identify an association between use of therapeutic hypothermia and lower mortality.

Effect of Nitric Oxide via Cardiopulmonary Bypass on Ventilator-Free Days in Young Children Undergoing Congenital Heart Disease Surgery: The NITRIC Randomized Clinical Trial.

Importance: In children undergoing heart surgery, nitric oxide administered into the gas flow of the cardiopulmonary bypass oxygenator may reduce postoperative low cardiac output syndrome, leading to improved recovery and shorter duration of respiratory support. It remains uncertain whether nitric oxide administered into the cardiopulmonary bypass oxygenator improves ventilator-free days (days alive and free from mechanical ventilation). Objective: To determine the effect of nitric oxide applied into the cardiopulmonary bypass oxygenator vs standard care on ventilator-free days in children undergoing surgery for congenital heart disease. Design, Setting, and Participants: Double-blind, multicenter, randomized clinical trial in 6 pediatric cardiac surgical centers in Australia, New Zealand, and the Netherlands. A total of 1371 children younger than 2 years undergoing congenital heart surgery were randomized between July 2017 and April 2021, with 28-day follow-up of the last participant completed on May 24, 2021. Interventions: Patients were assigned to receive nitric oxide at 20 ppm delivered into the cardiopulmonary bypass oxygenator (n = 679) or standard care cardiopulmonary bypass without nitric oxide (n = 685). Main Outcomes and Measures: The primary end point was the number of ventilator-free days from commencement of bypass until day 28. There were 4 secondary end points including a composite of low cardiac output syndrome, extracorporeal life support, or death; length of stay in the intensive care unit; length of stay in the hospital; and postoperative troponin levels. Results: Among 1371 patients who were randomized (mean [SD] age, 21.2 [23.5] weeks; 587 girls [42.8%]), 1364 (99.5%) completed the trial. The number of ventilator-free days did not differ significantly between the nitric oxide and standard care groups, with a median of 26.6 days (IQR, 24.4 to 27.4) vs 26.4 days (IQR, 24.0 to 27.2), respectively, for an absolute difference of -0.01 days (95% CI, -0.25 to 0.22; P = .92). A total of 22.5% of the nitric oxide group and 20.9% of the standard care group developed low cardiac output syndrome within 48 hours, needed extracorporeal support within 48 hours, or died by day 28, for an adjusted odds ratio of 1.12 (95% CI, 0.85 to 1.47). Other secondary outcomes were not significantly different between the groups. Conclusions and Relevance: In children younger than 2 years undergoing cardiopulmonary bypass surgery for congenital heart disease, the use of nitric oxide via cardiopulmonary bypass did not significantly affect the number of ventilator-free days. These findings do not support the use of nitric oxide delivered into the cardiopulmonary bypass oxygenator during heart surgery. Trial Registration: anzctr.org.au Identifier: ACTRN12617000821392.

Predicting Fatigue 12 Months after Child Traumatic Brain Injury: Child Factors and Postinjury Symptoms.

OBJECTIVES: Fatigue is a common and persisting symptom after childhood brain injury. This study examined whether child characteristics and symptomatology preinjury or 6 months postinjury (pain, sleep, and mood, inattention) predicted fatigue at 12months postinjury. METHODS: Parents of 79 children (0-18 years) rated fatigue at 12 months after injury on a multidimensional scale (general, sleep/rest, and cognitive). Demographic and clinical data were collected at injury. Parents rated child sleep, pain, physical/motor function, mood, and inattention at injury (preinjury description), and 6 months postinjury. Children were divided into two traumatic brain injury severity groups: mild TBI (n=57) and moderate/severe TBI (n=27). Hierarchical regression models were used to examine (i) preinjury factors and (ii) symptoms 6 months postinjury predictive of fatigue (general, sleep/rest, and cognitive) at 12 months postinjury. RESULTS: Sleep/rest fatigue was predicted by preinjury fatigue (7% of variance) and psychological symptoms preinjury (10% of variance). General fatigue was predicted by physical/motor symptoms (27%), sleep (10%) and mood symptoms (9%) 6 months postinjury. Sleep/rest fatigue was predicted by physical/motor symptoms (10%), sleep symptoms (13%) and mood symptoms (9%) 6 months postinjury. Cognitive fatigue was predicted by physical/motor symptoms (17%) 6 months postinjury. CONCLUSIONS: Preinjury fatigue and psychological functioning identified those at greatest risk of fatigue 12 months post-TBI. Predictors of specific fatigue domains at 12 months differed across each of the domains, although consistently included physical/motor function as well as sleep and mood symptoms postinjury. (JINS, 2018, 24, 224-236).

Fatigue Following Traumatic Brain Injury in Children and Adolescents: A Longitudinal Follow-Up 6 to 12 Months After Injury.

BACKGROUND: Longitudinal fatigue data in children suffering from traumatic brain injury (TBI) are lacking. OBJECTIVES: To examine the effects of time postinjury (6-12 months) and injury severity on fatigue after childhood TBI. Secondarily, we compared fatigue 12 months postinjury against published control data. SETTING: Three tertiary children's hospitals across Australia (n = 1) and Canada (n = 2). PARTICIPANTS: Parents (n = 109) of children (mean [M] = 9.9 years at injury; range, 1.0-16.9 years) admitted to one of 3 participating hospitals with mild (n = 69) or moderate/severe (n = 37) TBI. DESIGN: Longitudinal prospective study. MEASURES: Primary: Pediatric Quality of Life Multidimensional Fatigue Scale (total, general, sleep/rest, and cognitive), rated by parents 6 and 12 months postinjury. Secondary: Pediatric Injury Functional Outcome Scale (fatigue and sleep items, rated on recruitment and 6 and 12 months postinjury). Demographic and children data were collected at recruitment. RESULTS: Mixed-models analysis demonstrated nonsignificant effects of time (6 vs 12 months postinjury) on multidimensional fatigue scores. Cognitive fatigue worsened over time. Moderate/severe TBI was associated with worse fatigue 12 months postinjury (general, P = .03; cognitive, P = .02). Across all severities, fatigue 12 months postinjury was significantly worse compared with control data (total fatigue, P < .001; all domains, all Ps < .025). CONCLUSION: Fatigue remains significant at 12 months since injury, particularly for those with moderate/severe TBI.

A Case-Control Analysis of Postoperative Fluid Balance and Mortality After Pediatric Cardiac Surgery.

OBJECTIVES: A positive fluid balance after cardiac surgery may be associated with poor outcomes; however, previous studies looking at this association have been limited by the number of deaths in the study population. Our primary aim was to determine the relationship between postoperative cumulative fluid balance and mortality in cardiac surgical patients. Secondary aims were to study the association between fluid balance and duration of mechanical ventilation, intensive care and hospital length of stay. DESIGN: Case-control study. SETTING: A 30-bed multidisciplinary PICU. PATIENTS: All patients admitted to the PICU following cardiac surgery from 2010 to 2014. INTERVENTIONS: Deaths during PICU admission following cardiac surgery (cases) were matched 1:3 with children who survived to PICU discharge (controls) using the following criteria: age at surgery (within a 20% age range), Risk Adjusted Congenital Heart Surgery (RACHS-1) category, and year of admission. MEASUREMENTS AND MAIN RESULTS: Of 1,996 eligible children, 46 died (2.3%) of whom 45 (98%) were successfully matched. Cumulative fluid balance on days 2 and 7 was not associated with PICU mortality. On multivariable analysis, factors associated with mortality were cardiopulmonary bypass time (per 10-min increase, odds ratio [95% CI], 1.06 [1.00-1.12]; p = 0.03), extracorporeal membrane oxygenation requirement within 3 days (46.6 [9.47-230.11]; p < 0.001), peak serum chloride (mmol/L) in the first 48 hours (1.12 [1.01-1.23]), and time to start peritoneal dialysis after surgery (in comparison to no peritoneal dialysis, odds ratio [95% CI] in those started on early peritoneal dialysis was 1.07 [0.33-3.41]; p = 0.90 and in late peritoneal dialysis 3.65 [1.21-10.99]; p = 0.02). Children with cumulative fluid balance greater than or equal to 5% by day 2 spent longer on mechanical ventilation (median [interquartile range], 211 hr [97-539] vs 93 hr [34-225]; p <0.001), in PICU (11 d [8-26] vs 6 [3-13]; p < 0.001) and in hospital (22 d [13-39] vs 14 d [8-30]; p = 0.001). CONCLUSIONS: Early fluid overload is not associated with mortality. However, it is associated with increased duration of mechanical ventilation and PICU length of stay. Early peritoneal dialysis commencement (compared with late peritoneal dialysis) after surgery was associated with decreased mortality.

Prediction of Multidimensional Fatigue After Childhood Brain Injury.

OBJECTIVES: To determine (1) the presence of fatigue symptoms and predictors of fatigue after childhood brain injury and examine (2) the feasibility, reliability, and validity of a multidimensional fatigue measure (PedsQL Multidimensional Fatigue Scale [MFS]) obtained from parent and child perspectives. SETTING: Emergency and intensive care units of a hospital in Melbourne, Australia. PARTICIPANTS: Thirty-five families (34 parent-proxies and 32 children) aged 8 to 18 years (mean child age = 13.29 years) with traumatic brain injury (TBI) of all severities (27 mild, 5 moderate, and 3 severe) admitted to the Royal Children's Hospital. DESIGN: Longitudinal prospective study. Fatigue data collected at 6-week follow-up (mean = 6.9 weeks). MAIN OUTCOME MEASURES: Postinjury child- and parent-rated fatigue (PedsQL MFS), mood, sleep, and pain based on questionnaire report: TBI severity (mild vs moderate/severe TBI). RESULTS: A score greater than 2 standard deviations below healthy control data indicated the presence of abnormal fatigue, rates of which were higher compared with normative data for both parent and child reports (47% and 29%). Fatigue was predicted by postinjury depression and sleep disturbance for parent, but not child ratings. Fatigue, as rated by children, was not significantly predicted by TBI severity or other symptoms. The PedsQL MFS demonstrated acceptable measurement properties in child TBI participants, evidenced by good feasibility and reliability (Cronbach α values >0.90). Interrater reliability between parent and child reports was poor to moderate. CONCLUSIONS: Results underscore the need to assess fatigue and associated sleep-wake disturbance and depression after child TBI from both parent and child perspectives.

Hemofiltration is not associated with increased mortality in children receiving extracorporeal membrane oxygenation.

OBJECTIVES: To investigate whether the use of continuous renal replacement therapy is independently associated with increased in-hospital mortality in children on extracorporeal membrane oxygenation. DESIGN: Retrospective, 1:1 propensity-matched cohort study. SETTING: Tertiary PICU. PATIENTS: Eighty-six children on extracorporeal membrane oxygenation, 43 of whom also received hemofiltration. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographics, pre-extracorporeal membrane oxygenation hemodynamic data, fluid status, and biochemistry tests were collected, as well as duration of extracorporeal membrane oxygenation, blood product use, complications, and mortality. Forty-three children receiving extracorporeal membrane oxygenation and continuous renal replacement therapy were matched to a cohort of 43 children on extracorporeal membrane oxygenation not receiving continuous renal replacement therapy. The main indication for hemofiltration was fluid overload in 29 patients (67.4%), renal failure in nine patients (20.9%), and electrolyte abnormalities in five patients (11.6%). The median duration of hemofiltration was 108 hours (47-209 hr). Patients receiving hemofiltration had a longer duration of extracorporeal membrane oxygenation (127 hr [94-302 hr] vs 121 hr [67-182 hr]; p = 0.05) and received more platelet transfusions (0.91 mL/kg/hr [0.43-1.58 mL/kg/hr] vs 0.63 mL/kg/hr [0.30-0.79 mL/kg/hr]; p = 0.01). There were otherwise no differences in mechanical or patient-related complications between both groups. There was no difference in the proportion of patients who were successfully decannulated (81.4% vs 74.4%; p = 0.44), survived to ICU discharge (65.1% vs 55.8%; p = 0.38), or survived to hospital discharge (62.8% vs 48.8%; p = 0.19) in the controls versus the hemofiltration group. CONCLUSIONS: In-hospital mortality was similar between children on extracorporeal membrane oxygenation with and without hemofiltration although hemofiltration appeared to be associated with a slight increase in the duration of extracorporeal membrane oxygenation and more liberal platelet transfusions.

Prevalence of dysglycemia and association with outcomes in pediatric extracorporeal membrane oxygenation.

OBJECTIVES: To evaluate the relationship between glucose derangement, insulin administration, and mortality among children on extracorporeal membrane oxygenation. DESIGN: Retrospective cohort. SETTING: Tertiary PICU. PATIENTS: Two hundred nine children receiving extracorporeal membrane oxygenation, including 97 neonates. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hyperglycemia and severe hyperglycemia were defined as a single blood glucose level greater than 15 mmol/L (270 mg/dL) and greater than 20 mmol/L (360 mg/dL), respectively. Hypoglycemia and severe hypoglycemia were defined as any single glucose level less than 3.3 mmol/L (60 mg/dL) and less than 2.2 mmol/L (40 mg/dL), respectively. A total of 15,912 glucose values were recorded. The median number of glucose values was 59 per patient, corresponding to a mean 0.53 ± 0.12 tests per hour. Sixty-nine patients (33.0%) without dysglycemia and who received no insulin were defined as the control group. Eighty-nine (42.6%) and 26 (12.4%) patients developed hyperglycemia and severe hyperglycemia, respectively. Sixty-three (30.1%) and 17 (8.1%) patients developed hypoglycemia and severe hypoglycemia, respectively. Sixty-one patients (29.2%) received IV insulin during extracorporeal membrane oxygenation. Both hyperglycemia and hypoglycemia were associated with increased mortality on extracorporeal membrane oxygenation (46% and 48%, respectively, vs 29% of controls; p = 0.03). However, after adjusting for severity of illness and extracorporeal membrane oxygenation complications, abnormal glucose levels were not independently related to mortality. CONCLUSIONS: Dysglycemia in children on extracorporeal membrane oxygenation was common but not independently associated with increased mortality. The optimal glucose range for this high-risk population requires further investigation.

Safety of therapeutic hypothermia in children on veno-arterial extracorporeal membrane oxygenation after cardiac surgery.

OBJECTIVE: The aim of this study was to evaluate whether the use of therapeutic hypothermia in patients receiving extracorporeal membrane oxygenation after paediatric cardiac surgery is associated with increased complication rates. METHODS: We undertook a retrospective study to compare the complication rates and clinical course of children after cardiac surgery in two groups ­ extracorporeal membrane oxygenation without therapeutic hypothermia (group 1) and extracorporeal membrane oxygenation with therapeutic hypothermia (group 2). Therapeutic hypothermia was performed via the extracorporeal membrane oxygenation circuit heater-cooler device. RESULTS: A total of 96 patients were included in this study (59 in group 1 and 37 in group 2). Complications were comparable between group 1 and group 2, except that more patients with therapeutic hypothermia had hypertension while on extracorporeal membrane oxygenation. Therapeutic hypothermia was not independently associated with in-hospital mortality (adjusted odds ratio 1.16, 95% CI: 0.33-4.03; p=0.82). CONCLUSION: Therapeutic hypothermia can be safely provided to children on extracorporeal membrane oxygenation after cardiac surgery without an increase in complication rates.

Hemolysis in pediatric patients receiving centrifugal-pump extracorporeal membrane oxygenation: prevalence, risk factors, and outcomes.

OBJECTIVES: To explore the prevalence and risk factors for hemolysis in children receiving extracorporeal membrane oxygenation and examine the relationship between hemolysis and adverse outcomes. DESIGN: Retrospective, single-center study. SETTING: Tertiary PICU. PATIENTS: Two hundred seven children receiving extracorporeal membrane oxygenation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma-free hemoglobin was tested daily and hemolysis was diagnosed based on peak plasma-free hemoglobin as mild (< 0.5 g/L), moderate (0.5-1.0 g/L), or severe (> 1.0 g/L). Gender, age, weight, diagnosis, oxygenator type, cannulation site, mean venous inlet pressure, mean pump speed, mean flow, and visible clots in the extracorporeal membrane oxygenation circuit were entered into the ordered logistic regression model to identify risk factors of hemolysis. Complications and clinical outcomes were compared across four hemolysis groups. Of the 207 patients, 69 patients (33.3%; 95% CI, 27.0-40.2%) did not have hemolysis, 98 patients (47.3%; 95% CI, 40.4-54.4%) had mild hemolysis, 26 patients (12.5%; 95% CI, 8.4-17.9%) had moderate hemolysis, and 14 patients (6.8%; 95% CI, 3.7-11.1%) had severe hemolysis with a median peak plasma-free hemoglobin of 1.51 g/L (1.18-2.05 g/L). The independent risk factors for hemolysis during extracorporeal membrane oxygenation were use of Quadrox D (odds ratio, 7.25; 95% CI, 3.10-16.95; p < 0.001) or Lilliput (odds ratio, 37.32; 95% CI, 8.95-155.56; p < 0.001) oxygenators, mean venous inlet pressure (odds ratio, 0.95; 95% CI, 0.91-0.98; p = 0.002), and mean pump speed (odds ratio, 2.89; 95% CI, 1.36-6.14; p = 0.006). Patients with hemolysis were more likely to experience a longer extracorporeal membrane oxygenation run and require more blood products. After controlling for age, weight, pediatric index of mortality 2, and diagnosis, patients with severe hemolysis were more likely to die in the ICU (odds ratio, 5.93; 95% CI, 1.64-21.43; p = 0.007) and in hospital (odds ratio, 6.34; 95% CI, 1.71-23.54; p = 0.006). CONCLUSIONS: Hemolysis during extracorporeal membrane oxygenation with centrifugal pumps was common and associated with a number of adverse outcomes. Risk factors for hemolysis included oxygenator types, mean venous inlet pressure, and mean pump speed. Further studies are warranted comparing pump types while controlling both physical and nonphysical confounders.

Long-stay children in intensive care: long-term functional outcome and quality of life from a 20-yr institutional study.

OBJECTIVE: Long-stay patients (≥28 days) in pediatric intensive care units consume a disproportionate amount of resources, and very few studies have reported their outcome. We determined the long-term outcome of these children admitted to intensive care over a 20-yr period (January 1, 1989 to December 31, 2008). SETTING: Pediatric intensive care unit in a university-affiliated tertiary pediatric hospital in Melbourne, Australia METHODS: Demographic and clinical characteristics were compared after dividing patients into four groups depending on year of admission (1989-1993, 1994-1998, 1999-2003, and 2004-2008). Preadmission health status and long-term functional outcome were evaluated by a modified Glasgow outcome scale. Quality of life was assessed by using the Health Utilities Index Mark 1. RESULTS: Over the 20-yr period, 233 long-stay patients had 269 long stay admission episodes to the pediatric intensive care unit, accounting for 1% (269 of 27,536) of all pediatric intensive care unit admissions and utilized 18.5% (15,740 of 85,032) of occupied bed days. Bed occupancy of long stay patients (as percentage of overall pediatric intensive care unit bed occupancy) increased from 8% in 1989 to 21% in 2008 (p = .001). Median age at admission was 4.2 months [interquartile range 0.38-41.5] and median length of stay was 40 days [interquartile range 32-57]. One hundred sixteen of 233 (49.8%) patients had died at the time of follow-up. Children who died were younger compared to survivors (median 3.4 months [interquartile range 0.38-41.5 vs. median 7.6 months, interquartile range 0.6-71.1, p = .026], had a higher proportion of comorbid illness (91% vs. 80%, p = .026), and 63% had a preexisting moderate or severe disability compared to 51% of survivors (p = .215). One hundred seventeen of 233 children survived and long-term functional outcome was favorable (normal, functionally normal, or mild disability) in 27% (63 of 233) and unfavorable (moderate or severe disability) for 17.2% (40 of 233). Outcome status was not known for 6% (14 of 233). Among survivors (n = 117), more than 50% (63 of 117) had favorable outcome. The quality of life in patients aged >2 yrs at follow up was good in 21% (40 of 222), moderate in 8% (16 of 222), poor quality in 68% (130 of 222, this includes deaths), and very poor in 3% (5 of 222). CONCLUSIONS: More than two-thirds of children who stay in intensive care for ≥28 days have an unfavorable outcome (moderate disability, severe disability, or death). Long-stay patients in pediatric intensive care utilized a large proportion of resources and this utilization has considerably increased with time. Service provision and policy making should expect worsening of these trends in the future; its effects on critical care bed availability and overall activity levels could be substantial.

Study protocol and statistical analysis plan for the Early Peritoneal Dialysis in Infants after Cardiac Surgery (EPICS) trial.

Background: Peritoneal dialysis (PD) is a commonly used therapy after infant cardiac surgery. It is unclear whether early PD commenced soon after admission to an intensive care unit (ICU) after cardiac surgery results in better outcomes. Objective: To describe the study protocol and statistical analysis plan for the Early Peritoneal Dialysis in Infants after Cardiac Surgery (EPICS) trial. Design, setting, participants and intervention: The EPICS trial is an open, randomised, two-group, single-centre clinical study of infants ≤ 180 days of age who had cardiac surgery (in Risk-Adjusted Classification for Congenital Heart Surgery version 1 categories 3-6) with cardiopulmonary bypass. Participants will be randomly assigned 1:1 to early PD (treatment group) or no early PD (control group). Those assigned to the treatment group will begin receiving PD soon after ICU admission and continue receiving it for 24 hours. Those in the control group will not receive PD during the first 24 hours. Main outcome measures: The primary outcome is a composite measure consisting of one or more of death, cardiac arrest, emergency chest reopening, and requirement for extracorporeal membrane oxygenation (ECMO) within 90 days. The main secondary outcomes are duration of mechanical ventilation, ICU length of stay, hospital length of stay, vasoactive-inotropic score at 24 hours, and cumulative per cent fluid balance by end of Day 2. At Day 90, events such as mortality, requirement for ECMO, cardiac arrest, chest reopening, volume of packed red blood cell transfusion, postoperative infection, readmission to ICU, renal injury and brain injury will be assessed. Conclusions: The EPICS trial aims to evaluate the role of early PD after infant cardiac surgery in lowering the rate of a composite major outcome. In addition, it will test the effect of early PD on duration of mechanical ventilation, and on ICU and hospital length of stay. Trial registration: ACTRN12617001614381.

Priorities for paediatric critical care research: a modified Delphi study by the Australian and New Zealand Intensive Care Society Paediatric Study Group.

Objective: Most interventions in paediatric critical care lack high grade evidence. We aimed to identify the key research priorities and key clinical outcome measures pertinent to research in paediatric intensive care patients. Design: Modified three-stage Delphi study combining staged online surveys, followed by a face-to-face discussion and final voting. Setting: Paediatric intensive care units in Australia and New Zealand. Participants: Medical and nursing staff working in intensive care. Main outcome measurements: Self-reported priorities for research. Results: 193 respondents provided a total of 267 research questions and 234 outcomes. In Stage 3, the top 56 research questions and 50 outcomes were discussed face to face, which allowed the identification of the top 20 research questions with the Hanlon prioritisation score and the top 20 outcomes. Topics centred on the use of intravenous fluids (restrictive v liberal fluids, use of fluid resuscitation bolus, early inotrope use, type of intravenous fluid, and assessment of fluid responsiveness), and patient- and family-centred outcomes (health-related quality of life, liberation) emerged as priorities. While mortality, length of stay, and organ support/organ dysfunction were considered important and the most feasible outcomes, long term quality of life and neurodevelopmental measures were rated highly in terms of their importance. Conclusions: Using a modified Delphi method, this study provides guidance towards prioritisation of research topics in paediatric critical care in Australia and New Zealand, and identifies study outcomes of key relevance to clinicians and experts in the field.

Interleukin-8 Predicts Fatigue at 12 Months Post-Injury in Children with Traumatic Brain Injury.

Despite many children experiencing fatigue after childhood brain injury, little is known about the predictors of this complaint. To date, traditional indices of traumatic brain injury (TBI) severity have not predicted reliably persisting fatigue (up to three years post-injury). This study aimed to establish whether persisting fatigue is predicted by serum biomarker concentrations in child TBI. We examined whether acute serum biomarker expression would improve prediction models of 12-month fatigue based on injury severity. Blood samples were collected from 87 children (1-17 years at injury) sustaining mild to severe TBI (Glasgow Coma Scale [GCS] range 3-15; mean 12.43; classified as mild TBI [n = 50, 57%] vs. moderate/severe TBI [n = 37, 43%]), and presenting to the emergency departments (ED) and pediatric intensive care units (PICU) at one of three tertiary pediatric hospitals (Royal Children's Hospital (RCH); Hospital for Sick Children (HSC), Toronto; St Justine Children's Hospital (SJH), Montreal). Six serum biomarker concentrations were measured within 24 h of injury (interleukin-6, interleukin-8 [IL-8], soluble vascular cell adhesion molecule [SVCAM], S100 calcium binding protein B [S100B], neuron specific enolase [NSE], and soluble neural cell adhesion molecule [sNCAM]). Fatigue at 12 months post-injury was measured using the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (parent report), classified as present/absent using previously derived cut-points. At 12 months post-injury, 22% of participants experienced fatigue. A model including IL-8 was the best serum biomarker for estimating the probability of children experiencing fatigue at 12 months post-injury. The IL-8 also significantly improved predictive models of fatigue based on severity.

Statistical analysis plan for the NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) trial.

Background: The NITric oxide during cardiopulmonary bypass (CPB) to improve Recovery in Infants with Congenital heart defects (NITRIC) trial, a 1320-patient, multicentre, randomised controlled trial, is aiming to improve survival free of ventilation after CPB by using nitric oxide delivered into the oxygenator of the CPB. Objective: To provide a statistical analysis plan before completion of patient recruitment and data monitoring. Final analyses for this study will adhere to this statistical analysis plan, which details all key pre-planned analyses. Stata scripts for analyses have been prepared alongside this statistical analysis plan. Methods: The statistical analysis plan was designed collaboratively by the chief investigators and trial statistician and builds on the previously published study protocol. All authors remain blinded to treatment allocation. Detail is provided on statistical analyses including cohort description, analysis of primary and secondary outcomes and adverse events. Statistical methods to compare outcomes are planned in detail to ensure methods are verifiable and reproducible. Results: The statistical analysis plan developed provides the trial outline, list of mock tables, and analysis scripts. The plan describes statistical analyses on cohort and baseline description, primary and secondary outcome analyses, process of care measures, physiological descriptors, and safety and adverse event reporting. We define the pre-specified subgroup analyses and the respective statistical tests used to compare subgroups. Conclusion: The statistical analysis plan for the NITRIC trial establishes detailed pre-planned analyses alongside Stata scripts to analyse the largest trial in the field of neonatal and paediatric heart surgery. The plan ensures standards for trial analysis validity aiming to minimise bias of analyses. Trial registration: ACTRN12617000821392.

Three decades of pediatric intensive care: Who was admitted, what happened in intensive care, and what happened afterward.

OBJECTIVE: To describe the characteristics of children admitted to intensive care in 1982, 1995, and 2005-2006, and their long-term outcome. SETTING: Pediatric intensive care unit in a university-affiliated children's hospital. DESIGN/METHODS: Information for 2005-2006 admissions was obtained from pediatric intensive care unit database, and long-term outcome was ascertained through telephone interviews. Results were compared to previous cohorts from 1982 and 1995. RESULTS: A total of 4010 children were admitted on 5250 occasions. Readmissions increased from 11% for 1982 to 31% in 2005 to 2006 (p < .001). In 2005-2006, fewer children were admitted after accidents (p < .001), or with croup (p < .001), or epiglottitis (p = .01), and 8% were treated with noninvasive ventilation compared to none in 1982 (p < .0001). Among children aged > or =1 month, pediatric intensive care unit length of stay remained constant. The risk of death predicted by the Pediatric Index of Mortality (PIM) remained constant (approximately 6%) between 1995 and 2005-2006.The proportion that died in the pediatric intensive care unit fell from 11.0% in 1982 to 4.8% in 2005-2006 (p < .001). Among children aged >/=1 month, proportion admitted with a preexisting moderate or severe disability was similar: 12.0% in 1982 and 14.6% in 2005-2006 (p = .11), but the proportion with a moderate or severe disability at follow-up increased from 8.4% in 1982 to 17.9% in 2005-2006 (p < .001). The proportion of children aged > or =1 month who either died in the pediatric intensive care unit or survived with disability did not improve: it was 19.4% in 1982 and 22.7% in 2005-2006. CONCLUSION: Over the last three decades, the length of stay in the pediatric intensive care unit and the severity of illness have not changed, but there has been a substantial reduction in pediatric intensive care unit mortality. However, the proportion of survivors with moderate or severe disability increased significantly. Some children who would have been allowed to die in 1982 and 1995 were kept alive in 2005-2006, but survived with disability. This trend has important implications for our patients and their families, and for the community as a whole.

Improving transport time for babies with antenatally diagnosed transposition of the great arteries reduces the need for ECMO.

OBJECTIVE: To assess the effect of reducing retrieval team response time on the outcomes of babies born outside a cardiac centre (outborn) with antenatally diagnosed transposition of the great arteries. STUDY DESIGN: Retrospective cohort study of all outborn babies with antenatally diagnosed TGA anticipated to require transfer for urgent balloon atrial septostomy over a 6-year period (15 babies pre intervention and 27 post intervention). The intervention involved a collaborative multicomponent practice change aiming to reduce retrieval team response time. RESULT: The mean (SD) time from birth to cardiac ICU arrival was 159 (12) min pre intervention and 103 (6) min post intervention (mean difference -57 min [95% CI, -81 to -32]). There was a significant decrease in need for extracorporeal membrane oxygenation (33% versus 4%), RR 0.11 [95% CI, 0.02-0.65]), with a number needed to treat of 3.4 to prevent one ECMO episode. CONCLUSION: Reducing retrieval time is achievable with collaborative systems, and significantly improves clinical outcomes.