Defining the Typical Course of Persistent Pulmonary Hypertension of the Newborn: When to Think Beyond Reversible Causes.

OBJECTIVES: To describe the typical clinical course of reversible persistent pulmonary hypertension of the newborn (PPHN) from perinatal etiologies and compare that with the clinical course of PPHN due to underlying fetal developmental etiologies. STUDY DESIGN: This was a single-center, retrospective cohort study of liveborn newborns either born or transferred to our facility for higher level of care between 2015 and 2020 with gestational age ≥35 weeks and a clinical diagnosis of PPHN in the electronic health record. Newborns with complex congenital heart disease and congenital diaphragmatic hernia were excluded. Using all data available at time of collection, newborns were stratified into 2 groups by PPHN etiology - perinatal and fetal developmental causes. Primary outcomes were age at initiation, discontinuation, and total duration of extracorporeal life support, mechanical ventilation, supplemental oxygen, inhaled nitric oxide, inotropic support, and prostaglandin E1. Our secondary outcome was age at echocardiographic resolution of pulmonary hypertension. Groups were compared by t-test. Time-to-event Kaplan Meier curves described and compared (log-rank test) discontinuation of each therapy. RESULTS: Sixty-four (72%) newborns had perinatal etiologies whereas 24 (28%) had fetal developmental etiologies. The resolution of perinatal PPHN was more rapid compared with fetal developmental PPHN. By 10 days of age, more neonates were off inotropes (98% vs 29%, P < .01), decannulated from extracorporeal life support (100% vs 0%, P < .01), extubated (75% vs 37%, P < .01), and had echocardiographic resolution of PH (35% vs 7%, P = .02). CONCLUSIONS: An atypical PPHN course, characterized by persistent targeted therapies in the second week of life, warrants further work-up for fetal developmental causes.

Double Jeopardy: A Distinct Mortality Pattern Among Preterm Infants with Congenital Heart Disease.

Contemporary United States (US) data on the survival of preterm infants with congenital heart disease (CHD) are unavailable despite the over-representation of CHD and improving surgical outcomes in the preterm population. The aim of this study is to use population-based data to compare 1-year survival and early mortality (< 3 days) by gestational age (GA) between preterm infants with and without cyanotic CHD (CCHD) in the US. This national retrospective cohort included all liveborn, preterm infants between 21 and 36 weeks GA with a birth certificate indicating the presence or absence of CCHD (n = 2,654,253) born between 2014 and 2019 in the US. Data were provided by the US Center for Disease Control database linking birth and death certificates. Of liveborn preterm infants, 0.13% (n = 3619) had CCHD. 1-year survival was significantly lower in infants 23-36 weeks with CCHD compared to those without. The greatest survival gap occurred between 28 and 31 weeks (28 weeks adjusted risk difference 37.5%; 95% CI 28.4, 46.5; 31 weeks 37.9%; 30.5, 45.3). Early mortality accounted for more than half of deaths among infants 23-31 weeks with CCHD (23 weeks-68%, CI 46.7, 83.7; 31 weeks-63.9%, 52.9, 73.6). Survival trends demonstrated worsened 1-year survival in infants 35-36 weeks with CCHD over the study period. The pattern of mortality for preterm infants with CCHD is distinct from those without. The significant survival gap in the very preterm population and notably high rate of early death in the infants with CCHD calls for renewed attention to early neonatal intensive care for this dually affected population.

The Association of Gestational Age and Size with Management Strategies and Outcomes in Symptomatic Neonatal Tetralogy of Fallot.

 In neonatal, symptomatic tetralogy of Fallot (sTOF), data are lacking on whether high-risk groups would benefit from staged (SR) or complete repair (CR). We studied the association of gestational age (GA) at birth and z-score for birth weight (BWz), with management strategy and outcomes in sTOF. California population-based cohort study (2011-2017) of infants with sTOF (defined as catheter or surgical intervention prior to 44 weeks corrected GA) was performed, comparing management strategy and timing by GA and BWz categories. Multivariable models evaluated composite outcomes and days alive and out of hospital (DAOOH) in the first year of life. Among 345 patients (SR = 194; CR = 151), management strategy did not differ by GA or BWz with complete repair defined as prior to 44 weeks corrected gestational age; however, did differ by GA with regard to complete/timely repair (defined as complete repair within first 30 days of life). Full-term and early-term neonates underwent CR 20 (95%CI: - 27.1, - 14.1; p < 0.001) and 15 days (95%CI: - 22.1, - 8.2; p < 0.001) sooner than preterm neonates. Prematurity and major anomaly were associated with mortality or non-cardiac morbidity, while only major anomaly was associated with mortality or cardiac morbidity (OR = 3.5, 95%CI: 1.8,6.7, p < .0001). Full-term infants had greater DAOOH compared to preterm infants (35.2 days, 95%CI: 4.0, 66.5, p = 0.03). LGA infants and those with major anomaly had significantly lower DAOOH. In sTOF, patient specific risk factors such as prematurity and major anomaly were more associated with outcomes than management strategy.

The hydrocortisone-responsive urinary metabolome of premature infants.

BACKGROUND: Extremely premature infants are at risk for circulatory collapse or respiratory failure that are often treated with hydrocortisone (HC); however, there is no information on the metabolic consequences of this therapy. METHODS: Longitudinal urine samples from infants <28 weeks gestation in the Trial of Late Surfactant were analyzed by untargeted UHPLC:MS/MS. Fourteen infants who received a tapering course of HC beginning at 3 mg/kg/day for ≥9 days were compared to 14 matched control infants. A secondary cross-sectional analysis by logistic regression used urines from 314 infants. RESULTS: Of 1145 urinary metabolites detected, abundance of 219, representing all the major biochemical pathways, changed at p < 0.05 in the HC-treated group with 90% decreasing; 3 cortisol derivatives increased ~2-fold with HC therapy. Only 11% of regulated metabolites remained responsive at the lowest HC dose. Regulated metabolites included two steroids and thiamin that are associated with lung inflammation in infants. HC responsiveness was confirmed in 57% of metabolites by cross-sectional analysis. CONCLUSIONS: HC treatment of premature infants influenced in a dose-dependent manner abundance of 19% of identified urinary metabolites of diverse biochemical systems, primarily reducing concentrations. These findings indicate that exposure to HC reversibly impacts the nutritional status of premature infants. IMPACT: Hydrocortisone treatment of premature infants with respiratory failure or circulatory collapse alters levels of a subset of urinary metabolites representing all major biochemical pathways. This is the first description of the scope, magnitude, timing and reversibility of metabolomic changes in infants in response to hydrocortisone, and it confirms corticosteroid regulation of three biochemicals that are associated with lung inflammatory status. The findings indicate a dose-dependency of hydrocortisone for metabolomic and anti-inflammatory effects, that prolonged therapy may lower the supply of many nutrients, and that monitoring concentrations of cortisol and inflammation markers may be a useful clinical approach during corticosteroid therapy.

Association Between Birth Weight Z-Scores and Early Outcomes Following Truncus Arteriosus Repair.

In infants undergoing truncus arteriosus (TA) repair, we sought to determine associations between fetal growth restrictions as measured by birth weight Z-score and early outcomes. We utilized the Pediatric Health Information System (PHIS) database to identify infants < 90 days old who underwent TA repair from 2004 to 2019. The primary exposure variable was birth weight Z-score, calculated based on gestational age at birth, gender, and birth weight. The primary outcome was postoperative hospital mortality. Secondary outcomes included major complications, prolonged postoperative length of hospital stay (LOS; > 30 days), and hospital readmission within 1 year. Generalized estimating equation (GEE) models were used to identify adjusted associations between birth weight Z-score, small for gestational age (SGA) status, and mortality and included were 1039 subjects. Median birth weight was 2960 g, gestational age at birth was 38 weeks, and birth weight Z-score was - 0.47. SGA was present in 21% of subjects. Hospital mortality occurred in 104 patients (10%). By multivariable analysis, lower birth weight Z-score was associated with higher hospital mortality [for each unit decrease in birth weight Z-score below - 1.0, adjusted OR 1.71 (95% CI 1.10-4.25)]. SGA status was associated with increased hospital mortality (adjusted OR 2.17; 95% CI 1.39-3.40). Birth weight Z-scores and SGA status were not significantly associated with occurrence of cardiac arrest, ECMO use, gastrostomy tube placement, tracheostomy, seizures, infection, prolonged postoperative LOS, or hospital readmission. In infants undergoing TA repair, lower birth weight Z-scores and SGA status were strongly associated with increased hospital mortality.

Adverse Maternal Fetal Environment Partially Mediates Disparate Outcomes in Non-White Neonates with Major Congenital Heart Disease.

OBJECTIVE: To determine whether differential exposure to an adverse maternal fetal environment partially explains disparate outcomes in infants with major congenital heart disease (CHD). STUDY DESIGN: Retrospective cohort study utilizing a population-based administrative California database (2011-2017). Primary exposure: Race/ethnicity. Primary mediator: Adverse maternal fetal environment (evidence of maternal metabolic syndrome and/or maternal placental syndrome). OUTCOMES: Composite of 1-year mortality or severe morbidity and days alive out of hospital in the first year of life (DAOOH). Mediation analyses determined the percent contributions of mediators on pathways between race/ethnicity and outcomes after adjusting for CHD severity. RESULTS: Included were 2747 non-Hispanic White infants (reference group), 5244 Hispanic, and 625 non-Hispanic Black infants. Hispanic and non-Hispanic Black infants had a higher risk for composite outcome (crude OR: 1.18; crude OR: 1.25, respectively) and fewer DAOOH (-6 & -12 days, respectively). Compared with the reference group, Hispanic infants had higher maternal metabolic syndrome exposure (43% vs 28%, OR: 1.89), and non-Hispanic Black infants had higher maternal metabolic syndrome (44% vs 28%; OR: 1.97) and maternal placental syndrome exposure (18% vs 12%; OR, 1.66). Both maternal metabolic syndrome exposure (OR: 1.21) and maternal placental syndrome exposure (OR: 1.56) were related to composite outcome and fewer DAOOH (-25 & -16 days, respectively). Adverse maternal fetal environment explained 25% of the disparate relationship between non-Hispanic Black race and composite outcome and 18% of the disparate relationship between Hispanic ethnicity and composite outcome. Adverse maternal fetal environment explained 16% (non-Hispanic Black race) and 21% (Hispanic ethnicity) of the association with DAOOH. CONCLUSIONS: Increased exposure to adverse maternal fetal environment contributes to racial and ethnic disparities in major CHD outcomes.

Residential particulate matter, proximity to major roads, traffic density and traffic volume as risk factors for preterm birth in California.

BACKGROUND: While pollution from vehicle sources is an established risk factor for preterm birth, it is unclear whether distance of residence to the nearest major road or related measures like major road density represent useful measures for characterising risk. OBJECTIVE: To determine whether major road proximity measures (including distance to major road, major road density and traffic volume) are more useful risk factors for preterm birth than other established vehicle-related measures (including particulate matter <2.5 µm in diameter (PM2.5 ) and diesel particulate matter (diesel PM)). METHODS: This retrospective cohort study included 2.7 million births across the state of California from 2011-2017; each address at delivery was geocoded. Geocoding was used to calculate distance to the nearest major road, major road density within a 500 m radius and major road density weighted by truck volume. We measured associations with preterm birth using risk ratios adjusted for target demographic, clinical, socioeconomic and environmental covariates (aRRs). We compared these to the associations between preterm birth and PM2.5 and diesel PM by census tract of residence. RESULTS: Findings showed that whereas higher mean levels of PM2.5 and diesel PM by census tract were associated with a higher risk of preterm birth, living closer to roads or living in higher traffic density areas was not associated with higher risk. Residence in a census tract with a mean PM2.5 in the top quartile compared with the lowest quartile was associated with the highest observed risk of preterm birth (aRR 1.04, 95% CI 1.04, 1.05). CONCLUSIONS: Over a large geographical region with a diverse population, PM2.5 and diesel PM were associated with preterm birth, while measures of distance to major road were not, suggesting that these distance measures do not serve as a proxy for measures of particulate matter in the context of preterm birth.

The Effect of Size and Asymmetry at Birth on Brain Injury and Neurodevelopmental Outcomes in Congenital Heart Disease.

Poor and asymmetric fetal growth have been associated with neonatal brain injury (BI) and worse neurodevelopmental outcomes (NDO) in the growth-restricted population due to placental insufficiency. We tested the hypothesis that postnatal markers of fetal growth (birthweight (BW), head circumference (HC), and head to body symmetry) are associated with preoperative white matter injury (WMI) and NDO in infants with single ventricle physiology (SVP) and d-transposition of great arteries (TGA). 173 term newborns (106 TGA; 67 SVP) at two sites had pre-operative brain MRI to assess for WMI and measures of microstructural brain development. NDO was assessed at 30 months with the Bayley Scale of Infant Development-II (n = 69). We tested the association between growth parameters at birth with the primary outcome of WMI on the pre-operative brain MRI. Secondary outcomes included measures of NDO. Newborns with TGA were more likely to have growth asymmetry with smaller heads relative to weight while SVP newborns were symmetrically small. There was no association between BW, HC or asymmetry and WMI on preoperative brain MRI or with measures of microstructural brain development. Similarly, growth parameters at birth were not associated with NDO at 30 months. In a multivariable model only cardiac lesion and site were associated with NDO. Unlike other high-risk infant populations, postnatal markers of fetal growth including head to body asymmetry that is common in TGA is not associated with brain injury or NDO. Lesion type appears to play a more important role in NDO in CHD.

Longitudinal B-Type Natriuretic Peptide Levels Predict Outcome in Infants with Congenital Diaphragmatic Hernia.

OBJECTIVE: To evaluate B-type natriuretic peptide (BNP) as a longitudinal biomarker of clinical outcome in infants with congenital diaphragmatic hernia (CDH). STUDY DESIGN: We conducted a retrospective study of 49 infants with CDH, classifying the cohort by respiratory status at 56 days, based on a proposed definition of bronchopulmonary dysplasia for infants ≥32 weeks' gestation: good outcome (alive with no respiratory support) and poor outcome (ongoing respiratory support or death). BNP levels were available at age 1-5 weeks. Longitudinal BNP trends were assessed using mixed-effects modeling. Receiver operating characteristic curves were generated to identify BNP cutoffs maximizing correct outcome classification at each time point. The time to reach BNP cutoff by outcome was assessed using Kaplan-Meier curves for weeks 3-5. RESULTS: Twenty-nine infants (59%) had a poor outcome. Infants with a poor outcome were more likely than those with a good outcome to have liver herniated into the thorax (90% vs 50%; P = .002) and to undergo nonprimary repair (93% vs 35%; P < .001). Mixed-effects modeling demonstrated a differing decline in BNP over time by outcome group (P = .003 for interaction). BNP accurately predicted outcome at 3-5 weeks (area under the curve, 0.81-0.82). BNP cutoffs that maximized correct outcome classification decreased over time from 285 pg/mL at 3 weeks to 100 pg/mL at 4 weeks and 48 pg/mL at 5 weeks. Time to reach the cutoffs of 100 pg/mL and 48 pg/mL were longer in the poor outcome group (log-rank P = .006 and <.0001, respectively). CONCLUSIONS: Elevated BNP accurately predicts poor outcome in infants with CDH at age 3-5 weeks, with declining cutoffs over 3-5 weeks of age.

Outcomes of Very Preterm Infants Conceived with Assisted Reproductive Technologies.

OBJECTIVE: To compare mortality and early respiratory outcomes of very preterm infants conceived via assisted reproductive technology (ART) vs spontaneously. STUDY DESIGN: We identified inborn infants (July 2014-July 2019) with gestational age <32 weeks (n = 439); 54 cases were ART conceived. Spontaneously conceived controls (n = 103) were matched by multiple gestation status and gestational age. Primary outcome was 1-year mortality. Secondary outcomes were receipt of respiratory support and supplemental oxygen at 7 and 28 days and 36 weeks of postmenstrual age. We evaluated the association between conception method and outcomes by logistic regression, with adjustment for sociodemographic status. RESULTS: Women who conceived via ART had increased rates of prepregnancy and gestational diabetes, and no differences in rates of hypertensive disorders. Infant 1-year mortality was not different by mode of conception (ART 11.8% vs spontaneous 7.1%, P = .49). Infants conceived by ART were less likely to receive respiratory support or supplemental oxygen at all time points, but this relationship only reached significance for receipt of oxygen at 28 days (ART 20.8% vs spontaneous 39.0%, P = .03); this remained true after adjustment for race/ethnicity and socioeconomic index. CONCLUSIONS: When controlling for gestational age and multiple gestation status, very preterm infants conceived following ART had similar outcomes as those conceived spontaneously.

Mortality and Major Neonatal Morbidity in Preterm Infants with Serious Congenital Heart Disease.

OBJECTIVE: To investigate the trends of 1-year mortality and neonatal morbidities in preterm infants with serious congenital heart disease (CHD). STUDY DESIGN: This cohort study used a population-based administrative dataset of all liveborn infants of 26-36 weeks gestational age with serious CHD born in California between 2011 and 2017. We assessed 1-year mortality and major neonatal morbidities (ie, retinopathy of prematurity, bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage grade >2, and periventricular leukomalacia) across the study period and compared these outcomes with those in infants without CHD. RESULTS: We identified 1921 preterm infants with serious CHD. The relative risk (RR) of death decreased by 10.6% for each year of the study period (RR, 0.89; 95% CI, 0.84-0.95), and the RR of major neonatal morbidity increased by 8.3% for each year (RR, 1.08; 95% CI, 1.02-1.15). Compared with preterm neonates without any CHD (n = 234 522), the adjusted risk difference (ARD) for mortality was highest at 32 weeks of gestational age (9.7%; 95% CI, 8.3%-11.2%), that for major neonatal morbidity was highest at 28 weeks (21.9%; 95% CI, 17.0%-26.9%), and that for the combined outcome was highest at 30 weeks (26.7%; 95% CI, 23.3%-30.1%). CONCLUSIONS: Mortality in preterm neonates with serious CHD decreased over the last decade, whereas major neonatal morbidities increased. Preterm infants with a gestational age of 28-32 weeks have the highest mortality or morbidity compared with their peers without CHD. These results support the need for specialized and focused medical neonatal care in preterm neonates with serious CHD.

Newborn metabolic vulnerability profile identifies preterm infants at risk for mortality and morbidity.

BACKGROUND: Identifying preterm infants at risk for mortality or major morbidity traditionally relies on gestational age, birth weight, and other clinical characteristics that offer underwhelming utility. We sought to determine whether a newborn metabolic vulnerability profile at birth can be used to evaluate risk for neonatal mortality and major morbidity in preterm infants. METHODS: This was a population-based retrospective cohort study of preterm infants born between 2005 and 2011 in California. We created a newborn metabolic vulnerability profile wherein maternal/infant characteristics along with routine newborn screening metabolites were evaluated for their association with neonatal mortality or major morbidity. RESULTS: Nine thousand six hundred and thirty-nine (9.2%) preterm infants experienced mortality or at least one complication. Six characteristics and 19 metabolites were included in the final metabolic vulnerability model. The model demonstrated exceptional performance for the composite outcome of mortality or any major morbidity (AUC 0.923 (95% CI: 0.917-0.929). Performance was maintained across mortality and morbidity subgroups (AUCs 0.893-0.979). CONCLUSIONS: Metabolites measured as part of routine newborn screening can be used to create a metabolic vulnerability profile. These findings lay the foundation for targeted clinical monitoring and further investigation of biological pathways that may increase the risk of neonatal death or major complications in infants born preterm. IMPACT: We built a newborn metabolic vulnerability profile that could identify preterm infants at risk for major morbidity and mortality. Identifying high-risk infants by this method is novel to the field and outperforms models currently in use that rely primarily on infant characteristics. Utilizing the newborn metabolic vulnerability profile for precision clinical monitoring and targeted investigation of etiologic pathways could lead to reductions in the incidence and severity of major morbidities associated with preterm birth.

Variation in Arterial and Central Venous Catheter Use in Pediatric Intensive Care Units.

OBJECTIVE: Describe patient and hospital characteristics associated with Arterial Catheter (AC) or Central Venous Catheter (CVC) use among pediatric intensive care units (ICUs). DESIGN: Hierarchical mixed effects analyses were used to identify patient and hospital characteristics associated with AC or CVC placement. The ICU adjusted median odds ratios (ICU-AMOR) for the admission ICU, marginal R2, and conditional intraclass correlation coefficient were reported. SETTING: 166 PICUs in the Virtual PICU Systems (VPS, LLC) Database. PATIENTS: 682,791 patients with unscheduled admissions to the PICU. INTERVENTION: None. MEASURES AND MAIN RESULTS: ACs were placed in (median, [interquartile range]) 8.2% [4.9%-11.3%] of admissions, and CVCs were placed in 14.9% [10.4%-19.3%] of admissions across cohort ICUs. Measured patient characteristics explained about 25% of the variability in AC and CVC placement. Higher Pediatric Index of Mortality 2 (PIM2) illness severity scores were associated with increased odds of placement (Odds Ratio (95th% Confidence Interval)) AC: 1.88 (1.87-1.89) and CVC: 1.82 (1.81-1.83) per 1 unit increase in PIM2 score. Primary diagnoses of cardiovascular, gastrointestinal, hematology/oncology, infectious, renal/genitourinary, rheumatology, and transplant were associated with increased odds of AC or CVC placement compared to a primary respiratory diagnosis. Presence of in-house attendings 24/7 was associated with increased odds of AC placement 1.32 (1.11-1.57). Admission ICU explained 4.9% and 3.5% of the variability in AC or CVC placement, respectively. The ICU-AMOR showed a patient would have a median increase in odds of 55% and 43% for AC or CVC placement, respectively, if the same patient moved from an ICU with lower odds of placement to an ICU with higher odds of placement. CONCLUSIONS: Variation in AC or CVC use exists among PICUs. The admission ICU was more strongly associated with AC than with CVC placement. Further study is needed to understand unexplained variation in AC and CVC use.

Cohort study of respiratory hospital admissions, air quality and sociodemographic factors in preterm infants born in California.

BACKGROUND: Preterm infants suffer from respiratory morbidity especially during the first year of life. OBJECTIVE: To investigate the association of air quality and sociodemographic indicators on hospital admission rates for respiratory causes. METHODS: This is a retrospective cohort study. We identified all live-born preterm infants in California from 2007 to 2012 in a population-based administrative data set and linked them to a data set measuring several air quality and sociodemographic indicators at the census tract level. All sociodemographic and air quality predictors were divided into quartiles (first quartile most favourable to the fourth quartile least favourable). Mixed effect logistic models to account for clustering at the census tract level were used to investigate associations between chronic air quality and sociodemographic indicators respiratory hospital admission during the first year of life. RESULTS: Of 205 178 preterm infants, 5.9% (n = 12 033) were admitted to the hospital for respiratory causes during the first year. In the univariate analysis, comparing the first to the fourth quartile of chronic ozone (risk ratio [RR] 1.29, 95% confidence interval [CI] 1.21, 1.37), diesel (RR 1.10, 95% CI 1.02, 1.17) and particulate matter 2.5 (RR 1.07, 95% CI 1.01, 1.14) exposure were associated with hospital admission during the first year. Following adjustment for confounders, the risk ratios for hospital admission during the first year were 1.53 (95% CI 1.37, 1.72) in relation to educational attainment (per cent of the population over age 25 with less than a high school education) and 1.23 (95% CI 1.09, 1.38) for poverty (per cent of the population living below two times the federal poverty level). CONCLUSIONS: Among preterm infants, respiratory hospital admissions in the first year in California are associated with socioeconomic characteristics of the neighbourhood an individual is living in.

Extracorporeal Membrane Oxygenation in Pediatric Pulmonary Hypertension.

OBJECTIVE: To describe the epidemiology, critical care interventions, and mortality of children with pulmonary hypertension receiving extracorporeal membrane oxygenation. DESIGN: Retrospective analysis of prospectively collected multicenter data. SETTING: Data entered into the Extracorporeal Life Support Organization database between January 2007 and November 2018. PATIENTS: Pediatric patients between 28 days and 18 years old with a diagnosis of pulmonary hypertension. MEASUREMENTS AND MAIN RESULTS: Six hundred thirty-four extracorporeal membrane oxygenation runs were identified (605 patients). Extracorporeal membrane oxygenation support type was pulmonary (43.1%), cardiac (40.2%), and extracorporeal cardiopulmonary resuscitation (16.7%). The majority of cannulations were venoarterial (80.4%), and 30% had a pre-extracorporeal membrane oxygenation cardiac arrest. Mortality in patients with pulmonary hypertension was 51.3% compared with 44.8% (p = 0.001) in those without pulmonary hypertension. In univariate analyses, significant predictors of mortality included age less than 6 months and greater than 5 years; pre-extracorporeal membrane oxygenation cardiac arrest; pre-extracorporeal membrane oxygenation blood gas with pH less than 7.12, PaCO2 greater than 75, PaO2 less than 35, and arterial oxygen saturation less than 60%; extracorporeal membrane oxygenation duration greater than 280 hours; extracorporeal cardiopulmonary resuscitation; and extracorporeal membrane oxygenation complications including cardiopulmonary resuscitation, inotropic support, myocardial stun, tamponade, pulmonary hemorrhage, intracranial hemorrhage, seizures, other hemorrhage, disseminated intravascular coagulation, renal replacement therapy, mechanical/circuit problem, and metabolic acidosis. A co-diagnosis of pneumonia was associated with significantly lower odds of mortality (odds ratio, 0.5; 95% CI, 0.3-0.8). Prediction models were developed using three sets of variables: 1) pre-extracorporeal membrane oxygenation (age, absence of pneumonia, and pH < 7.12; area under the curve, 0.62); 2) extracorporeal membrane oxygenation related (extracorporeal cardiopulmonary resuscitation, any neurologic complication, pulmonary hemorrhage, renal replacement therapy, and metabolic acidosis; area under the curve, 0.72); and 3) all variables combined (area under the curve, 0.75) (p < 0.001). CONCLUSIONS: Children with pulmonary hypertension who require extracorporeal membrane oxygenation support have a significantly greater odds of mortality compared with those without pulmonary hypertension. Risk factors for mortality include age, absence of pneumonia, pre-extracorporeal membrane oxygenation acidosis, extracorporeal cardiopulmonary resuscitation, pulmonary hemorrhage, neurologic complications, renal replacement therapy, and acidosis while on extracorporeal membrane oxygenation. Identification of those pulmonary hypertension patients requiring extracorporeal membrane oxygenation who are at even higher risk for mortality may inform clinical decision-making and improve prognostic awareness.

Measuring the accuracy of propofol target-controlled infusion (TCI) before and after surgery with major blood loss.

Target-controlled infusion (TCI) is based on pharmacokinetic models designed to achieve a desired drug level in the blood. TCI's predictive accuracy of plasma propofol levels at the end of surgery with major blood loss has not been well established. This prospective observational study included adult patients (BMI 20-35 kg/m2) undergoing surgery with expected blood loss ≥ 1500 mL. The study was conducted with the Schnider TCI propofol model (Alaris PK Infusion Pump, CareFusion, Switzerland). Propofol levels were assessed in steady-state at the end of anaesthesia induction (Tinitial) and before the end of surgery (Tfinal). Predicted propofol levels (CTCI) were compared to measured levels (Cblood). Twenty-one patients were included. The median estimated blood loss was 1600 mL (IQR 1000-2300), and the median fluid balance at Tfinal was + 3200 mL (IQR 2320-4715). Heart rate, mean arterial blood pressure, and blood lactate did not differ significantly between Tinitial and Tfinal. The median bispectral index (0-100) was 50 (IQR 42-54) and 49 (IQR 42-56) at the two respective time points. At Tinitial, median CTCI was 2.2 µmol/L (IQR 2-2.45) and Cblood was 2.0 µmol/L (bias 0.3 µmol/L, limits of agreement - 1.1 to 1.3, p = 0.33). CTCI and Cblood at Tfinal were 2.0 µmol/L (IQR 1.6-2.2) and 1 µmol/L (IQR 0.8-1.4), respectively (bias 0.6 µmol/L, limits of agreement - 0.89 to 1.4, p < 0.0001). Propofol TCI allows clinically unproblematic conduct of general anaesthesia. In cases of major blood loss, the probability of propofol TCI overestimating plasma levels increases.Trial registration German Clinical Trials Register (DRKS; DRKS00009312).

Morbidity of Persistent Pulmonary Hypertension of the Newborn in the First Year of Life.

OBJECTIVE: To assess postdischarge mortality and morbidity in infants diagnosed with different etiologies and severities of persistent pulmonary hypertension of the newborn (PPHN), and to identify risk factors for these adverse clinical outcomes. STUDY DESIGN: This was a population-based study using an administrative dataset linking birth and death certificates, hospital discharge and readmissions records from 2005 to 2012 in California. Cases were infants ≥34 weeks' gestational age with International Classification of Diseases,9th edition, codes consistent with PPHN. The primary outcome was defined as postdischarge mortality or hospital readmission during the first year of life. Crude and adjusted risk ratio (aRR) with 95% CIs were calculated to quantify the risk for the primary outcome and to identify risk factors. RESULTS: Infants with PPHN (n = 7847) had an aRR of 3.5 (95% CI, 3.3-3.7) for the primary outcome compared with infants without PPHN (n = 3 974 536), and infants with only mild PPHN (n = 2477) had an aRR of 2.2 (95% CI, 2.0-2.5). Infants with congenital diaphragmatic hernia as the etiology for PPHN had an aRR of 8.2 (95% CI, 6.7-10.2) and infants with meconium aspiration syndrome had an aRR of 4.2 (95% CI, 3.7-4.6) compared with infants without PPHN. Hispanic ethnicity, small for gestational age, severe PPHN, and etiology of PPHN were risk factors for the primary outcome. CONCLUSIONS: The postdischarge morbidity burden of infants with PPHN is large. These findings extend to infants with mild PPHN and etiologies with pulmonary vascular changes that are thought to be short term and recoverable. These data could inform counseling of parents.

Pediatric Hematopoietic Cell Transplant Patients Who Survive Critical Illness Frequently Have Significant but Recoverable Decline in Functional Status.

The number of pediatric hematopoietic cell transplant (HCT) patients who survive pediatric intensive care unit (PICU) admission is increasing, yet little is known about their functional morbidity after PICU discharge. We hypothesized that relative to control subjects, pediatric HCT patients who survive PICU admission would have greater rates of new functional morbidity at the time of PICU discharge and only some of these patients would return to their functional baseline by the end of the hospitalization. We performed a retrospective cohort study with secondary data analysis of the Trichotomous Outcomes in Pediatric Critical Care dataset. The pediatric HCT cohort was identified by querying International Classification of Diseases, 9th edition, diagnostic codes. A control group consisted of previously healthy patients matched 4:1 on age, sex, and illness severity, as estimated by the Pediatric Risk of Mortality (PRISM) score. We benchmarked our findings by comparing with a previously healthy group of children with lower respiratory tract infections. Functional impairment was measured by the Functional Status Scale, wherein new morbidity was defined as an increase of ≥3 points relative to the prehospital baseline. Relative to matched control subjects, HCT patients had similar admission PRISM scores (P = .516) but greater PICU mortality (12.9% [11/85] versus 6.2% [21/340], P = .035). However, among those who survived to PICU discharge, HCT patients had similar rates of new morbidity at PICU discharge (14.9% [11/74] versus 17.2% [55/319], P = .622) and similar rates of resolution of new morbidity by hospital discharge (54.5% [6/11] versus 60.0% [33/55], P = .737). Relative to the comparison group with lower respiratory tract infections, HCT patients had both greater admission PRISM scores (P < .001) and greater PICU mortality (12.9% [11/85] versus 1.6% [5/308], P < .001). However, among those who survived to PICU discharge, HCT patients again displayed similar rates of new morbidity at PICU discharge (14.9% [11/74] versus 22.1% [67/303], P = .168) as well as resolution of new morbidity by hospital discharge (54.5% [6/11] versus 71.6% [48/67], P = .299). For pediatric HCT patients PICU survival with new functional morbidity is as prevalent an outcome as PICU mortality. Although pediatric HCT patients have greater PICU mortality than age-, sex-, and PRISM-matched control subjects, they have similar rates of new functional morbidity at PICU discharge and similar resolution of new functional morbidity at hospital discharge. Future interventions focused on improving functional status in pediatric HCT survivors of critical illness are warranted.

Maternal Black Race and Persistent Wheezing Illness in Former Extremely Low Gestational Age Newborns: Secondary Analysis of a Randomized Trial.

OBJECTIVE: To evaluate the relationship between maternal self-reported race/ethnicity and persistent wheezing illness in former high-risk, extremely low gestational age newborns, and to quantify the contribution of socioeconomic, environmental, and biological factors on this relationship. STUDY DESIGN: We assessed persistent wheezing illness determined at 18-24 months corrected (for prematurity) age in survivors of a randomized trial. Parents/caregivers were surveyed for wheeze and inhaled asthma medication use quarterly to 12 months, and at 18 and 24 months. We used multivariable analysis to evaluate the relationship of maternal race to persistent wheezing illness, and identified mediators for this relationship via formal mediation analysis. RESULTS: Of 420 infants (25.2 ± 1.2 weeks of gestation and 714 ± 166 g at birth, 57% male, 34% maternal black race), 189 (45%) had persistent wheezing illness. After adjustment for gestational age, birth weight, and sex, infants of black mothers had increased odds of persistent wheeze compared with infants of nonblack mothers (OR = 2.9, 95% CI 1.9, 4.5). Only bronchopulmonary dysplasia, breast milk diet, and public insurance status were identified as mediators. In this model, the direct effect of race accounted for 69% of the relationship between maternal race and persistent wheeze, whereas breast milk diet, public insurance status, and bronchopulmonary dysplasia accounted for 8%, 12%, and 10%, respectively. CONCLUSIONS: Among former high-risk extremely low gestational age newborns, infants of black mothers have increased odds of developing persistent wheeze. A substantial proportion of this effect is directly accounted for by race, which may reflect unmeasured environmental influences, and acquired and innate biological differences. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580.