Ventilator strategies in congenital diaphragmatic hernia.

This review focuses on contemporary mechanical ventilator practices used in the initial management of neonates born with congenital diaphragmatic hernia (CDH). Both conventional and non-conventional ventilation modes in CDH are reviewed. Special emphasis is placed on the rationale for gentle ventilation and the current evidence-based clinical practice guidelines that are recommended for supporting these fragile infants. The interplay between CDH lung hypoplasia and other key cardiopulmonary elements of the disease, namely a reduced pulmonary vascular bed, abnormal pulmonary vascular remodeling, and left ventricular hypoplasia, are discussed. Finally, we provide insights into future avenues for mechanical ventilator research in CDH.

Two-Year Outcomes of Umbilical Cord Milking in Nonvigorous Infants: A Secondary Analysis of the MINVI Randomized Clinical Trial.

Importance: Compared with early cord clamping (ECC), umbilical cord milking (UCM) reduces delivery room cardiorespiratory support, hypoxic-ischemic encephalopathy, and therapeutic hypothermia in nonvigorous near-term and full-term infants. However, UCM postdischarge outcomes are not known. Objective: To determine the 2-year outcomes of children randomized to UCM or ECC at birth in the Milking in Nonvigorous Infants (MINVI) trial. Design, Setting, and Participants: A secondary analysis to evaluate longer-term outcomes of a cluster-randomized crossover trial was conducted from January 9, 2021, to September 25, 2023. The primary trial took place in 10 medical centers in the US, Canada, and Poland from January 5, 2019, to June 1, 2021, and hypothesized that UCM would reduce admission to the neonatal intensive care unit compared with ECC; follow-up concluded September 26, 2023. The population included near-term and full-term infants aged 35 to 42 weeks' gestation at birth who were nonvigorous; families provided consent to complete developmental screening questionnaires through age 2 years. Intervention: UCM and ECC. Main Outcomes and Measures: Ages and Stages Questionnaire, 3rd Edition (ASQ-3) and Modified Checklist for Autism in Toddlers, Revised/Follow-Up (M-CHAT-R/F) questionnaires at ages 22 to 26 months. Intention-to-treat analysis and per-protocol analyses were used. Results: Among 1730 newborns from the primary trial, long-term outcomes were evaluated in 971 children (81%) who had ASQ-3 scores available at 2 years or died before age 2 years and 927 children (77%) who had M-CHAT-R/F scores or died before age 2 years. Maternal and neonatal characteristics by treatment group were similar, with median birth gestational age of 39 (IQR, 38-40) weeks in both groups; 224 infants (45%) in the UCM group and 201 (43%) in the ECC group were female. The median ASQ-3 total scores were similar (UCM: 255 [IQR, 225-280] vs ECC: 255 [IQR, 230-280]; P = .87), with no significant differences in the ASQ-3 subdomains. Medium- to high-risk M-CHAT-R/F scores were also similar (UCM, 9% [45 of 486] vs ECC, 8% [37 of 441]; P = .86). Conclusions and Relevance: In this secondary analysis of a randomized clinical trial among late near-term and full-term infants who were nonvigorous at birth, ASQ-3 scores at age 2 years were not significantly different between the UCM and ECC groups. Combined with previously reported important short-term benefits, this follow-up study suggests UCM is a feasible, no-cost intervention without longer-term neurodevelopmental risks of cord milking in nonvigorous near-term and term newborns. Trial Registration: ClinicalTrials.gov Identifier: NCT03631940.

Impact of neonatal noninvasive resuscitation strategies on lung mechanics, tracheal pressure, and tidal volume in preterm lambs.

This study investigated the relationship between three respiratory support approaches on lung volume recruitment during the first 2 h of postnatal life in preterm lambs. We estimated changes in lung aeration, measuring respiratory resistance and reactance by oscillometry at 5 Hz. We also measured intratracheal pressure in subsets of lambs. The first main finding is that sustained inflation (SI) applied noninvasively (Mask SI; n = 7) or invasively [endotracheal tube (ETT) SI; n = 6] led to similar rapid lung volume recruitment (∼6 min). In contrast, Mask continuous positive airway pressure (CPAP) without SI (n = 6) resuscitation took longer (∼30-45 min) to reach similar lung volume recruitment. The second main finding is that, in the first 15 min of postnatal life, the Mask CPAP without SI group closed their larynx during custom ventilator-driven expiration, leading to intratracheal positive end-expiratory pressure of ∼17 cmH2O (instead of 8 cmH2O provided by the ventilator). In contrast, the Mask SI group used the larynx to limit inspiratory pressure to ∼26 cmH2O (instead of 30 cmH2O provided by the ventilator). These different responses affected tidal volume, being larger in the Mask CPAP without SI group [8.4 mL/kg; 6.7-9.3 interquartile range (IQR)] compared to the Mask SI (5.0 mL/kg; 4.4-5.2 IQR) and ETT SI groups (3.3 mL/kg; 2.6-3.7 IQR). Distinct physiological responses suggest that spontaneous respiratory activity of the larynx of preterm lambs at birth can uncouple pressure applied by the ventilator to that applied to the lung, leading to unpredictable lung pressure and tidal volume delivery independently from the ventilator settings.NEW & NOTEWORTHY We compared invasive and noninvasive resuscitation on lambs at birth, including or not sustained inflation (SI). Lung volume recruitment was faster in those receiving SI. During noninvasive resuscitation, larynx modulation reduced tracheal pressure from that applied to the mask in lambs receiving SI, while it led to increased auto-positive end-expiratory pressure and very large tidal volumes in lambs not receiving SI. Our results highlight the need for individualizing pressures and monitoring tidal volumes during resuscitation at birth.

Comparison of current to past outcomes in congenital diaphragmatic hernia using MRI observed-to-expected total fetal lung volume.

BACKGROUND: Fetal Centers use imaging studies to predict congenital diaphragmatic hernia (CDH) prognosis and the need for fetal therapy. Given improving CDH survival, we hypothesized that current fetal imaging severity predictions no longer reflect true outcomes and fail to justify the risks of fetal therapy. METHODS: We analyzed our single-center contemporary data in a left-sided CDH cohort (n = 58) by prognostic criteria determined by MRI observed-to-expected total fetal lung volumes: severe <25%, moderate 25-35%, and mild >35%. We compared contemporary survival to prior studies and the TOTAL trials. RESULTS: Contemporary survival was significantly higher than past studies for all prognostic classifications (mild 100% vs 80-94%, moderate 95% vs 59-75%, severe 79% vs 13-25%; P < 0.01), and to either control or fetal therapy arms of the TOTAL trials. CONCLUSIONS: Current fetal imaging criteria are overly pessimistic and may lead to unwarranted fetal intervention. Fetal therapies remain experimental. Future studies will require updated prognostic criteria.

Effect of Early vs Late Inguinal Hernia Repair on Serious Adverse Event Rates in Preterm Infants: A Randomized Clinical Trial.

Importance: Inguinal hernia repair in preterm infants is common and is associated with considerable morbidity. Whether the inguinal hernia should be repaired prior to or after discharge from the neonatal intensive care unit is controversial. Objective: To evaluate the safety of early vs late surgical repair for preterm infants with an inguinal hernia. Design, Setting, and Participants: A multicenter randomized clinical trial including preterm infants with inguinal hernia diagnosed during initial hospitalization was conducted between September 2013 and April 2021 at 39 US hospitals. Follow-up was completed on January 3, 2023. Interventions: In the early repair strategy, infants underwent inguinal hernia repair before neonatal intensive care unit discharge. In the late repair strategy, hernia repair was planned after discharge from the neonatal intensive care unit and when the infants were older than 55 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was occurrence of any prespecified serious adverse event during the 10-month observation period (determined by a blinded adjudication committee). The secondary outcomes included the total number of days in the hospital during the 10-month observation period. Results: Among the 338 randomized infants (172 in the early repair group and 166 in the late repair group), 320 underwent operative repair (86% were male; 2% were Asian, 30% were Black, 16% were Hispanic, 59% were White, and race and ethnicity were unknown in 9% and 4%, respectively; the mean gestational age at birth was 26.6 weeks [SD, 2.8 weeks]; the mean postnatal age at enrollment was 12 weeks [SD, 5 weeks]). Among 308 infants (91%) with complete data (159 in the early repair group and 149 in the late repair group), 44 (28%) in the early repair group vs 27 (18%) in the late repair group had at least 1 serious adverse event (risk difference, -7.9% [95% credible interval, -16.9% to 0%]; 97% bayesian posterior probability of benefit with late repair). The median number of days in the hospital during the 10-month observation period was 19.0 days (IQR, 9.8 to 35.0 days) in the early repair group vs 16.0 days (IQR, 7.0 to 38.0 days) in the late repair group (82% posterior probability of benefit with late repair). In the prespecified subgroup analyses, the probability that late repair reduced the number of infants with at least 1 serious adverse event was higher in infants with a gestational age younger than 28 weeks and in those with bronchopulmonary dysplasia (99% probability of benefit in each subgroup). Conclusions and Relevance: Among preterm infants with inguinal hernia, the late repair strategy resulted in fewer infants having at least 1 serious adverse event. These findings support delaying inguinal hernia repair until after initial discharge from the neonatal intensive care unit. Trial Registration: ClinicalTrials.gov Identifier: NCT01678638.

Can Red Blood Cell and Platelet Transfusions Have a Pathogenic Role in Bronchopulmonary Dysplasia?

OBJECTIVE: To evaluate whether transfusions in infants born preterm contribute to the pathogenesis of bronchopulmonary dysplasia (BPD). STUDY DESIGN: We conducted a multihospital, retrospective study seeking associations between red blood cell or platelet transfusions and BPD. We tabulated all transfusions administered from January 2018 through December 2022 to infants born ≤29 weeks or <1000 g until 36 weeks postmenstrual age and compared those with BPD grade. We performed a sensitivity analysis to assess the possibility of a causal relationship. We then determined whether each transfusion was compliant with restrictive guidelines, and we estimated effects fewer transfusions might have on future BPD incidence. RESULTS: Eighty-four infants did not develop BPD and 595 did; 352 developed grade 1 (mild), 193 grade 2 (moderate), and 50 grade 3 (severe). Transfusions were given at <36 weeks to 7% of those who did not develop BPD, 46% who did, and 98% who developed severe BPD. For every transfusion the odds of developing BPD increased by a factor of 2.27 (95% CI, 1.59-3.68; P < .001). Sensitivity analyses suggested that transfusions might contribute to BPD. Fifty-seven percent of red blood cell transfusions and 68% of platelet transfusions were noncompliant with new restrictive guidelines. Modeling predicted that complying with restrictive guidelines could reduce the transfusion rate by 20%-30% and the moderate to severe BPD rate by ∼4%-6%. CONCLUSIONS: Transfusions were associated with BPD incidence and severity. Lowering transfusion rates to comply with current restrictive guidelines might result in a small but meaningful reduction in BPD rates.

Parental perspectives on a trial using waived informed consent at birth.

OBJECTIVES: To determine parental perspectives in a trial with waived consent. STUDY DESIGN: Anonymous survey of birth parents with term infants who were randomized using a waiver of consent, administered after infant discharge. RESULTS: 121 (11%) survey responses were collected. Of the 121 responding parents 111 (92%) reported that this form of consent was acceptable and 116 (96%) reported feeling comfortable having another child participate in a similar study. 110 (91%) respondents reported that they both understood the information provided in the consent process and had enough time to consider participation. Four percent had a negative opinion on the study's effect on their child's health. CONCLUSIONS: Most responding parents reported both acceptability of this study design in the neonatal period and that the study had a positive effect on their child's health. Future work should investigate additional ways to involve parents and elicit feedback on varied methods of pediatric consent.

Functions of the primary cilium in the kidney and its connection with renal diseases.

The nonmotile primary cilium is a sensory structure found on most mammalian cell types that integrates multiple signaling pathways involved in tissue development and postnatal function. As such, mutations disrupting cilia activities cause a group of disorders referred to as ciliopathies. These disorders exhibit a wide spectrum of phenotypes impacting nearly every tissue. In the kidney, primary cilia dysfunction caused by mutations in polycystin 1 (Pkd1), polycystin 2 (Pkd2), or polycystic kidney and hepatic disease 1 (Pkhd1), result in polycystic kidney disease (PKD), a progressive disorder causing renal functional decline and end-stage renal disease. PKD affects nearly 1 in 1000 individuals and as there is no cure for PKD, patients frequently require dialysis or renal transplantation. Pkd1, Pkd2, and Pkhd1 encode membrane proteins that all localize in the cilium. Pkd1 and Pkd2 function as a nonselective cation channel complex while Pkhd1 protein function remains uncertain. Data indicate that the cilium may act as a mechanosensor to detect fluid movement through renal tubules. Other functions proposed for the cilium and PKD proteins in cyst development involve regulation of cell cycle and oriented division, regulation of renal inflammation and repair processes, maintenance of epithelial cell differentiation, and regulation of mitochondrial structure and metabolism. However, how loss of cilia or cilia function leads to cyst development remains elusive. Studies directed at understanding the roles of Pkd1, Pkd2, and Pkhd1 in the cilium and other locations within the cell will be important for developing therapeutic strategies to slow cyst progression.