A clinical consensus guideline for nutrition in infants with congenital diaphragmatic hernia from birth through discharge.

OBJECTIVE: To develop a consensus guideline to meet nutritional challenges faced by infants with congenital diaphragmatic hernia (CDH). STUDY DESIGN: The CDH Focus Group utilized a modified Delphi method to develop these clinical consensus guidelines (CCG). Topic leaders drafted recommendations after literature review and group discussion. Each recommendation was sent to focus group members via a REDCap survey tool, and members scored on a Likert scale of 0-100. A score of > 85 with no more than 25% outliers was designated a priori as demonstrating consensus among the group. RESULTS: In the first survey 24/25 recommendations received a median score > 90 and after discussion and second round of surveys all 25 recommendations received a median score of 100. CONCLUSIONS: We present a consensus evidence-based framework for managing parenteral and enteral nutrition, somatic growth, gastroesophageal reflux disease, chylothorax, and long-term follow-up of infants with CDH.

Efficacy of Sildenafil in Infants with Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension.

Background: Pulmonary hypertension (PH) is a common comorbidity in infants with bronchopulmonary dysplasia (BPD). Sildenafil is a widely recognized therapy for PH, but its efficacy in infants with BPD is questionable. We propose to assess the efficacy of sildenafil in BPD-associated PH as evaluated based on transthoracic echocardiography (TTE) changes and clinical measures. Methods: Data were retrospectively and prospectively collected. Inclusion criteria were gestational age (GA) < 32 weeks, birth weight (BW) < 1500 g with severe BPD, diagnosis of PH via TTE on sildenafil treatment. PH was evaluated via TTE, which was performed monthly after 36 weeks post-menstrual age (PMA) as a standard of care, and re-reviewed by a single pediatric cardiologist, who was blind to the initial reading. Results: In total, 19 patients were enrolled in the study, having a median GA of 24 3/7 weeks (IQR 23 5/7-25 5/7) and a median BW of 598 g (IQR 572-735). Sildenafil treatment was started at a median PMA of 40.4 weeks. The median respiratory severity score (RSS) at 28 d was 6.5, RSS and FiO2 showed improvement about 12 weeks after starting sildenafil treatment. Conclusions: Improvement in PH was noted via TTE, and patients had improvement in their RSS and FiO2 after prolonged therapy. However, TTE improvements did not correlate with clinical improvements.

Variability for Age at Successful Extubation in Infants with Congenital Diaphragmatic Hernia.

OBJECTIVE: The objective of this study was to characterize clinical factors associated with successful extubation in infants with congenital diaphragmatic hernia. STUDY DESIGN: Using the Children's Hospitals Neonatal Database, we identified infants with congenital diaphragmatic hernia from 2017 to 2020 at 32 centers. The main outcome was age in days at the time of successful extubation, defined as the patient remaining extubated for 7 consecutive days. Unadjusted Kaplan-Meier and multivariable Cox proportional hazards ratio equations were used to estimate associations between clinical factors and the main outcome. Observations occurred through 180 days after birth. RESULTS: There were 840 eligible neonates with a median gestational age of 38 weeks and birth weight of 3.0 kg. Among survivors (n = 693), the median age at successful extubation was 15 days (interquartile range [IQR]: 8-29 days, 95th percentile: 71 days). For nonsurvivors (n = 147), the median age at death was 21 days (IQR: 11-39 days, 95th percentile: 110 days). Center (adjusted hazards ratio: 0.22-15, P < .01), low birth weight, intrathoracic liver position, congenital heart disease, lower 5-minute Apgar score, lower pH upon admission to Children's Hospitals Neonatal Database center, and use of extracorporeal support were independently associated with older age at successful extubation. Tracheostomy was associated with multiple failed extubations. CONCLUSION: Our findings suggest that infants who have not successfully extubated by about 3 months of age may be candidates for tracheostomy with chronic mechanical ventilation or palliation. The variability of timing of successful extubation among our centers supports the development of practice guidelines after validating clinical criteria.

Analgesia, Sedation, and Neuromuscular Blockade in Infants with Congenital Diaphragmatic Hernia.

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 < 0.001) and longer length of stay (p < 0.001). Use of sedation or neuromuscular blockade prior to or after surgery was each associated with increased mortality (p ≤ 0.01). CONCLUSION: Opioids, sedatives, and neuromuscular blockade were used commonly in infants with CDH with variable duration across centers. Prolonged combined use ≥5 days is associated with mortality. KEY POINTS: · Use of analgesia and sedation varies across children's hospital NICUs.. · Prolonged opioid and benzodiazepine use is associated with increased mortality.. · Postsurgery sedation and neuromuscular blockade are associated with mortality..

Ventilation Strategies During Extracorporeal Membrane Oxygenation for Neonatal Respiratory Failure: Current Approaches Among Level IV Neonatal ICUs.

To describe ventilation strategies used during extracorporeal membrane oxygenation (ECMO) for neonatal respiratory failure among level IV neonatal ICUs (NICUs). DESIGN: Cross-sectional electronic survey. SETTING: Email-based Research Electronic Data Capture survey. PATIENTS: Neonates undergoing ECMO for respiratory failure at level IV NICUs. INTERVENTIONS: A 40-question survey was sent to site sponsors of regional referral neonatal ECMO centers participating in the Children's Hospitals Neonatal Consortium. Reminder emails were sent at 2- and 4-week intervals. MEASUREMENTS AND MAIN RESULTS: Twenty ECMO centers responded to the survey. Most primarily use venoarterial ECMO (65%); this percentage is higher (90%) for congenital diaphragmatic hernia. Sixty-five percent reported following protocol-based guidelines, with neonatologists primarily responsible for ventilator management (80%). The primary mode of ventilation was pressure control (90%), with synchronized intermittent mechanical ventilation (SIMV) comprising 80%. Common settings included peak inspiratory pressure (PIP) of 16-20 cm H2O (55%), positive end-expiratory pressure (PEEP) of 9-10 cm H2O (40%), I-time 0.5 seconds (55%), rate of 10-15 (60%), and Fio2 22-30% (65%). A minority of sites use high-frequency ventilation (HFV) as the primary mode (5%). During ECMO, 55% of sites target some degree of lung aeration to avoid complete atelectasis. Fifty-five percent discontinue inhaled nitric oxide (iNO) during ECMO, while 60% use iNO when trialing off ECMO. Nonventilator practices to facilitate decannulation include bronchoscopy (50%), exogenous surfactant (25%), and noninhaled pulmonary vasodilators (50%). Common ventilator thresholds for decannulation include PEEP of 6-7 (45%), PIP of 21-25 (55%), and tidal volume 5-5.9 mL/kg (50%). CONCLUSIONS: The majority of level IV NICUs follow internal protocols for ventilator management during neonatal respiratory ECMO, and neonatologists primarily direct management in the NICU. While most centers use pressure-controlled SIMV, there is considerable variability in the range of settings used, with few centers using HFV primarily. Future studies should focus on identifying respiratory management practices that improve outcomes for neonatal ECMO patients.

Pilot Study of Sham Feeding in Postoperative Neonates.

OBJECTIVE: Sham feeding may enhance development of oral skills in neonates after bowel surgery and decrease stress levels in mothers. In this pilot study, we test the feasibility of sham feeding, identify safety hazards, and assess maternal satisfaction. STUDY DESIGN: A convenience sample of 15 postoperative neonates was enrolled. Sham feeding with unfortified human milk was offered following a strict advancement protocol beginning with 5 mL once daily and increasing up to 30 mL, three times daily. Continuous gastric suction was used during sham feeding. Each mother completed a satisfaction survey. Sham-fed gastroschisis patients were compared with a historic cohort. RESULTS: All 15 patients were able to sham feed. A total of 312 sham feeds were offered with a median of 23 sham events per patient. Four minor complications occurred during sham feeding. No differences were noted between 11 sham-fed gastroschisis patients and 81 historic controls. The mothers reported a decrease in stress after sham feeding using a 5-point score (3.8 ± 1.4 vs. 1.5 ± 0.7, p < 0.005) and 100% satisfaction with sham feeding. CONCLUSION: Sham feeding is feasible for neonates after bowel surgery and is highly rated by mothers. KEY POINTS: · Sham-feeding human milk to neonates after bowel surgery is feasible and safe.. · A novel postoperative sham feeding protocol is described.. · Mothers of sham-fed infants report it reduces stress compared with not feeding..

Predicting treatment of pulmonary hypertension at discharge in infants with congenital diaphragmatic hernia.

OBJECTIVE: To predict pulmonary hypertension (PH) therapy at discharge in a large multicenter cohort of infants with congenital diaphragmatic hernia (CDH). STUDY DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

Central Line Utilization and Complications in Infants with Congenital Diaphragmatic Hernia.

OBJECTIVE: Infants with congenital diaphragmatic hernia (CDH) require multiple invasive interventions carrying inherent risks, including central venous and arterial line placement. We hypothesized that specific clinical or catheter characteristics are associated with higher risk of nonelective removal (NER) due to complications and may be amenable to efforts to reduce patient harm. STUDY DESIGN: Infants with CDH were identified in the Children's Hospital's Neonatal Database (CHND) from 2010 to 2016. Central line use, duration, and complications resulting in NER are described and analyzed by extracorporeal membrane oxygenation (ECMO) use. RESULTS: A total of 1,106 CDH infants were included; nearly all (98%) had a central line placed, (average of three central lines) with a total dwell time of 22 days (interquartile range [IQR]: 14-39). Umbilical arterial and venous lines were most common, followed by extremity peripherally inserted central catheters (PICCs); 12% (361/3,027 central lines) were removed secondary to complications. Malposition was the most frequent indication for NER and was twice as likely in infants with intrathoracic liver position. One quarter of central lines in those receiving ECMO was placed while receiving this therapy. CONCLUSION: Central lines are an important component of intensive care for infants with CDH. Careful selection of line type and location and understanding of common complications may attenuate the need for early removal and reduce risk of infection, obstruction, and malposition in this high-risk group of patients. KEY POINTS: · Central line placement near universal in congenital diaphragmatic hernia infants.. · Mean of three lines placed per patient; total duration 22 days.. · Clinical patient characteristics affect risk..

A novel variant in the dystonin gene causing hereditary sensory autonomic neuropathy type VI in a male infant: Case report and literature review.

The DST gene is located on chromosome 6p and encodes for a large protein. Alternative splicing of this protein produces the neuronal (a1-a3), muscular (b1-b3), and epithelial (e) isoforms. Hereditary sensory and autonomic neuropathy (HSAN) type VI is a rare autosomal recessive disorder due to mutations affecting the a2 isoform. We present a case of HSAN-VI in a male neonate born to consanguineous parents. Genome sequencing revealed a novel homozygous variant (DST_c.1118C > T; p.Pro373Leu) inherited from both parents. This case further expands the phenotype and genotype of this rare syndrome.

Venovenous versus venoarterial extracorporeal membrane oxygenation among infants with hypoxic-ischemic encephalopathy: is there a difference in outcome?

OBJECTIVE: Our hypothesis was that among infants with hypoxic-ischemic encephalopathy (HIE), venoarterial (VA), compared to venovenous (VV), extracorporeal membrane oxygenation (ECMO) is associated with an increased risk of mortality or intracranial hemorrhage (ICH). DESIGN/METHODS: Retrospective cohort analysis of infants in the Children's Hospitals Neonatal Database from 2010 to 2016 with moderate or severe HIE, gestational age ≥36 weeks, and ECMO initiation <7 days of age. The primary outcome was mortality or ICH. RESULTS: Severe HIE was more common in the VA ECMO group (n = 57), compared to the VV ECMO group (n = 53) (47.4% vs. 26.4%, P = 0.02). VA ECMO was associated with a significantly higher risk of death or ICH [57.9% vs. 34.0%, aOR 2.39 (1.08-5.28)] and mortality [31.6% vs. 11.3%, aOR 3.06 (1.08-8.68)], after adjusting for HIE severity. CONCLUSIONS: In HIE, VA ECMO was associated with a higher incidence of mortality or ICH. VV ECMO may be beneficial in this population.

Treatment of pulmonary hypertension during initial hospitalization in a multicenter cohort of infants with congenital diaphragmatic hernia (CDH).

OBJECTIVE: Describe inpatient pulmonary hypertension (PH) treatment and factors associated with therapy at discharge in a multicenter cohort of infants with CDH. METHODS: 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. RESULTS: 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 < 0.0001). Nearly one-third of infants discharged without PHM had PH on last inpatient echo. CONCLUSIONS: PH medication use is common in CDH. Identification of infants at risk for persistent PH may impact ongoing management. Post-discharge follow-up of all CDH infants with echocardiographic evidence of PH is warranted.

Risk-stratification enables accurate single-center outcomes assessment in congenital diaphragmatic hernia (CDH).

BACKGROUND: Management of CDH is highly variable from center to center, as are patient outcomes. The purpose of this study was to examine risk-stratified survival and extracorporeal membrane oxygenation (ECMO) rates at a single center, and to determine whether adverse outcomes are related to patient characteristics or management. METHODS: A retrospective single-center review of CDH patients was performed, and outcomes compared to those reported by the CDH Study Group (CDHSG) registry. Patient demographics, disparities, and clinical characteristics were examined to identify unique features of the cohort. A model derived using the registry that estimates probability of ECMO use or death in CDH newborns was used to risk-stratify patients and assess mortality rates. Observed over expected (O/E) ECMO use rates were calculated to measure whether "excess" or "appropriate" ECMO use was occurring. RESULTS: There were 81 CDH patients treated between 2004-2017, and 5034 in the CDHSG registry. Mortality in ECMO-treated patients was higher than the registry. Socioeconomic variables were not significantly associated with outcomes. The strongest predictors of mortality were ECMO use and early blood gas variables. The risk model accurately predicted ECMO use with a c-statistic of 0.79. Compared with the registry, the disparity in mortality rates was greatest for moderate-risk patients. O/E ECMO use was highest in low and moderate-risk patients. CONCLUSIONS: ECMO use is a more consistent predictor of mortality than CDH severity at a single center, and there is relative overuse of ECMO in lower-risk patients. Risk stratification allows for more accurate institutional assessment of mortality and ECMO use, and other centers could consider such an adjusted analysis to identify opportunities for outcomes improvement. LEVEL OF EVIDENCE: III.

Hemodynamically significant patent ductus arteriosus and the development of bronchopulmonary dysplasia.

Patent ductus arteriosus (PDA) is prevalent in premature newborns and has been linked to the development of bronchopulmonary dysplasia (BPD), a serious pulmonary complication of premature birth. Although a causal relationship has not been proven, the link is greatest among infants born at lower gestational age who are treated with mechanical ventilation in the presence of a large ductal shunt. Despite strong association in epidemiological studies, treatment of a patent ductus arteriosus has not been shown to prevent BPD, and some therapies may increase the risk of BPD. We describe preclinical and clinical data demonstrating the association of a PDA with BPD, highlight the effects of surgical and pharmacological treatment, and explore the implications of recent clinical trials for the management of PDA in the premature newborn.

Survey of ECMO practices for infants with hypoxic ischemic encephalopathy.

OBJECTIVE: Historically, some physicians are reluctant to offer extracorporeal membrane oxygenation (ECMO) to infants with neonatal encephalopathy. This study describes how ECMO practices have changed since the development of therapeutic hypothermia (TH) for neonatal encephalopathy. STUDY DESIGN: A 22-question electronic survey was sent to neonatal medical directors and ECMO directors in the USA and Canada. Participants were queried on TH and ECMO practices and if they would offer ECMO given certain clinical factors; confidential responses were compared with a similar survey conducted in 2008. RESULT: A total of 356 physicians were invited to participate, and the response rate was 25%. Seventy-two percent had initiated or referred for ECMO during cooling therapy. Compared with the 2008 survey, participants were more likely to offer ECMO for moderate and severe encephalopathy. Ninety-four percent offer hypothermia for neonatal encephalopathy, but only 24% have written ECMO criteria for such patients. Neonatologists were more likely than non-neonatologists to offer ECMO for mild and moderate encephalopathy. CONCLUSION: ECMO use with neonatal encephalopathy has increased since TH has become standard care. Wide variability in practice remains with important differences between neonatologists and non-neonatologists.

The Role of Extracorporeal Membrane Oxygenation Simulation Training at Extracorporeal Life Support Organization Centers in the United States.

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) requires a multidisciplinary healthcare team. The Extracorporeal Life Support Organization publishes training guidelines but leaves specific requirements up to each institution. Simulation training has shown promise, but it is unclear how many institutions have incorporated simulation techniques into ECMO training to date. METHODS: We sent an electronic survey to ECMO coordinators at Extracorporeal Life Support Organization sites in the United States. Participants were asked about training practices and the use of simulation for ECMO training. Descriptive results were reported as the percentage of total responses for each question. Logistic regression was used to identify characteristics associated with simulation use. RESULTS: Of 94 responses (62% response rate), 46% had an ECMO simulation program, whereas 26% report a program is in development. Most (61%) have been in operation for 2 to 5 years. Sixty-three percent use simulation for summative assessment, and 76% have multidisciplinary training. Access to a simulation center [odds ratio (OR) = 4.7, 95% confidence interval (CI) = 1.7-12.5], annual ECMO caseload of greater than 20 (OR = 2.5, 95% CI = 1.5-5.8), and having a pediatric cardiothoracic intensive care unit (OR = 2.8, 95% CI = 1.2-6.7) are each associated with increased likelihood of mannequin-based ECMO simulation. Common scenarios include pump failure (93%), oxygenator failure (90%), and circuit rupture (76%). DISCUSSION: Extracorporeal membrane oxygenation simulation is growing but remains in its infancy. Centers with access to a simulation center, higher caseloads, and pediatric cardiothoracic intensive care units are more likely to have ECMO simulation programs. Extracorporeal membrane oxygenation simulation is felt to be beneficial, and further work is needed to delineate best training practices for ECMO providers.