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To predict pulmonary hypertension (PH) therapy at discharge in a large multicenter cohort of infants with congenital diaphragmatic hernia (CDH). Six-year linked records from Children’s Hospitals Neonatal Database and Pediatric Health Information System were used; patients whose diaphragmatic hernia was repaired before admission or referral, who were previously home before admission or referral, and non-survivors were excluded. The primary outcome was the use of PH medications at discharge and the secondary outcome was an inter-center variation of therapies during inpatient utilization. Clinical factors were used to develop a multivariable equation randomly applied to 80% cohort; validated in the remaining 20% infants. A total of 831 infants with CDH from 23 centers were analyzed. Overall, 11.6% of survivors were discharged on PH medication. Center, duration of mechanical ventilation, and duration of inhaled nitric oxide were associated with the use of PH medication at discharge. This model performed well in the validation cohort area under the receiver operating characteristic curve of 0.9, goodness-of-fit χ2, p = 0.17. Clinical variables can predict the need for long-term PH medication after NICU hospitalization in surviving infants with CDH. This information may be useful to educate families and guide the development of clinical guidelines.

In congenital diaphragmatic hernia (CDH), ultrasound (U/S) measurements of the contralateral lung commonly provide the observed-to-expected lung-to-head ratio (O/E LHR) and are used to determine the severity of pulmonary hypoplasia. Fetal magnetic resonance imaging (MRI) measurement of the observed-to-expected total lung volume (O/E TLV) has been used as an adjunct to O/E LHR in predicting outcomes. Since O/E LHR only measures the contralateral lung, we sought to investigate if MRI measurements of the contralateral lung volume (O/E CLV) can accurately predict outcomes in CDH. We hypothesize that O/E CLV is a better predictor of CDH outcomes than O/E LHR. We identified all infants with a prenatal diagnosis of CDH at our fetal center who had both MRI and U/S measurements. Using lung volume ratios of right–left 55:45, we calculated O/E CLV from O/E TLV. We used receiver-operating characteristic (ROC) curves to calculate the area under the curve (AUC) to compare the predictive accuracy of O/E CLV to O/E LHR for ECMO support, as well as survival to both discharge and 1 year. Seventy-four patients had complete prenatal imaging with 39% requiring ECMO support. The median O/E CLV was 48.0% and the median O/E LHR was 42.3%. O/E CLV was a better predictor of the need for ECMO support (AUC 0.81 vs. 0.74). O/E CLV was a better predictor of survival to discharge (AUC 0.84 vs. 0.64) and 1-year survival (AUC 0.83 vs. 0.63) than O/E LHR. O/E LHR is a well-validated standard for predicting outcomes and guiding prenatal counseling in CDH. We provide evidence that fetal MRI measurements of the contralateral lung volume corrected for gestational age were more accurate in predicting the need for ECMO and survival. Future prospective studies validating O/E CLV regarding outcomes and ECMO utilization are warranted. Level III, retrospective comparative study.

Objective To examine incidence of acute kidney injury (AKI), antenatal and postnatal predictors, and impact of AKI on outcomes in infants with congenital diaphragmatic hernia (CDH). Study design Single center retrospective study of 90 CDH infants from 2009–2017. Baseline characteristics, CDH severity, possible AKI predictors, and clinical outcomes were compared between infants with and without AKI. Result In total, 38% of infants developed AKI, 44% stage 1, 29% stage 2, 27% stage 3. Lower antenatal lung volumes and liver herniation were associated with AKI. Extracorporeal life support (ECLS), diuretics, abdominal closure surgery, hypotension, and elevated plasma free hemoglobin were associated with AKI. Overall survival was 79%, 47% with AKI, and 35% with AKI on ECLS. AKI is associated with increased mechanical ventilation duration and length of stay. Conclusion AKI is common among CDH infants and associated with adverse outcomes. Standardized care bundles addressing AKI risk factors may reduce AKI incidence and severity.

OBJECTIVE The aim of this study was to describe the use, duration, and intercenter variation of analgesia and sedation in infants with congenital diaphragmatic hernia (CDH). STUDY DESIGN This is a retrospective analysis of analgesia, sedation, and neuromuscular blockade use in neonates with CDH. Patient data from 2010 to 2016 were abstracted from the Children's Hospitals Neonatal Database and linked to the Pediatric Health Information System. Patients were excluded if they also had non-CDH conditions likely to affect the use of the study medications. RESULTS A total of 1,063 patients were identified, 81% survived, and 30% were treated with extracorporeal membrane oxygenation (ECMO). Opioid (99.8%), sedative (93.4%), and neuromuscular blockade (87.9%) use was common. Frequency of use was higher and duration was longer among CDH patients treated with ECMO. Unadjusted duration of use varied 5.6-fold for benzodiazepines (median: 14 days) and 7.4-fold for opioids (median: 16 days). Risk-adjusted duration of use varied among centers, and prolonged use of both opioids and benzodiazepines ≥5 days was associated with increased mortality (p

Over the last two decades, fetal imaging has greatly improved, and new prenatal imaging measurements have been developed to characterize congenital diaphragmatic hernia (CDH) severity.To determine the best prenatal imaging predictor of postnatal CDH outcomes, including use of extracorporeal membrane oxygenation (ECMO) and in-hospital mortality, with particular attention to the percentage of liver herniation (%LH) as a predictor. Additionally, we sought to guide best practices across hospital systems including improved models of prenatal risk assessment.We conducted a retrospective review of infants with left CDH who were prenatally diagnosed. We analyzed prenatal imaging measurements including observed-to-expected (O/E) lung-to-head ratio (LHR) on US, percentage predicted lung volume (PPLV) on MRI, and O/E total fetal lung volume (TFLV) and %LH on MRI. We compared prenatal imaging characteristics for infants with (1) in-hospital postnatal mortality and (2) use of ECMO. Then we performed multivariate logistic regression to determine independent predictors of postnatal outcomes.We included 63 infants with a median gestation of 34 weeks at the time of prenatal MRI. Low O/E LHR (31.2 vs. 50, P 0.0001), PPLV (14.7 vs. 22.6, P 0.0001) and O/E TLFV (24.6 vs. 38.3, P 0.0001) and high %LH (15.1 vs. 2.1, P = 0.0006) were associated with worse postnatal outcomes; however, only PPLV was predictive of survival and need for ECMO on multivariable analysis. PPLV survival to discharge model showed an area under the curve (AUC) of 0.93 (95% confidence interval [CI]: 0.86, 0.99), P 0.0001; and an odds ratio of 68.7 (95% CI: 6.5-2,302), P = 0.003. PPLV need for ECMO model showed AUC = 0.87 (95% CI: 0.78, 0.96), P 0.0001; and odds ratio = 20.1 (95% CI: 3.1-226.3), P = 0.011.Low O/E LHR, PPLV and O/E TFLV and high %LH in the third trimester are associated with worse postnatal outcomes. PPLV most strongly predicted outcome using a logistic regression model. Percentage of liver herniation was not an independent predictor of outcomes.

Introduction: We aimed to characterize acute kidney injury (AKI), fluid overload (FO), and renal replacement therapy (RRT) utilization by diagnostic categories and examine associations between these complications and mortality by category. Methods: To test our hypotheses, we conducted a retrospective multicenter, cohort study including 446 neonates (categories: 209 with cardiac disease, 114 with congenital diaphragmatic hernia [CDH], 123 with respiratory disease) requiring extracorporeal membrane oxygenation (ECMO) between January 1, 2007, and December 31, 2011. Results: AKI, FO, and RRT each varied by diagnostic category. AKI and RRT receipt were most common in those neonates with cardiac disease. Subjects with CDH had highest peak %FO (51% vs. 28% cardiac vs. 32% respiratory; p < 0.01). Hospital survival was 55% and varied by diagnostic category (45% cardiac vs. 48% CDH vs. 79% respiratory; p < 0.001). A significant interaction suggested risk of mortality differed by diagnostic category in the presence or absence of AKI. In its absence, diagnosis of CDH (vs. respiratory disease) (OR 3.04, 95% CL 1.14–8.11) independently predicted mortality. In all categories, peak %FO (OR 1.20, 95% CL 1.11–1.30) and RRT receipt (OR 2.12, 95% CL 1.20–3.73) were independently associated with mortality. Discussion/Conclusions: Physiologically distinct ECMO diagnoses warrant individualized treatment strategies given variable incidence and effects of AKI, FO, and RRT by category on mortality.

Randomized controlled trials in the 1990s confirmed the safety and efficacy of inhaled nitric oxide (iNO) in near-term and term newborns with hypoxemic respiratory failure and pulmonary hypertension, demonstrating improved oxygenation and reduced need for extracorporeal membrane oxygenation (ECMO) therapy. However, in about 30% to 40% of sick newborns, these improvements in oxygenation and hemodynamics are not sustained and affected infants often require rapid transfer to an ECMO center despite the initiation of iNO. Abrupt discontinuation of iNO therapy before transport in patients who have had little apparent clinical benefit can be harmful because of acute deterioration with severe hypoxemia. Thus, continued use of iNO therapy during hospital transfer of infants with pulmonary hypertension is important. In this review, we describe: 1) the history of iNO use during transport; 2) a practical approach to iNO during transport; and 3) guidelines for the initiation of iNO before or during transport.

Background Congenital diaphragmatic hernia (CDH) repair is technically challenging with different approaches for repair. The aim of this study was to compare outcomes between patch and flap repair. Methods CDH repairs performed at a quaternary care children's hospital between 2008 and 2018 were reviewed. Seventy CDH repairs were analyzed after primary repairs were excluded (n = 52). Analysis included proportions or median with interquartile range and chi-square or Wilcoxon rank-sum test. Results Comparing patch and flap repairs, demographic characteristics and hernia parameters were similar. Examining outcomes, length of stay, 30-day mortality, and 1-year mortality were all similar between groups, but total/symptomatic recurrence was higher in the patch group (10%/7% vs. 3%/0%), and the median time to recurrence was 3 months. A sub-analysis comparing those who recurred to those who did not demonstrated no significant difference between the two groups. Conclusion Patients who undergo flap repair have a lower risk of recurrence compared to those who undergo patch repair, and this may be due to the ability of the flap to grow over time with the child. Type of Study Treatment Study. Level of Evidence III

Survival for severe (observed to expected lung-head ratio (O:E LHR) 25%) congenital diaphragmatic hernia (CDH) remains a challenge (15-25%). Management strategies have focused on fetal endoscopic tracheal occlusion (FETO) and/or extracorporeal membrane oxygenation therapy (ECMO) utilization.Describe single center outcomes for infants with severe CDH.Observational study of 13 severe CDH infants managed with ECMO, a protocolized DR algorithm, and early repair on ECMO with an innovative perioperative anticoagulation strategy.13/140 (9.3%) infants met criteria and were managed with ECMO. 77% survived ECMO and 69% survived to discharge. 22% underwent tracheostomy. Median days on mechanical ventilation was 39 days (IQR 22:107.5) and length of stay 135 days (IQR 62.5:211.5). All infants received a gastrostomy tube (GT) and were discharged home on oxygen and pulmonary hypertension (PH) meds.Survival for infants with severe CDH can be optimized with early aggressive intervention and protocolized algorithms (149).

Acute kidney injury (AKI) and fluid overload (FO) are common complications of extracorporeal membrane oxygenation (ECMO). The purpose of this study was to characterize AKI and FO in children receiving extracorporeal cardiopulmonary resuscitation (eCPR). We performed a multicenter retrospective study of children who received eCPR. AKI was assessed during ECMO and FO defined as

To determine how blood gas exchange is altered during the transition in the first hour of life in infants with congenital diaphragmatic hernia (CDH).This was a prospective observational cohort study evaluating arterial blood gas (ABG) samples and ventilator support in 34 infants with CDH in the first hour of life. Infants were stratified into mild, moderate, and severe CDH. The first ABG was compared with the umbilical cord ABGs and response to intervention evaluated on subsequent ABGs among infants with different CDH severities.Infants were intubated at a median of 120 seconds (range 50-240 seconds) and ABGs obtained at a median of 6 minutes (IQR 4, 8 minutes), 16 minutes (IQR 13.5, 22.5 minutes), and 60 minutes (IQR 56, 64 minutes). Compared with the cord ABG, first ABG mean partial pressure of carbon dioxide (PaCOGas exchange is markedly altered in the first hour of life in infants with CDH with abrupt onset of acidemia and a mixed respiratory and metabolic acidosis. Early implementation of adequate cardiopulmonary support may contribute to more timely stabilization of gas exchange.

In congenital diaphragmatic hernia (CDH), ultrasound (U/S) measurements of the contralateral lung commonly provide the observed-to-expected lung-to-head ratio (O/E LHR) and are used to determine the severity of pulmonary hypoplasia. Fetal magnetic resonance imaging (MRI) measurement of the observed-to-expected total lung volume (O/E TLV) has been used as an adjunct to O/E LHR in predicting outcomes. Since O/E LHR only measures the contralateral lung, we sought to investigate if MRI measurements of the contralateral lung volume (O/E CLV) can accurately predict outcomes in CDH. We hypothesize that O/E CLV is a better predictor of CDH outcomes than O/E LHR.We identified all infants with a prenatal diagnosis of CDH at our fetal center who had both MRI and U/S measurements. Using lung volume ratios of right-left 55:45, we calculated O/E CLV from O/E TLV. We used receiver-operating characteristic (ROC) curves to calculate the area under the curve (AUC) to compare the predictive accuracy of O/E CLV to O/E LHR for ECMO support, as well as survival to both discharge and 1 year.Seventy-four patients had complete prenatal imaging with 39% requiring ECMO support. The median O/E CLV was 48.0% and the median O/E LHR was 42.3%. O/E CLV was a better predictor of the need for ECMO support (AUC 0.81 vs. 0.74). O/E CLV was a better predictor of survival to discharge (AUC 0.84 vs. 0.64) and 1-year survival (AUC 0.83 vs. 0.63) than O/E LHR.O/E LHR is a well-validated standard for predicting outcomes and guiding prenatal counseling in CDH. We provide evidence that fetal MRI measurements of the contralateral lung volume corrected for gestational age were more accurate in predicting the need for ECMO and survival. Future prospective studies validating O/E CLV regarding outcomes and ECMO utilization are warranted.Level III, retrospective comparative study.

Fluid overload (FO) and acute kidney injury (AKI) occur commonly in children supported with extracorporeal membrane oxygenation (ECMO). Continuous renal replacement therapy (CRRT) may be used to manage AKI and FO in children on ECMO. In 2012, our group surveyed ECMO centers to begin to understand the practice patterns around CRRT and ECMO. Since then, more centers are initiating ECMO for increasingly diverse indications and an increased volume of research quantifies the detrimental impacts of AKI and FO. We, therefore, investigated practice patterns of CRRT utilization during ECMO in children. A multi-point survey instrument was distributed to 116 international neonatal and pediatric ECMO centers. Sixty of 116 (51.7%) international neonatal and pediatric ECMO centers responded. All reports using CRRT on ECMO, compared with 75% from the 2012 survey. Eighty-five percent use CRRT to treat or prevent FO, an increased from 59%. The modality of CRRT therapy differed between in-line (slow continuous ultrafiltration, 84.4%) and machine-based (continuous venovenous hemodiafiltration, 87.3%) methods. Most (65%) do not have protocols for fluid management, AKI, or CRRT on ECMO. Trialing off CRRT is dictated by physician preference in 90% (54/60), with varying definitions of success. In this survey study, we found that CRRT use during pediatric ECMO has increased since 2012 with fluid management representing the predominant indication for initiation. Despite the expanded utilization of CRRT with ECMO, there remains significant practice variation in terms of method, modality, indication, the timing of initiation, fluid management, and discontinuation.

Rationale: Acute kidney injury (AKI), a common complication of sepsis, is associated with substantial morbidity and mortality and lacks definitive disease-modifying therapy. Early, reliable identification of at-risk patients is important for targeted implementation of renal protective measures. The updated Pediatric Sepsis Biomarker Risk Model (PERSEVERE-II) is a validated, multibiomarker prognostic enrichment strategy to estimate baseline mortality risk in pediatric septic shock. Objectives: To assess the association between PERSEVERE-II mortality probability and the development of severe, sepsis-associated AKI on Day 3 (D(3) SA-AKI) in pediatric septic shock. Methods: We performed secondary analysis of a prospective observational study of children with septic shock in whom the PERSEVERE biomarkers were measured to assign a PERSEVERE-II baseline mortality risk. Measurements and Main Results: Among 379 patients, 65 (17%) developed severe D(3) SA-AKI. The proportion of patients developing severe D(3) SA-AKI increased directly with increasing PERSEVERE-II risk category, and increasing PERSEVERE-II mortality probability was independently associated with increased odds of severe D(3) SA-AKI after adjustment for age and illness severity (odds ratio, 1.4; 95% confidence interval, 1.2–1.7; P

Congenital diaphragmatic hernia (CDH) is a rare developmental defect of the diaphragm, characterized by herniation of abdominal contents into the chest that results in varying degrees of pulmonary hypoplasia and pulmonary hypertension (PH). Significant advances in the prenatal diagnosis and identification of prognostic factors have resulted in the continued refinement of the approach to fetal therapies for CDH. Postnatally, protocolized approaches to lung-protective ventilation, nutrition, prevention of infection, and early aggressive management of PH have led to improved outcomes in infants with CDH. Advances in our understanding of the associated left ventricular (LV) hypoplasia and myocardial dysfunction in infants with severe CDH have allowed for the optimization of hemodynamics and management of PH. This article provides a comprehensive review of CDH for the anesthesiologist, focusing on the complex pathophysiology, advances in prenatal diagnosis, fetal interventions, and optimal postnatal management of CDH.

BACKGROUND: Most studies of neonatal acute kidney injury (AKI) have focused on the first week following birth. Here, we determined the outcomes and risk factors for late AKI (>7d). METHODS: The international AWAKEN study examined AKI in neonates admitted to an intensive care unit. Late AKI was defined as occurring >7 days after birth according to the KDIGO criteria. Models were constructed to assess the association between late AKI and death or length of stay. Unadjusted and adjusted odds for late AKI were calculated for each perinatal factor. RESULTS: Late AKI occured in 202/2152 (9%) of enrolled neonates. After adjustment, infants with late AKI had higher odds of death (aOR:2.1, p=0.02) and longer length of stay (parameter estimate:21.9, p

Over one-third of infants with congenital diaphragmatic hernia (CDH) eventually require a Nissen fundoplication (NF). We examined pre- and intraoperative predictors for need of a NF in children undergoing CDH repair to elucidate, which patients will need a later NF. A retrospective analysis of all consecutive patients undergoing CDH repair at our institution from 2008 to 2018 was performed. Patients who underwent a NF were compared to those who did not (noNissen). Logistic regression analysis was performed to find independent predictors for NF in patients undergoing CDH repair. Severe Defect Grade was defined as defect >50% of the hemidiaphragm and intrathoracic liver. One hundred twenty-six patients were included, 42 (33%) underwent NF at a median of 61 days after CDH repair. Intrathoracic liver was more frequent in the NF (71%) versus noNissen (45%) group (P = .008). Absence of >50% of the hemidiaphragm was more frequent in the NF group (76% vs 31%, P

To identify factors associated with gastrostomy tube (GT) placement in infants with congenital diaphragmatic hernia (CDH).Retrospective cohort study of 114 surviving infants with CDH at a single tertiary care neonatal intensive care unit from 2010-2019. Prenatal, perinatal and postnatal characteristics were compared between patients who were discharged home with and without a GT. Prenatal imaging was available for 50.9% of the cohort. Logistic regression was used to assess the association between GT placement and pertinent clinical factors. ROC curves were generated, and Youden's J statistic was used to determine optimal predictive cutoffs for continuous variables. Elastic net regularized regression was used to identify variables associated with GT placement in multivariable analysis.GT was placed in 43.9% of surviving infants with CDH. Prenatal variables predictive of GT placement were percent predicted lung volume (PPLV)21%, total lung volume (TLV)30 ml, lung-head ratio (LHR)1.2 or observed to expected LHR (O/E LHR)55%. Infants who required a GT were diagnosed earlier prenatally (23.6 ± 3.4 vs. 26.4 ± 5.6 weeks). Patients whose stomach was above the diaphragm on prenatal ultrasound (up) had a higher odds of GT placement compared to those with stomachs below the diaphragm (down) position by a factor of 2.9 (95% CI: 1.25, 7.1); p = 0.0154. Postnatally, infants with GT had lower Apgar scores at 1 and 5 min, longer lengths of stay and higher proportion of flap closures. Infants with a type C or D defect and extracorporeal membrane oxygenation (ECMO) were associated with increased odds of needing a GT. Postnatal association included being NPO for12 days, need for transpyloric (TP) feeds for10 days,14 days to transition to a 30 min bolus feed, presence of gastro-esophageal reflux (GER), chronic lung disease and pulmonary hypertension. In multivariable analysis, duration of NPO, time to TP feeds, transition to 30 min bolus feeds remained significantly associated with GT placement after adjusting for severity of pulmonary hypertension (PH), GER diagnosis and sildenafil treatment.Identification of risk factors associated with need for long-term feeding access may improve timing of GT placement and prevent prolonged hospitalization related to feeding issues.Level II (Retrospective Study).

Congenital diaphragmatic hernia (CDH) can cause severe hemodynamic deterioration requiring support with extracorporeal membrane oxygenation (ECMO). ECMO is associated with hemorrhagic and thromboembolic complications. In 2015, we standardized anti-coagulation management on ECMO, incorporating thromboelastography (TEG) as an adjunct to manage hemostasis of CDH patients. The purpose of this study is to evaluate our blood product utilization, choice of blood product use in response to abnormal TEG parameters, and the associated effect on bleeding and thrombotic complications. We retrospectively reviewed all CDH neonates supported by ECMO between 2008 and 2018. Blood product administration, TEG data, and hemorrhagic and thrombotic complications data were collected. We divided subjects into two groups pre-2015 and post-2015. After 2015, platelet transfusion was administered for a low maximum amplitude (MA) more frequently (77% compared to 65%, p = 0.0007). Cryoprecipitate was administered less frequently for a low alpha-angle (28% compared to 41%, p = 0.0016). There was no difference in fresh frozen plasma use over time. After standardizing the use of TEG, we observed a significant reduction in hemothoraces (18% compared to 54%, p = 0.026). Institutional standardization of anti-coagulation management of CDH neonates on ECMO, including the use of goal-directed TEG monitoring may lead to improved blood product utilization and a decrease in bleeding complications in neonates with CDH supported by ECMO. Level III, Retrospective comparative study

To predict pulmonary hypertension (PH) therapy at discharge in a large multicenter cohort of infants with congenital diaphragmatic hernia (CDH).Six-year linked records from Children's Hospitals Neonatal Database and Pediatric Health Information System were used; patients whose diaphragmatic hernia was repaired before admission or referral, who were previously home before admission or referral, and non-survivors were excluded. The primary outcome was the use of PH medications at discharge and the secondary outcome was an inter-center variation of therapies during inpatient utilization. Clinical factors were used to develop a multivariable equation randomly applied to 80% cohort; validated in the remaining 20% infants.A total of 831 infants with CDH from 23 centers were analyzed. Overall, 11.6% of survivors were discharged on PH medication. Center, duration of mechanical ventilation, and duration of inhaled nitric oxide were associated with the use of PH medication at discharge. This model performed well in the validation cohort area under the receiver operating characteristic curve of 0.9, goodness-of-fit χClinical variables can predict the need for long-term PH medication after NICU hospitalization in surviving infants with CDH. This information may be useful to educate families and guide the development of clinical guidelines.

Describe inpatient pulmonary hypertension (PH) treatment and factors associated with therapy at discharge in a multicenter cohort of infants with CDH. Six years linked records from Children’s Hospitals Neonatal Database and Pediatric Health Information System were used to describe associations between prenatal/perinatal factors, clinical outcomes, echocardiographic findings and PH medications (PHM), during hospitalization and at discharge. Of 1106 CDH infants from 23 centers, 62.8% of infants received PHM, and 11.6% of survivors were discharged on PHM. Survivors discharged on PHM more frequently had intrathoracic liver, small for gestational age, and low 5 min APGARs compared with those discharged without PHM (p

Objective The aim of this study is to determine patterns of neurally adjusted ventilatory assist (NAVA) use in ventilator-dependent preterm infants with evolving or established severe bronchopulmonary dysplasia (sBPD) among centers of the BPD Collaborative, including indications for its initiation, discontinuation, and outcomes. Study Design Retrospective review of infants with developing or established sBPD who were placed on NAVA after ≥4 weeks of mechanical ventilation and were ≥ 30 weeks of postmenstrual age (PMA). Results Among the 13 sites of the BPD collaborative, only four centers (31%) used NAVA in the management of infants with evolving or established BPD. A total of 112 patients met inclusion criteria from these four centers. PMA, weight at the start of NAVA and median number of days on NAVA, were different among the four centers. The impact of NAVA therapy was assessed as being successful in 67% of infants, as defined by the ability to achieve respiratory stability at a lower level of ventilator support, including extubation to noninvasive positive pressure ventilation or support with a home ventilator. In total 87% (range: 78–100%) of patients survived until discharge. Conclusion We conclude that NAVA can be used safely and effectively in selective infants with sBPD. Indications and current strategies for the application of NAVA in infants with evolving or established BPD, however, are highly variable between centers. Although this pilot study suggests that NAVA may be successfully used for the management of infants with BPD, sufficient experience and well-designed clinical studies are needed to establish standards of care for defining the role of NAVA in the care of infants with sBPD.

OBJECTIVE: The aim of this study was to characterize continuous renal replacement therapy (CRRT) utilization on extracorporeal membrane oxygenation (ECMO) and to determine the association of both fluid overload (FO) at CRRT initiation and fluid removal during CRRT with mortality in a large multicenter cohort. METHODS: Retrospective chart review of all children < 18 years of age concurrently treated with ECMO and CRRT from January 1, 2007 to December 31, 2011 at 6 tertiary care children’s hospital. Children treated with hemodialysis or peritoneal dialysis were excluded from the FO analysis. MEASUREMENTS AND MAIN RESULTS: A total of 756 of the 1009 children supported with ECMO during the study period had complete FO data. Of these, 357 (47.2%) received either CRRT or were treated with an in-line filter and thus entered into the final analysis. Survival to ECMO decannulation was 66.4% and survival to hospital discharge was 44.3%. CRRT initiation occurred at median of 1 day (IQR 0, 2) after ECMO initiation. Median FO at CRRT initiation was 20.1% (IQR 5, 40) and was significantly lower in ECMO survivors vs. non-survivors (15.3% vs. 30.5% p= 0.005) and in hospital survivors vs. non-survivors (13.5% vs. 25.9%, p= 0.004). Median FO at CRRT discontinuation was significantly lower in ECMO survivors (23% vs. 37.6% p= 0.002) and hospital survivors vs. non-survivors (22.6% vs. 36.1%, p=0.002). In ECMO survivors, after adjusting for pH at CRRT initiation, non-renal complications, ECMO mode, support type, center, patient age and AKI, FO at CRRT initiation (p = 0.01), and FO at CRRT discontinuation (p = 0.0002) were independently associated with duration of ECMO. In a similar multivariable analysis, FO at CRRT initiation (adjusted adds ratio [aOR] 1.09, 95% CI 1.00–1.18, p=0.045) and at CRRT discontinuation (aOR 1.11, 95% CI 1.03–1.19, p=0.01) were independently associated with hospital mortality. CONCLUSIONS: In a multicenter pediatric ECMO cohort, this study demonstrates that severe FO was very common at CRRT initiation. We found an independent association between the degree of FO at CRRT initiation with adverse outcomes including mortality and increased duration of ECMO support. The results suggest intervening prior to the development of significant FO may be a clinical therapeutic target and warrants further evaluation.

Intrauterine growth restriction (IUGR) in premature newborns increases the risk for bronchopulmonary dysplasia, a chronic lung disease characterized by disrupted pulmonary angiogenesis and alveolarization. We previously showed that experimental IUGR impairs angiogenesis; however, mechanisms that impair pulmonary artery endothelial cell (PAEC) function are uncertain. The NF-κB pathway promotes vascular growth in the developing mouse lung, and we hypothesized that IUGR disrupts NF-κB-regulated proangiogenic targets in fetal PAEC. PAECs were isolated from the lungs of control fetal sheep and sheep with experimental IUGR from an established model of chronic placental insufficiency. Microarray analysis identified suppression of NF-κB signaling and significant alterations in extracellular matrix (ECM) pathways in IUGR PAEC, including decreases in collagen 4α1 and laminin α4, components of the basement membrane and putative NF-κB targets. In comparison with controls, immunostaining of active NF-κB complexes, NF-κB-DNA binding, baseline expression of NF-κB subunits p65 and p50, and LPS-mediated inducible activation of NF-κB signaling were decreased in IUGR PAEC. Although pharmacological NF-κB inhibition did not affect angiogenic function in IUGR PAEC, angiogenic function of control PAEC was reduced to a similar degree as that observed in IUGR PAEC. These data identify reductions in endothelial NF-κB signaling as central to the disrupted angiogenesis observed in IUGR, likely by impairing both intrinsic PAEC angiogenic function and NF-κB-mediated regulation of ECM components necessary for vascular development. These data further suggest that strategies that preserve endothelial NF-κB activation may be useful in lung diseases marked by disrupted angiogenesis such as IUGR.

BACKGROUND In addition to substantial medical and surgical intervention, neonates with congenital diaphragmatic hernia often have concurrent concerns for acquired infection. However, few studies focus on infection and corresponding antimicrobial utilization in this population. METHODS The Children's Hospital Neonatal Database was queried for congenital diaphragmatic hernia infants hospitalized from January 2010 to February 2016. Patient charts were linked to the Pediatric Health Information Systems database. Descriptive clinical data including delivery history, cultures sent, diagnosed infection, antimicrobial use and outcomes were reported. RESULTS A total of 1085 unique patients were identified after data linkages; 275 (25.3%) were born at

Appropriate post-natal growth remains a mainstay of therapeutic goals for infants with CDH, with the hypothesis that optimizing linear growth will improve survival through functional improvements in pulmonary hypoplasia. However, descriptions of growth and the effect on survival are limited in affected infants.Describe in-hospital weight gain related to survival among infants with CDH.Children's Hospitals Neonatal Database (CHND) identified infants with CDH born ≥34weeks' gestation (2010-14). Exclusion criteria were: admission age7days, death/discharge age14days, or surgical CDH repair prior to admission. Weight gain velocity (WGV: g/kg/day) was calculated using an established exponential approximation and the cohort stratified by Q1:25%ile, Q2-3: 25-75%ile, and Q4:75%ile. Descriptive measures and unadjusted Kaplan-Meier analyses describe the implications of WGV on mortality/discharge.In 630 eligible infants, median WGV was 4.6g/kg/day. After stratification by WGV [Q1: (n=156;3.1g/kg/day); Q2-3 (n=316; 3.1-5.9g/kg/day), and Q4 (n=158,5.9g/kg/day)] infants in Q1 had shortest median length of stay, less time on TPN and intervention for gastro-esophageal reflux relative to the other WGV strata (p0.01 for all). Unadjusted survival estimates revealed that Q1 [hazard ratio (HR)=9.5, 95% CI: 5.7, 15.8] and Q4 [HR=2.9, 95% CI: 1.7, 5.1, p0.001 for both] WGV were strongly associated with NICU mortality relative to Q2-3 WGV.Variable WGV is evident in infants with CDH. Highest and lowest WGV appear to be related to adverse outcomes. Efforts are needed to develop nutritional strategies targeting optimal growth.

Introduction Accurate, real-time technology is needed to predict which newborns with congenital diaphragmatic hernia (CDH) will require ECMO. The Compensatory Reserve Index (CRI) is a noninvasive monitoring technology that continuously trends an individual's capacity to compensate from normovolemia (CRI = 1) to decompensation (CRI = 0). We hypothesized that postnatal CRI values would be lower in CDH newborns that required ECMO than those who did not require ECMO. Methods Newborns with a CDH were prospectively monitored with a CipherOx® CRI M1 device. We compared CRI values from delivery to ECMO (ECMO group) versus delivery to clinical stabilization (non-ECMO group). Results Postnatal CRI values were available from 26 newborns. Eight underwent ECMO within 33 h of delivery, and median CRI prior to ECMO was 0.068 (IQR: 0.057, 0.078). Eighteen did not require ECMO. Median CRI from birth to 48 h was 0.112 (IQR: 0.082, 0.15). CRI values were significantly lower in newborns that required ECMO versus those who did not (p = 0.0035). Postnatal CRI had the highest AUC (0.85) compared to other prenatal prognostic measures. Conclusion Humans from newborns to adults share elemental features of the pulsatile waveform that are associated with progression to decompensation. CRI may be helpful when deciding when to initiate ECMO. Level of evidence Level III. Type of study Diagnostic test.

Objective To determine whether postnatal echocardiographic indices of left ventricular (LV) size and function are associated with atrial-level shunt direction and investigate whether a relationship exists between LV function and LV size in patients with congenital diaphragmatic hernia (CDH). Study design This was a single-center retrospective study of 51 neonates with CDH evaluated at Children's Hospital Colorado. Initial postnatal echocardiograms were analyzed for cardiac dimensions, valvar integrity, cardiac time intervals, and biventricular function. Comparisons were made between neonates with left-to-right vs right-to-left atrial-level shunting, as well as between those with decreased (ejection fraction Results The majority (82.4%) of infants with CDH had a left-to-right atrial-level shunt, and 84.3% had systemic or suprasystemic pulmonary artery pressure. Decreased LV function was demonstrated in 37.2% and was associated with smaller LV volumes and worse outcomes, including the need for extracorporeal membrane oxygenation (ECMO) and survival. Conclusions Left-to-right atrial-level shunting is common in neonates with severe CDH, even in the presence of suprasystemic pulmonary artery pressure. LV dysfunction correlates with decreased LV volumes and is associated with adverse neonatal outcomes, including increased need for ECMO and decreased survival.

BACKGROUND AND OBJECTIVES: Neonatal AKI is associated with poor short- and long-term outcomes. The objective of this study was to describe the risk factors and outcomes of neonatal AKI in the first postnatal week. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The international retrospective observational cohort study, Assessment of Worldwide AKI Epidemiology in Neonates (AWAKEN), included neonates admitted to a neonatal intensive care unit who received at least 48 hours of intravenous fluids. Early AKI was defined by an increase in serum creatinine >0.3 mg/dl or urine output

Background The clinical needs of infants with severe bronchopulmonary dysplasia (BPD) that remain ventilator-dependent are complex, and management strategies that optimize survival and long-term outcomes controversial. We hypothesized that an interdisciplinary ventilator care program (VCP), committed to the care of this population will improve survival through standardized approaches to cardiopulmonary care and related comorbidities, enhanced communication, and continuity of care. Methods Retrospective chart reviews were performed on patients at Children's Hospital Colorado's neonatal intensive care unit, who underwent tracheostomy placement between 2000 and 2013. Data were collected for two time periods: 2000 to 2005 and 2006 to 2013, before and after initiation of the VCP. Collected data on infants with ventilator-dependent BPD included: gestational age (GA), age at tracheostomy, respiratory severity score (RSS; mean airway pressure [MAP] × fraction of inspired oxygen [FiO 2 ]), comorbidities, medication use, and the age of death. Tracheostomy patients without severe BPD were excluded. Results Despite no difference in GA, birth weight, or cardiorespiratory comorbidities, survival to discharge increased from 50 to 85% after implementation of the VCP ( p Conclusion These findings suggest an interdisciplinary approach to the care of infants with ventilator-dependent BPD can improve survival.

In infants with congenital diaphragmatic hernia (CDH), a posterolateral diaphragmatic defect results in herniation of abdominal contents into the chest and compression of the intrathoracic structures. In the most severe cases, hypoplasia of the ipsilateral and contralateral lungs, severe pulmonary hypertension (PH) and left ventricular (LV) hypoplasia/dysfunction all contribute to increased mortality. The management of PH in CDH is complicated by structural and functional changes in the heart, pulmonary vasculature, airways and lung parenchyma; consequently, determining optimal management strategies is challenging. Treatment of PH in patients with CDH changes as the underlying pathophysiology evolves in the days and weeks after birth. During the early transition, the use of pulmonary vasodilators is limited by LV structural and functional abnormalities, and pulmonary vasodilators such as inhaled nitric oxide (iNO) may have a limited role (for example, stabilization for extracorporeal membrane oxygenation (ECMO), treatment of marked preductal desaturation and treatment of PH as LV performance improves). In contrast, subacute treatment of PH in CDH with iNO has an important role in recurrent or persistent PH and potentially improves survival. Chronic PH and vascular abnormalities may persist into childhood in patients with CDH, contributing to late mortality. It is unclear how pulmonary vasodilator therapies, such as iNO, sildenafil and bosentan, will modulate late outcomes in CDH with late/chronic PH.

To predict mortality or length of stay (LOS)109 days (90th percentile) among infants with congenital diaphragmatic hernia (CDH).We conducted a retrospective analysis using the Children's Hospital Neonatal Database during 2010 to 2014. Infants born34 weeks gestation with CDH admitted at 22 participating regional neonatal intensive care units were included; patients who were repaired or were at home before admission were excluded. The primary outcome was death before discharge or LOS109 days. Factors associated with this outcome were used to develop a multivariable equation using 80% of the cohort. Validation was performed in the remaining 20% of infants.The median gestation and age at referral in this cohort (n=677) were 38 weeks and 6 h, respectively. The primary outcome occurred in 242 (35.7%) infants, and was distributed between mortality (n=180, 27%) and LOS109 days (n=66, 10%). Regression analyses showed that small for gestational age (odds ratio (OR) 2.5, P=0.008), presence of major birth anomalies (OR 5.9, P0.0001), 5- min Apgar score ⩽3 (OR 7.0, P=0.0002), gradient of acidosis at the time of referral (P0.001), the receipt of extracorporeal support (OR 8.4, P0.0001) and bloodstream infections (OR 2.2, P=0.004) were independently associated with death or LOS109 days. This model performed well in the validation cohort (area under curve (AUC)=0.856, goodness-of-fit (GF) χ(2), P=0.16) and acted similarly even after omitting extracorporeal support (AUC=0.82, GF χ(2), P=0.05).Six variables predicted death or LOS ⩾109 days in this large, contemporary cohort with CDH. These results can assist in risk adjustment for comparative benchmarking and for counseling affected families.

Vitamin D [vit D; 1,25-(OH)2D] treatment improves survival and lung alveolar and vascular growth in an experimental model of bronchopulmonary dysplasia (BPD) after antenatal exposure to endotoxin (ETX). However, little is known about lung-specific 1,25-(OH)2D3regulation during development, especially regarding maturational changes in lung-specific expression of the vitamin D receptor (VDR), 1α-hydroxylase (1α-OHase), and CYP24A1 during late gestation and the effects of antenatal ETX exposure on 1,25-(OH)2D3metabolism in the lung. We hypothesized that vit D regulatory proteins undergo maturation regulation in the late fetal and early neonatal lung and that prenatal exposure to ETX impairs lung growth partly through abnormal endogenous vit D metabolism. Normal fetal rat lungs were harvested between embryonic day 15 and postnatal day 14. Lung homogenates were assayed for VDR, 1α-OHase, and CYP24A1 protein contents by Western blot analysis. Fetal rats were injected on embryonic day 20 with intra-amniotic ETX, ETX + 1,25-(OH)2D3, or saline and delivered 2 days later. Pulmonary artery endothelial cells (PAECs) from fetal sheep were assessed for VDR, 1α-OHase, and CYP24A1 expression after treatment with 25-(OH)D3, 1,25-(OH)2D3, ETX, ETX + 25-(OH)D3, or ETX + 1,25-(OH)2D3. We found that lung VDR, 1α-OHase, and CYP2741 protein expression dramatically increase immediately before birth ( P < 0.01 vs. early fetal values). Antenatal ETX increases CYP24A1 expression ( P < 0.05) and decreases VDR and 1α-OHase expression at birth ( P < 0.001), but these changes are prevented with concurrent vit D treatment ( P < 0.001). ETX-induced reduction of fetal PAEC growth and tube formation and lung 1α-OHase expression are prevented by vit D treatment ( P < 0.001). We conclude that lung VDR, 1α-OHase, and CYP24A1 protein content markedly increase before birth and that antenatal ETX disrupts lung vit D metabolism through downregulation of VDR and increased vit D catabolic enzyme expression, including changes in developing endothelium. We speculate that endogenous vitamin D metabolism modulates normal fetal lung development and that prenatal disruption of vit D signaling may contribute to impaired postnatal lung growth at least partly through altered angiogenic signaling.

To predict incident bloodstream infection and urinary tract infection (UTI) in infants with congenital diaphragmatic hernia (CDH).We conducted a retrospective analysis using the Children's Hospital Neonatal Database during 2010-2016. Infants with CDH admitted at 22 participating regional neonatal intensive care units were included; patients repaired or discharged to home prior to admission/referral were excluded. The primary outcome was death or the occurrence of bloodstream infection or UTI prior to discharge. Factors associated with this outcome were used to develop a multivariable equation using 80% of the cohort. Validation was performed in the remaining 20% of infants.Median gestation and postnatal age at referral in this cohort (n = 1085) were 38 weeks and 3.1 hours, respectively. The primary outcome occurred in 395 patients (36%); and was associated with low birth weight, low Apgar, low admission pH, renal and associated anomalies, patch repair, and extracorporeal membrane oxygenation (P .001 for all; area under receiver operating curve = 0.824; goodness of fit χInfants with CDH are at high risk of infection which was predicted by clinical factors. Early identification and low threshold for sepsis evaluations in high-risk infants may attenuate acquisition and the consequences of these infections.

BACKGROUND: Acute kidney injury (AKI) is common in neonatal encephalopathy (NE) and is associated with worse outcomes. Our objectives were to determine the incidence, risk factors, and outcomes of AKI in infants with NE. METHODS: We performed a retrospective analysis of infants ≥ 34 weeks’ gestational age with a diagnosis of NE from the AWAKEN (Analysis of Worldwide Acute Kidney injury Epidemiology in Neonates) database. AKI was defined using the modified Kidney Disease Improving Global Outcomes criteria. Perinatal and postnatal factors were evaluated. Multivariate logistic and linear regression were performed. RESULTS: 113 patients with NE were included. 41.6% (47) developed AKI. Being born outside the admitting institution (OR 4.3; 95% CI:1.2 – 14.8; p = 0.02), intrauterine growth restriction (OR: 10.3, 95% CI:1.1 – 100.5; p = 0.04) and meconium at delivery (OR: 2.8, 95% CI:1.04 – 7.7; p = 0.04) conferred increased odds of AKI. After controlling for confounders, infants with AKI stayed in the hospital an average of 8.5 days longer than infants without AKI (95% CI: 0.79 – 16.2 days; p = 0.03). CONCLUSIONS: In this multi-national analysis, several important perinatal factors were associated with AKI and infants with both NE and AKI had longer length of stay than NE alone. Future research aimed at early AKI detection, renoprotective management strategies, and understanding the long-term renal consequences are warranted in this high-risk group of patients.