Clinical Effects of Nitric Oxide Added to the Oxygenator of Children on Extracorporeal Membrane Oxygenation: Pre-Post Cohort Study.

Nitric oxide (NO) can be safely delivered through the sweep gas to the oxygenator of an extracorporeal membrane oxygenation (ECMO) circuit. It has theoretical benefits such as preventing platelet adhesion to surfaces, mitigating inflammatory response and protection against ischemia-reperfusion injury. In this uncontrolled before-after study of children on ECMO, the outcomes of those who received NO were compared with those who did not. Among 393 ECMO runs (from 337 patients), 192 of 393 (49%) received NO and 201 of 393 (51%) did not. The use of NO was associated with a 37% reduction in circuit change (adjusted risk ratio [aRR]: 0.63, 95% confidence interval [CI]: 0.42-0.93). The aRR (95% CI) for risk of neurologic injury was 0.72 (0.47-1.11). We observed potential heterogeneity of treatment effect for the risk of neurologic injury in children who had cardiac surgery: the risk with NO was lower in those who had cardiac surgery (aRR: 0.50, 95% CI: 0.26-0.96). There was no difference in survival between the study groups. In children managed with NO delivered through the ECMO circuit, we report a reduction in observed rate of circuit change and lower risk of neurologic injury in children who underwent cardiac surgery. Nitric oxide therapy on ECMO warrants prospective evaluation in children.

High risk of necrotising enterocolitis in term-born neonates with CHD delivered by caesarean section: a case-control study.

OBJECTIVE: Necrotising enterocolitis is linked with altered intestinal microbiota, and caesarean birth is associated with imbalance of newborn intestinal microbiome. We aimed to investigate the role of delivery mode (vaginal or caesarean) and gestational age in the development of necrotising enterocolitis among term-born neonates (≥ 37 weeks) with CHD. METHODS: Case-control study. We studied all newborns with CHD who underwent cardiac surgery during the neonatal (≤ 28 days of age) period, between 2007 and 2017. Totally, 60 cases of necrotising enterocolitis were matched (by year of birth and type of congenital heart lesion) with 180 controls (1:3 ratio). Multivariable conditional logistic regression was used to assess the study question. RESULTS: The overall prevalence of necrotising enterocolitis was 6.3% in term-born newborns with CHD. Neonates with a left-ventricular outflow tract lesion or single ventricle lesion accounted for 55% (n = 33) of cases. 62% (n = 37) cases were in the modified Bell's stage 2 or more for necrotising enterocolitis classification. In multivariable modelling, gestational age at birth was not associated with the development of necrotising enterocolitis [adjusted odds ratio per week increase, 95% confidence interval: 1.20 (0.90-1.60)]. Birth by caesarean delivery (compared to vaginal) was strongly associated with development of necrotising enterocolitis [adjusted odds ratio (95% confidence interval): 2.64 (1.31-5.29)]. We failed to identify an association between preoperative enteral nutrition and necrotising enterocolitis. CONCLUSION: This study showed a high risk of necrotising enterocolitis in newborns with critical CHD born via caesarean. This information is important given the high prevalence of planned birth by caesarean in newborns with CHD.

Potential benefits of prenatal diagnosis of TGA in Australia may be outweighed by the adverse effects of earlier delivery: likely causation and potential solutions.

OBJECTIVE: Prenatal diagnosis of transposition of great arteries (TGA) is expected to improve postoperative outcomes after neonatal arterial switch operation (ASO); however, published reports give conflicting results. We aimed to determine the association between prenatal diagnosis and early postoperative outcomes after neonatal ASO. METHODS: Cohort study involving 243 newborns who underwent ASO (70% prenatally diagnosed) between 2010 and 2019. Multivariable regression was used to determine the association between prenatal diagnosis and (a) birth characteristics and (b) postoperative outcomes. RESULTS: Gestational age and birthweight centile were lower and small-for-gestational-age more common (11.8% vs 1.4%) in those diagnosed prenatally. Among births which followed labour induction or prelabour caesarean, prenatal diagnosis was associated with earlier gestation at birth (mean (SD), 38.5 (1.6) vs 39.2 (1.4), p=0.01). Among births which followed spontaneous labour, prenatal diagnosis was associated with earlier gestation at labour onset (38.2 (1.8) vs 39.2 (1.4), p=0.01). Prenatal diagnosis was associated with longer postoperative mechanical ventilation (incidence rate ratio 1.74, 95% CI 1.37 to 2.21), intensive care (1.70, 1.31 to 2.21) and hospital length of stay (1.37, 1.14 to 1.66) after ASO. Gestational age mediated up to 60% of the effect of prenatal diagnosis on postoperative outcomes. CONCLUSION: Among newborns undergoing ASO for TGA, prenatal diagnosis is associated with poorer early postoperative outcomes. In addition to minimising iatrogenic factors (such as planned births) resulting in earlier births, evaluation of other dynamics following a prenatal diagnosis which may result in poor fetal growth and earlier onset of spontaneous labour is important.

Trends in Childhood Oncology Admissions to ICUs in Australia and New Zealand.

OBJECTIVES: There are few robust, national-level reports of contemporary trends in pediatric oncology admissions, resource use, and mortality. We aimed to describe national-level data on trends in intensive care admissions, interventions, and survival for children with cancer. DESIGN: Cohort study using a binational pediatric intensive care registry. SETTING: Australia and New Zealand. PATIENTS: Patients younger than 16 years, admitted to an ICU in Australia or New Zealand with an oncology diagnosis between January 1, 2003, and December 31, 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We examined trends in oncology admissions, ICU interventions, and both crude and risk-adjusted patient-level mortality. Eight thousand four hundred ninety admissions were identified for 5,747 patients, accounting for 5.8% of PICU admissions. Absolute and population-indexed oncology admissions increased from 2003 to 2018, and median length of stay increased from 23.2 hours (interquartile range [IQR], 16.8-62 hr) to 38.8 hours (IQR, 20.9-81.1 hr) ( p < 0.001). Three hundred fifty-seven of 5,747 patients died (6.2%). There was a 45% reduction in risk-adjusted ICU mortality, which reduced from 3.3% (95% CI, 2.1-4.4) in 2003-2004 to 1.8% (95% CI, 1.1-2.5%) in 2017-2018 ( p trend = 0.02). The greatest reduction in mortality seen in hematological cancers and in nonelective admissions. Mechanical ventilation rates were unchanged from 2003 to 2018, while the use of high-flow nasal prong oxygen increased (incidence rate ratio, 2.43; 95% CI, 1.61-3.67 per 2 yr). CONCLUSIONS: In Australian and New Zealand PICUs, pediatric oncology admissions are increasing steadily and such admissions are staying longer, representing a considerable proportion of ICU activity. The mortality of children with cancer who are admitted to ICU is low and falling.

Opinion: on the importance of maintaining the functional form of explanatory variables.

In medical research, continuous variables are often categorised into two or more groups before being included in the analysis; this practice often comes with a cost, such as loss of power in analysis, less reliable estimates, and can often leave residual confounding in the results. In this research report, we show this by way of estimates from a regression analysis looking at the association between acute kidney injury and post-operative mortality in a sample of 194 neonates who underwent the Norwood operation. Two models were developed, one using a continuous measure of renal function as the main explanatory variable and second using a categorised version of the same variable. A continuous measure of renal function is more likely to yield reliable estimates and also maintains more statistical power in the analysis to detect a relation between the exposure and outcome. It also reveals the true biological relationship between the exposure and outcome. Categorising a continuous variable may not only miss an important message, it can also get it wrong. Additionally, given a non-linear relationship is commonly encountered between the exposure and outcome variable, investigators are advised to retain a predictor with a linear term only when supported by data. All of this is particularly important in small data sets which account for the majority of clinical research studies.

Early Peritoneal Dialysis and Postoperative Outcomes in Infants After Pediatric Cardiac Surgery: A Systematic Review and Meta-Analysis.

OBJECTIVE: Peritoneal dialysis (PD) is used in several cardiac surgical units after cardiac surgery, and early initiation of PD after surgery may have the potential to influence postoperative outcomes. This systematic review and meta-analysis aims to summarize the evidence for the association between early PD after cardiac surgery and postoperative outcomes. DATA SOURCES: MEDLINE, Embase, and PubMed from 1981 to November 1, 2021. STUDY SELECTION: Observational studies and randomized trials reporting on early PD after pediatric cardiac surgery. DATA EXTRACTION: Random-effects meta-analysis was used to estimate the pooled odds ratios (ORs) and their 95% CIs for postoperative mortality and pooled mean difference (MD) (95% CI) for duration of mechanical ventilation and ICU length of stay. DATA SYNTHESIS: We identified nine studies from the systematic review, and five were considered suitable for meta-analysis. Early initiation of PD after cardiac surgery was associated with a reduction in postoperative mortality (OR, 0.43 (95% CI, 0.23-0.80); number of estimates = 4). Early commencement of PD shortened duration of mechanical ventilation (MD [95% CI], -1.09 d [-1.86 to -0.33 d]; I2 = 56.1%; p = 0.06) and intensive care length of stay (MD [95% CI], -2.46 d [-3.57 to -1.35 d]; I2 = 18.7%; p = 0.30], respectively. All three estimates had broad 95% prediction intervals (crossing null) denoting major heterogeneity between studies and wide range of possible study estimates in similar future studies. Overall, studies reporting on the effects of early PD included only a subset of infants undergoing cardiac surgery (typically high-risk infants), so selection bias may be a major issue in published studies. CONCLUSIONS: This review suggests that early initiation of PD may be associated with beneficial postoperative outcomes in infants after cardiac surgery. However, these results were based on studies of varying qualities and risk of bias. Early identification of high-risk infants after cardiac surgery is important so that prevention or early mitigation strategies can be applied to this cohort. Future prospective studies in high-risk populations are needed to study the role of early PD in influencing postoperative outcomes.

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.

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.

Recurrent Extubation Failure Following Neonatal Cardiac Surgery Is Associated with Increased Mortality.

Extubation failure (EF) following neonatal cardiac surgery is associated with increased mortality. Neonates who experienced EF twice or more (recurrent EF) may have worse outcomes than those who have a single EF or no-EF. The aims of this study are to investigate the in hospital mortality for neonates with recurrent EF compared to those with single or no-EF, and determine factors associated with recurrent EF. Neonates' ≤ 28 days who underwent cardiac surgery from January 2008 to December 2019 were included. EF was defined as unplanned reintubation within 72 h after a planned extubation. 1187 (18 recurrent EF, 84 single EF and 1085 no-EF) neonates were included. Recurrent EF occurred in 18 (17.6%) of 102 neonates undergoing a second extubation. The median time (IQR) to reintubation after the first and second extubations were similar, being 20.9 (3.3-45.2) versus 19.4 (5.5-47) h. The reason for a second-time EF was respiratory in 39% and cardiovascular in 33%. Recurrent EF and single EF was associated with increased mortality (odds ratio, 95% confidence interval (CI) 23.5, 6.9-79.9) and (odds ratio, 95% CI 5.2, 2.3-12.0) compared to no-EF. Based on the final model with risk adjustment, predicted mortality was 29.0% in recurrent EF, 6.5% in single EF, and 1.2% in no-EF. First-time EF due to cardiovascular compromise was associated with recurrent EF (odds ratio, 95% CI 3.1, 1.0-9.7). This study confirmed that patients with recurrent EF have a high morality. Neonates with a cardiovascular reason for first-time EF are more likely to have a recurrent EF than those with other causes.

Role of levosimendan in weaning children requiring veno-arterial extracorporeal membrane oxygenation after cardiac surgery.

OBJECTIVES: Levosimendan use is associated with more successful decannulation from veno-arterial extracorporeal membrane oxygenation (VA ECMO) in adults. We sought to determine the role of levosimendan in children who required VA ECMO after cardiac surgery. METHODS: This observational study compares the outcomes of children who required VA ECMO after cardiac surgery and received levosimendan for weaning with those who did not receive the drug. A doubly robust estimation methodology (inverse probability of treatment weighting with regression adjustment) was used to balance study covariates (age, weight, sex, lactate pre-ECMO, vasoactive-inotropic score pre-ECMO, ECMO indication, ECMO modality, Risk Adjustment for Congenital Heart Surgery-1 category), and the final model was further adjusted for duration of ECMO. RESULTS: Between January 2012 and December 2018, 118 eligible children received 145 ECMO runs [failed weaning from cardiopulmonary bypass, 67/145 (46%); low cardiac output state, 30/145 (21%); extracorporeal cardiopulmonary resuscitation, 47/145 (32%); other reasons in 1]. Levosimendan was administered before decannulation in 54/145 (37%) runs. The median time to start levosimendan after ECMO cannulation was 39 h (interquartile range, 14-83 h). The unadjusted rates of weaning failure in the levosimendan vs control group were 7% (4/54) vs 19% (17/91). In the controlled analysis, levosimendan was associated with decreased risk of weaning failure [adjusted relative risk (95% confidence interval), 0.20 (0.07-0.57)] and decreased risk of in-hospital mortality [adjusted relative risk (95% confidence interval), 0.45 (0.26-0.76)]. CONCLUSIONS: Levosimendan administration in children requiring VA ECMO after cardiac surgery was associated with decreased risk of weaning failure and decreased in-hospital mortality.

Extubation Failure and Major Adverse Events Secondary to Extubation Failure Following Neonatal Cardiac Surgery.

OBJECTIVES: To describe the prevalence and consequences of major adverse events secondary to extubation failure after neonatal cardiac surgery. DESIGN: A single-center cohort study. SETTING: A medical-surgical, 30-bed PICU in Victoria, Australia. PATIENTS: One thousand one hundred eighty-eight neonates less than or equal to 28 days old who underwent cardiac surgery from January 2007 to December 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Extubation failure was defined as unplanned reintubation within 72 hours after a planned extubation. Major adverse event was defined as one or more of cardiac arrest, emergency chest reopening, extracorporeal membrane oxygenation, or death within 72 hours after extubation. One hundred fifteen of 1,188 (9.7%) neonates had extubation failure. Hospital mortality was 17.4% and 2.0% in neonates with and without extubation failure. Major adverse event occurred in 12 of 115 reintubated neonates (10.4%). major adverse event included cardiac arrest (n = 10), chest reopening (n = 8), extracorporeal membrane oxygenation (n = 5), and death (n = 0). Cardiovascular compromise accounted for major adverse event in eight: ventricular dysfunction (n = 3), pulmonary overcirculation (n = 2), coronary ischemia (n = 2), cardiac tamponade (n = 1). In a multivariable logistic regression, factors associated with major adverse event were high complexity in cardiac surgery (odds ratio 5.9; 95% CI: 1.1-32.2) and airway anomaly (odds ratio 6.0; 95% CI: 1.1-32.6). Hospital morality was 25% and 17% in reintubated neonates with and without major adverse event. CONCLUSIONS: Around 10% of reintubated neonates suffered major adverse event within 72 hours of extubation. Neonates suffering major adverse event had high mortality. Major adverse event should be monitored and reported in future studies of extubation failure. Along with tracking of extubation failure rates, major adverse event secondary to extubation failure may also serve as a key performance indicator for ICUs and registries.

Gestational Age and Risk of Mortality in Term-Born Critically Ill Neonates Admitted to PICUs in Australia and New Zealand.

OBJECTIVES: Gestational age at birth is declining, probably because more deliveries are being induced. Gestational age is an important modifiable risk factor for neonatal mortality and morbidity. We aimed to investigate the association between gestational age and mortality in hospital for term-born neonates (≥ 37 wk') admitted to PICUs in Australia and New Zealand. DESIGN: Observational multicenter cohort study. SETTING: PICUs in Australia and New Zealand. PATIENTS: Term-born neonates (≥ 37 wk) admitted to PICUs. INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS:: We studied 5,073 infants born with a gestational age greater than or equal to 37 weeks and were less than 28 days old when admitted to a PICU in Australia or New Zealand between 2007 and 2016. The association between gestational age and mortality was estimated using a multivariable logistic regression model, adjusting for age, sex, indigenous status, Pediatric Index of Mortality version 2, and site. The median gestational age was 39.1 weeks (interquartile range, 38.2-40 wk) and mortality in hospital was 6.6%. Risk of mortality declined log-linearly with gestational age. The adjusted analysis showed a 20% (95% CI, 11-28%) relative reduction in mortality for each extra week of gestation beyond 37 weeks. The effect of gestation was stronger among those who received extracorporeal life support: each extra week of gestation was associated with a 44% (95% CI, 25-57%) relative reduction in mortality. Longer gestation was also associated with reduced length of stay in hospital: each week increase in gestation, the average length of stay decreased by 4% (95% CI, 2-6%). CONCLUSIONS: Among neonates born at "term" who are admitted to a PICU, increasing gestational age at birth is associated with a substantial reduction in the risk of dying in hospital. The maturational influence on outcome was more strongly noted in the sickest neonates, such as those requiring extracorporeal life support. This information is important in view of the increasing proportion of planned births in both high- and low-/middle-income countries.

Peak Creatinine, Cardiopulmonary Bypass, and Mortality After Stage 1 Single-Ventricle Reconstruction.

BACKGROUND: Serum creatinine is the most commonly used marker to diagnose acute kidney injury. Studies exploring creatinine patterns in the single-ventricle population are scarce. We studied serum creatinine up to 5 postoperative days after the stage 1 operation and assessed its relationship with outcomes. METHODS: Neonates who underwent a first-stage single-ventricle operation (Norwood or a Damus-Kaye-Stansel) between 2005 and 2017 were retrospectively analyzed. Peak percentage creatinine change (PPCC) was defined as the difference between the baseline (preoperative) and the peak postoperative level (within 5 postoperative days), expressed as a percentage of the baseline level. RESULTS: Among 187 neonates included, the median PPCC was 38.7% (interquartile range, 14.1%-73.1%), and in-hospital mortality was 17% (31 of 187). A controlled analysis showed that for every 10-minute increase in cardiopulmonary bypass duration (CPB), the PPCC increased by 1.8% (95% confidence interval [CI], 0.7%-2.9%; P = .002). Risk of in-hospital death increased log-linearly with PPCC. The adjusted odds ratios for death in the hospital associated with a 50%, 100%, and 200%, increase in peak percentage creatinine change were 1.85 (95% CI, 1.23-2.78), 3.41 (95% CI, 1.15-7.72), and 11.66 (95% CI, 2.28-59.63), respectively. In-hospital death was also associated with CPB duration (adjusted odds ratio, 1.13 per 10-minute increase; 95% CI, 1.05-1.22; P = .001). CONCLUSIONS: Increase in CPB duration has a strong linear association with increase in PPCC after stage 1 single-ventricle reconstruction. Increase in PPCC and CPB duration has a strong linear association with hospital mortality. It is important to identify therapies that minimize complications associated with prolonged CPB duration in high-risk populations.

Two Randomized Trials of the Effect of the Russian Strain of Bacillus Calmette-Guérin Alone or With Oral Polio Vaccine on Neonatal Mortality in Infants Weighing <2000 g in India.

BACKGROUND: In randomized trials in Guinea-Bissau, the Danish strain of Bacillus Calmette-Guérin (BCG) reduces neonatal mortality, primarily by reducing deaths from pneumonia and sepsis. Because World Health Organization-prequalified BCG-Denmark was not available in India, we conducted 2 randomized trials to test whether BCG-Russia alone or with oral polio vaccine (OPV) has similar effects to BCG-Denmark. METHODS: We randomized neonates weighing <2000 g to a control group that was not vaccinated before 28 days of age or to receive either BCG-Russia alone (first trial) or BCG-Russia with OPV (second trial) soon after birth. We performed intention-to-treat analysis using Cox hazards models with age as the underlying time and adjusted for weight, sex and inborn versus outborn status. RESULTS: Administration of BCG-Russia alone had no effect on neonatal mortality (to 28 days of age): 15.6% of 1537 infants died in the BCG-Russia group and 16.1% of 1535 died in the control group; the adjusted hazard ratio was 0.95 [95% confidence interval (CI): 0.80-1.13]. Administration of BCG-Russia with OPV also had no effect on neonatal mortality: 18.0% of 1103 infants died in the BCG-OPV group and 17.6% of 1104 died in the control group; the adjusted hazard ratio was 1.01 (95% CI: 0.83-1.23). The adjusted hazard ratio for the 2 trials combined was 0.98 (95% CI: 0.85-1.11). CONCLUSIONS: BCG-Russia with or without OPV had no effect on neonatal mortality. It is important to determine which strains of BCG have the greatest specific effects (on tuberculosis) and nonspecific effects (on infections other than tuberculosis) in high-mortality regions.