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.

Early Ventilator Management for Infants With Congenital Diaphragmatic Hernia: Impact of a Standardized Clinical Practice Guideline.

BACKGROUND: Infants with congenital diaphragmatic hernia (CDH) experience high morbidity and mortality due to pulmonary arterial hypertension and hypoplasia. Mechanical ventilation is a central component of CDH management. Our objective was to evaluate the impact of a standardized clinical practice guideline (implemented in January 2012) on ventilator management for infants with CDH, and associate management changes with short-term outcomes, specifically extracorporeal membrane oxygenation (ECMO) utilization and survival to discharge. METHODS: We conducted a retrospective pre-post study of 103 CDH infants admitted from January 2007-July 2021, divided pre- (n = 40) and post-guideline (n = 63). Clinical outcomes, ventilator settings, and blood gas values in the first 7 days of mechanical ventilation were compared between the pre- and post-guideline cohorts. RESULTS: Post-guideline, ECMO utilization decreased (11% vs 38%, p = 0.001) and survival to discharge improved (92% vs 68%, p = 0.001). More post-guideline patients remained on conventional mechanical ventilation without need for escalation to high-frequency ventilation or ECMO, and had higher pressures and PaCO2 with lower FiO2 and PaO2 (p < 0.05). CONCLUSIONS: Standardized ventilator management optimizing pressures for adequate lung expansion and minimizing oxygen toxicity improves outcomes for infants with CDH. LEVEL OF EVIDENCE: III.

Neonatal Carotid Artery and Internal Jugular Vein Management Practices at Extracorporeal Membrane Oxygenation Decannulation: No Standard Approach.

BACKGROUND: There are currently no commonly accepted standardized guidelines for management of cervical vessels at neonatal extracorporeal membrane oxygenation (ECMO) decannulation. This study investigates neonatal ECMO decannulation practices regarding management of the carotid artery and internal jugular vein, use of post-repair anticoagulation, and follow-up imaging. METHODS: A survey was distributed to the 37 institutions in the Children's Hospitals Neonatal Consortium. Respondents reported their standard approach to carotid artery and internal jugular vein management (ligation or repair) at ECMO decannulation by their pediatric surgery and cardiothoracic (CT) surgery teams as well as post-repair anticoagulation practices and follow-up imaging protocols. RESULTS: The response rate was 95%. Pediatric surgeons performed most neonatal respiratory ECMO cannulations (88%) and decannulations (85%), while all neonatal cardiac ECMO cannulations and decannulations were performed by CT surgeons. Pediatric surgeons overwhelmingly ligate both vessels (90%) while CT surgeons typically repair both vessels at decannulation (83%). Of the responding centers that repair, 28% (7) have a standard anticoagulation protocol after neck vessel repair. While 52% (13) of centers routinely image cervical vessel patency at least once post repair, most do not subsequently repeat neck vessel imaging. CONCLUSIONS: Significant practice differences exist between pediatric and CT surgeons regarding the approach to cervical vessels at neonatal ECMO decannulation. For those centers that do repair the vessels there is little uniformity in post-repair anticoagulation or imaging protocols. There is a need to develop standardized cervical vessel management guidelines for neonatal ECMO patients and to study their impact on both short- and long-term outcomes. LEVEL OF EVIDENCE: IV.

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.

Impact of a standardized management guideline for infants with CDH: A single-center experience.

BACKGROUND: Infants with congenital diaphragmatic hernia (CDH) are at high risk of death, even despite extracorporeal membrane oxygenation (ECMO) support. In January 2012 we implemented a standardized clinical practice guideline (CPG) to manage infants with CDH. We hypothesized that infants with CDH managed with CPG had better clinical outcomes, less ECMO utilization, and increased survival to discharge. METHODS: We conducted a retrospective pre-post study of infants with CDH admitted between January 2007 and July 2021 (n = 133). Patients were divided into Cohort 1, pre-CPG (January 2007 to December 2011, n = 54), and Cohort 2, post-CPG (January 2012 to July 2021, n = 79). RESULTS: More patients in Cohort 1 were small for gestational age than in Cohort 2. No other patient demographics were different between cohorts. Cohort 2 had significantly lower ECMO utilization as compared to Cohort 1 (18% vs 50%, p<0.001). Cohort 2 had significantly higher survival to discharge compared to Cohort 1 (85% vs 57%, p<0.001). Survival for ECMO-treated patients in Cohort 2 was significantly higher than in Cohort 1 (71% vs 26%, p = 0.005). In Cohort 1, 70% of the non-survivors were repaired, of which 81% were repaired on ECMO. In Cohort 2, 8% of the non-survivors were repaired, none on ECMO. Only 3% in Cohort 2 were discharged with pulmonary hypertension medication. CONCLUSIONS: A standardized CPG to manage patients with CDH decreased ECMO utilization and improved clinical outcomes including survival to discharge. Refinement of management strategies, implementation of new interventions, and meticulous care can improve outcomes in patients with CDH.

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.

Current Practices for Genetic Testing in Neonatal Extracorporeal Membrane Oxygenation: Findings from a National survey.

Introduction: Comprehensive genetic testing with whole-exome (WES) or whole-genome (WGS) sequencing facilitates diagnosis, can optimize treatment, and may improve outcomes in critically ill neonates, including those requiring extracorporeal membrane oxygenation (ECMO) for respiratory failure. Our objective was to describe practice variation and barriers to the utilization of comprehensive genetic testing for neonates on ECMO.Methods: We performed a cross-sectional survey of Level IV neonatal intensive care units in the United States across the Children's Hospitals Neonatal Consortium (CHNC).Results: Common indications for WES and WGS included concerning phenotype, severity of disease, unexpected postnatal clinical course, and inability to wean from ECMO support. Unexpected severity of disease on ECMO was the most common indication for rapid genetic testing. Cost of utilization was the primary barrier to testing. If rapid WES or WGS were readily available, 63% of centers would consider incorporating universal screening for neonates upon ECMO cannulation.Conclusion: Despite variation in the use of WES and WGS, universal testing may offer earlier diagnosis and influence the treatment course among neonates on ECMO. Cost is the primary barrier to utilization and most centers would consider incorporating universal screening on ECMO if readily available.

Liver Microabscesses in a Premature Neonate With Eosinophilic Colitis.

Hepatic abscesses in premature infants are rare with less than 100 case reports documented in literature. We report a case of a premature infant diagnosed with hepatic microabscesses secondary to eosinophilic colitis. A 33 4/7-week preterm female neonate presented with bilious emesis, abdominal distention, and severe hematochezia. Eosinophilic enterocolitis was suspected. Hypoechoic regions in the anterior liver identified on computed tomography were considered liver microabscesses. This unique case exemplifies how prematurity increases the risk of mucosal damage in the presence of eosinophilic colitis causing enteric bacteria to seed into the liver through the portal vein, resulting in hepatic microabscesses.

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..

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.

Management of Congenital Diaphragmatic Hernia Treated With Extracorporeal Life Support: Interim Guidelines Consensus Statement From the Extracorporeal Life Support Organization.

The management of infants with congenital diaphragmatic hernia (CDH) receiving extracorporeal life support (ECLS) is complex. Significant variability in both practice and prevalence of ECLS use exists among centers, given the lack of evidence to guide management decisions. The purpose of this report is to review existing evidence and develop management recommendations for CDH patients treated with ECLS. This article was developed by the Extracorporeal Life Support Organization CDH interest group in cooperation with members of the CDH Study Group and the Children's Hospitals Neonatal Consortium.

Current trends in neonatal ECMO.

Extracorporeal membrane oxygenation (ECMO) is a life-saving therapy for patients with respiratory and cardiac failure refractory to maximal medical management. The extracorporeal life support organization registry is the largest available resource for describing the population and outcomes of patients treated with this therapy. The use of ECMO for neonatal patients is decreasing in proportion to the total annual ECMO runs most likely due to advancements in medical management. Although the overall survival for neonatal ECMO has decreased, this is likely a reflection of the increasingly complex neonatal patients treated with this therapy. Although many patient and mechanical complications are decreasing over time, there remains a high percentage of morbidities and risks associated with ECMO. Continued refinements in management strategies are important to improving overall patient outcomes.

First 24-h SNAP-II score and highest PaCO2 predict the need for ECMO in congenital diaphragmatic hernia.

BACKGROUND/PURPOSE: Early clinical predictors for the use of ECMO in patients with congenital diaphragmatic hernia (CDH) are lacking. We sought to evaluate the first 24-h SNAP-II score and highest PaCO2 as predictors of ECMO support and in-hospital mortality in neonates with CDH. METHODS: Retrospective review of 47 consecutive neonates with CDH admitted to our institution from January 2007 to December 2010 was performed. Covariates of ECMO use including SNAP-II score and highest PaCO2 within the first 24 h of NICU admission were evaluated. RESULTS: Of the 47 infants in this study, 24 patients were supported with ECMO. The ECMO group had a higher incidence of pulmonary hypertension, higher PaCO2, and higher 24-h SNAP-II scores. Only the SNAP-II score and not highest PaCO2 predicted mortality following multivariate adjustment. CONCLUSIONS: The first 24-h SNAP-II score and highest PaCO2 may provide some prognostic value in identifying neonates who undergo ECMO support; however neither measure was independently associated with the use of therapy. Only the SNAP-II score was associated with in-hospital mortality following multivariate adjustment. Additional study is needed to validate these results in a larger data set.

Unconjugated bilirubin efflux by bovine brain microvascular endothelial cells in vitro.

OBJECTIVES: The passage of unconjugated bilirubin (UCB) across the blood-brain barrier into the central nervous system is a crucial first step in the development of kernicterus. The objective of the current study was to characterize the passage of UCB across primary bovine brain microvascular endothelial cell (BBMVEC) monolayers in vitro. DESIGN: Experimental study. SETTING: Research institute. SUBJECTS: BBMVECs. INTERVENTIONS: Tritiated UCB (H-UCB) transport at 60, 80, 100, 200, 300, and 400 nM concentrations was tested in both the apical to basolateral (A--> B) and basolateral to apical (B-->A) directions in BBMVEC monolayers in vitro with or without preincubation with pharmacologic active transport inhibitors cyclosporine A, indomethacin, or MK571. MEASUREMENTS AND MAIN RESULTS: The rate of H-UCB transport in the B-->A direction was 6.2- to 7.3-fold higher than in the A-->B direction, suggesting active efflux of UCB. Cyclosporine A (5 microM), a model inhibitor of P-glycoprotein, enhanced A-->B while decreasing B-->A UCB transport, resulting in an overall decrease in BBMVEC UCB efflux of between 46% and 54%. Indomethacin (10 microM) and MK-571 (50 microM), respectively a substrate and potent inhibitor of multidrug resistance-associated protein-1, had no effect. CONCLUSIONS: We conclude that 1) UCB is transported by BBMVEC monolayers in vitro in a net B-->A direction (i.e., active efflux); and 2) cyclosporine A partially inhibits such transport. We speculate that the blood-brain barrier limits the passage and central nervous system retention of UCB by active transport and that this may be accounted in part by P-glycoprotein.