Mechanical ventilation in special populations.

Optimal respiratory support can only be achieved if the ventilator strategy utilized for each individual patient at any given point in the evolution of their disease process is tailored to the underlying pathophysiology. The critically ill newborn infant requires individualized patient care when it comes to mechanical ventilation. This can only occur if the clinician has a good understanding of the different pathophysiologies of a variety of conditions that can lead to respiratory failure. In this chapter we describe the key pathophysiological features of bronchopulmonary dysplasia, meconium aspiration syndrome and lung hypoplasia syndromes with emphasis on congenital diaphragmatic hernia. We review available evidence to guide management an provide specific recommendations for pathophysiologically-based mechanical ventilation support.

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.

Volume-targeted ventilation.

Despite strong evidence of important benefits of volume-targeted ventilation, many high-risk extremely preterm infants continue to receive traditional pressure-controlled ventilation in the United States and elesewhere. Reluctance to abandon one's comfort zone, lack of suitable equipment and a lack of understanding of the subtleties of volume-targeted ventilation appear to contribute to the relatively slow uptake of volume-targeted ventilation. This review will underscore the benefits of using tidal volume as the primary control variable, to improve clinicians' understanding of the way volume-targeted ventilation interacts with the awake, breathing infant and to provide information about evidence-based tidal volume targets in various circmstances. Focus on underlying lung pathophysiology, individualized ventilator settings and tidal volume targets are essential to successful use of this approach thereby improving important clinical outcomes.

Continuous Positive Airway Pressure versus Nasal Intermittent Positive Pressure Ventilation in Preterm Neonates: What if Mean Airway Pressures were Equivalent?

Respiratory support for preterm neonates in modern neonatal intensive care units is predominantly with the use of noninvasive interfaces. Continuous positive airway pressure (CPAP) and nasal intermittent positive pressure ventilation (NIPPV) are the prototypical and most commonly utilized forms of noninvasive respiratory support, and each has unique gas flow characteristics. In meta-analyses of clinical trials till date, NIPPV has been shown to likely reduce respiratory failure and need for intubation compared to CPAP. However, a significant limitation of the included studies has been the higher mean airway pressures used during NIPPV. Thus, it is unclear to what extent any benefits seen with NIPPV are due to the cyclic pressure application versus the higher mean airway pressures. In this review, we elaborate on these limitations and summarize the available evidence comparing NIPPV and CPAP at equivalent mean airway pressures. Finally, we call for further studies comparing noninvasive respiratory support modes at equal mean airway pressures. KEY POINTS: · Most current literature on CPAP vs. NIPPV in preterm neonates is confounded by use of higher mean airway pressures during NIPPV.. · In this review, we summarize existing evidence on CPAP vs. NIPPV at equivalent mean airway pressures.. · We call for future research on noninvasive support modes to account for mean airway pressures..

Evaluation of lung volumes and gas exchange in surfactant-deficient rabbits between variable and fixed servo pressures during high-frequency jet ventilation.

OBJECTIVE: To investigate a novel servo pressure (SP) setting during high-frequency jet ventilation (HFJV) for a lung protective strategy in a neonatal model of acute respiratory distress. STUDY DESIGN: Comparison of efficacy between variable (standard) and fixed SP settings in a randomized animal study using rabbits (n = 10, mean weight = 1.80 kg) with surfactant deficiency by repeated lung lavages. RESULTS: Rabbits in the fixed SP group had greater peak inspiratory pressure, SP, minute volume, pH, and PaO2, and lower PaCO2 after lung lavage than the variable SP group. Lung volume monitoring with electrical impedance tomography showed that fixed SP reduced the decline of the global lung tidal variation at 30 min after lung lavage (-17.4% from baseline before lavage) compared to variable SP (-44.9%). CONCLUSION: HFJV with fixed SP significantly improved gas exchange and lung volumes compared to variable SP. Applying a fixed SP may have important clinical implications for patients receiving HFJV.

Classifying multicenter approaches to invasive mechanical ventilation for infants with bronchopulmonary dysplasia using hierarchical clustering analysis.

INTRODUCTION: Evidence-based ventilation strategies for infants with severe bronchopulmonary dysplasia (BPD) remain unknown. Determining whether contemporary ventilation approaches cluster as specific BPD strategies may better characterize care and enhance the design of clinical trials. The objective of this study was to test the hypothesis that unsupervised, multifactorial clustering analysis of point prevalence ventilator setting data would classify a discrete number of physiology-based approaches to mechanical ventilation in a multicenter cohort of infants with severe BPD. METHODS: We performed a secondary analysis of a multicenter point prevalence study of infants with severe BPD treated with invasive mechanical ventilation. We clustered the cohort by mean airway pressure (MAP), positive end expiratory pressure (PEEP), set respiratory rate, and inspiratory time (Ti) using Ward's hierarchical clustering analysis (HCA). RESULTS: Seventy-eight patients with severe BPD were included from 14 centers. HCA classified three discrete clusters as determined by an agglomerative coefficient of 0.97. Cluster stability was relatively strong as determined by Jaccard coefficient means of 0.79, 0.85, and 0.77 for clusters 1, 2, and 3, respectively. The median PEEP, MAP, rate, Ti, and PIP differed significantly between clusters for each comparison by Kruskall-Wallis testing (p < 0.0001). CONCLUSIONS: In this study, unsupervised clustering analysis of ventilator setting data identified three discrete approaches to mechanical ventilation in a multicenter cohort of infants with severe BPD. Prospective trials are needed to determine whether these approaches to mechanical ventilation are associated with specific severe BPD clinical phenotypes and differentially modify respiratory outcomes.

Antenatal Steroids, Prophylactic Indomethacin, and the Risk of Spontaneous Intestinal Perforation.

OBJECTIVE: To estimate if the odds of spontaneous intestinal perforation (SIP) are increased when antenatal steroids (ANS) given close to delivery are combined with indomethacin on day 1 after birth (Indo-D1). STUDY DESIGN: A retrospective cohort study using the Neonatal Research Network (NRN) database of inborn infants, gestational age 220-286 weeks or birth weight of 401-1000 g, born between January 1, 2016 and December 31, 2019, and surviving >12 hours. The primary outcome was SIP through 14 days. Time of last ANS dose prior to delivery was analyzed as a continuous variable (using 169 hours for durations >168 hours or no steroid exposure). Associations between ANS, Indo-D1, and SIP were obtained from a multilevel hierarchical generalized linear mixed model after covariate adjustment. This yielded aOR and 95% CI. RESULTS: Of 6851 infants, 243 had SIP (3.5%). ANS exposure occurred in 6393 infants (93.3%) and IndoD1 was given to 1863 infants (27.2%). The time (median, IQR) from last dose of ANS to delivery was 32.5 hours (6-81) vs 37.1 hours (7-110) for infants with or without SIP, respectively (P = .10). Indo-D1 was given to 51.9 vs 26.3% of infants with SIP vs no SIP, respectively (P < .0001). Adjusted analysis indicated no interaction between time of last ANS dose and Indo-D1 for SIP (P = .7). Indo-D1 but not ANS was associated with increased odds of SIP (aOR: 1.73, 1.21-2.48, P = .003). CONCLUSION: The odds of SIP were increased after receipt of Indo-D1. Exposure to ANS prior to Indo-D1 was not associated with an increase in SIP.

High continuous positive airway pressures versus non-invasive positive pressure ventilation in preterm neonates: protocol for a multicentre pilot randomised controlled trial.

INTRODUCTION: Low pressure nasal continuous positive airway pressure (nCPAP) has long been the mainstay of non-invasive respiratory support for preterm neonates, at a constant distending pressure of 5-8 cmH2O. When traditional nCPAP pressures are insufficient, other modes including nasal intermittent positive pressure ventilation (NIPPV) are used. In recent years, high nCPAP pressures (≥9 cmH2O) have also emerged as an alternative. However, the comparative benefits and risks of these modalities remain unknown. METHODS AND ANALYSIS: In this multicentre pilot randomised controlled trial, infants <29 weeks' gestational age (GA) who either: (A) fail treatment with traditional nCPAP or (B) being extubated from invasive mechanical ventilation with mean airway pressure ≥10 cmH2O, will be randomised to receive either high nCPAP (positive end-expiratory pressure 9-15 cmH2O) or NIPPV (target mean Paw 9-15 cmH2O). Primary outcome is feasibility of the conduct of a larger, definitive trial as assessed by rates of recruitment and protocol violations. The main secondary outcome is failure of assigned treatment within 7 days postrandomisation. Multiple other clinical outcomes including bronchopulmonary dysplasia will be ascertained. All randomised participants will be analysed using intention to treat. Baseline and demographic variables as well as outcomes will be summarised and compared using univariate analyses, and a p<0.05 will be considered significant. ETHICS AND DISSEMINATION: The trial has been approved by the respective research ethics boards at each institution (McMaster Children's Hospital: Hamilton integrated REB approval #2113; Royal Alexandra Hospital: Health Research Ethics Board approval ID Pro00090244; Westmead Hospital: Human Research Ethics Committee approval ID 2022/ETH01343). Written, informed consent will be obtained from all parents/guardians prior to study enrolment. The findings of this pilot study will be disseminated via presentations at national and international conferences and via publication in a peer-reviewed journal. Social media platforms including Twitter will also be used to generate awareness. TRIAL REGISTRATION NUMBER: NCT03512158.

Maternal hypertensive disorders and survival without major morbidities among extremely low gestation newborns.

OBJECTIVE: Evaluate if odds of survival without major morbidity are higher among extremely low gestation neonates (ELGANs) born to mothers with chronic hypertension (cHTN) or hypertensive disorders of pregnancy (HDP) compared to ELGANs born to mothers without hypertension (HTN). STUDY DESIGN: Retrospective study of prospectively collected data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Included children had a birthweight of 401-1000 g and/or gestational age of 220/7 to 286/7 wks. The primary outcome was survival to discharge without major morbidity. Multivariable regression models were used to compare outcomes among ELGANs born to women with cHTN, HDP, and no HTN. RESULTS: Survival without morbidities for newborns of mothers with no HTN, cHTN and HDP (29.1%, 32.9%, 37.0% respectively) did not differ after adjustment. CONCLUSION: After adjusting for contributing variables maternal HTN is not associated with improved survival free of morbidity among ELGANs. TRIALS REGISTRATION: clinicaltrials.gov Identifier: NCT00063063 (generic database).

Automated prediction of extubation success in extremely preterm infants: the APEX multicenter study.

BACKGROUND: Extremely preterm infants are frequently subjected to mechanical ventilation. Current prediction tools of extubation success lacks accuracy. METHODS: Multicenter study including infants with birth weight ≤1250 g undergoing their first extubation attempt. Clinical data and cardiorespiratory signals were acquired before extubation. Primary outcome was prediction of extubation success. Automated analysis of cardiorespiratory signals, development of clinical and cardiorespiratory features, and a 2-stage Clinical Decision-Balanced Random Forest classifier were used. A leave-one-out cross-validation was done. Performance was analyzed by ROC curves and determined by balanced accuracy. An exploratory analysis was performed for extubations before 7 days of age. RESULTS: A total of 241 infants were included and 44 failed (18%) extubation. The classifier had a balanced accuracy of 73% (sensitivity 70% [95% CI: 63%, 76%], specificity 75% [95% CI: 62%, 88%]). As an additional clinical-decision tool, the classifier would have led to an increase in extubation success from 82% to 93% but misclassified 60 infants who would have been successfully extubated. In infants extubated before 7 days of age, the classifier identified 16/18 failures (specificity 89%) and 73/105 infants with success (sensitivity 70%). CONCLUSIONS: Machine learning algorithms may improve a balanced prediction of extubation outcomes, but further refinement and validation is required. IMPACT: A machine learning-derived predictive model combining clinical data with automated analyses of individual cardiorespiratory signals may improve the prediction of successful extubation and identify infants at higher risk of failure with a good balanced accuracy. Such multidisciplinary approach including medicine, biomedical engineering and computer science is a step forward as current tools investigated to predict extubation outcomes lack sufficient balanced accuracy to justify their use in future trials or clinical practice. Thus, this individualized assessment can optimize patient selection for future trials of extubation readiness by decreasing exposure of low-risk infants to interventions and maximize the benefits of those at high risk.

Age at First Extubation Attempt and Death or Respiratory Morbidities in Extremely Preterm Infants.

OBJECTIVE: To describe the timing of first extubation in extremely preterm infants and explore the relationship between age at first extubation, extubation outcome, and death or respiratory morbidities. STUDY DESIGN: In this subanalysis of a multicenter observational study, infants with birth weights of 1250 g or less and intubated within 24 hours of birth were included. After describing the timing of first extubation, age at extubation was divided into early (within 7 days from birth) vs late (days of life 8-35), and extubation outcome was divided into success vs failure (reintubation within 7 days after extubation), to create 4 extubation groups: early success, early failure, late success, and late failure. Logistic regression analyses were performed to evaluate associations between the 4 groups and death or bronchopulmonary dysplasia, bronchopulmonary dysplasia among survivors, and durations of respiratory support and oxygen therapy. RESULTS: Of the 250 infants included, 129 (52%) were extubated within 7 days, 93 (37%) between 8 and 35 days, and 28 (11%) beyond 35 days of life. There were 93, 36, 59, and 34 infants with early success, early failure, late success, and late failure, respectively. Although early success was associated with the lowest rates of respiratory morbidities, early failure was not associated with significantly different respiratory outcomes compared with late success or late failure in unadjusted and adjusted analyses. CONCLUSIONS: In a contemporary cohort of extremely preterm infants, early extubation occurred in 52% of infants, and only early and successful extubation was associated with decreased respiratory morbidities. Predictors capable of promptly identifying infants with a high likelihood of early extubation success or failure are needed.

Approaches to Interdisciplinary Care for Infants with Severe Bronchopulmonary Dysplasia: A Survey of the Bronchopulmonary Dysplasia Collaborative.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) remains the most common late morbidity for extremely premature infants. Care of infants with BPD requires a longitudinal approach from the neonatal intensive care unit to ambulatory care though interdisciplinary programs. Current approaches for the development of optimal programs vary among centers. STUDY DESIGN: We conducted a survey of 18 academic centers that are members of the BPD Collaborative, a consortium of institutions with an established interdisciplinary BPD program. We aimed to characterize the approach, composition, and current practices of the interdisciplinary teams in inpatient and outpatient domains. RESULTS: Variations exist among centers, including composition of the interdisciplinary team, whether the team is the primary or consult service, timing of the first team assessment of the patient, frequency and nature of rounds during the hospitalization, and the timing of ambulatory visits postdischarge. CONCLUSION: Further studies to assess long-term outcomes are needed to optimize interdisciplinary care of infants with severe BPD. KEY POINTS: · Care of infants with BPD requires a longitudinal approach from the NICU to ambulatory care.. · Benefits of interdisciplinary care for children have been observed in other chronic conditions.. · Current approaches for the development of optimal interdisciplinary BPD programs vary among centers..

Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia.

BACKGROUND: Bronchopulmonary dysplasia is a prevalent complication after extremely preterm birth. Inflammation with mechanical ventilation may contribute to its development. Whether hydrocortisone treatment after the second postnatal week can improve survival without bronchopulmonary dysplasia and without adverse neurodevelopmental effects is unknown. METHODS: We conducted a trial involving infants who had a gestational age of less than 30 weeks and who had been intubated for at least 7 days at 14 to 28 days. Infants were randomly assigned to receive either hydrocortisone (4 mg per kilogram of body weight per day tapered over a period of 10 days) or placebo. Mandatory extubation thresholds were specified. The primary efficacy outcome was survival without moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age, and the primary safety outcome was survival without moderate or severe neurodevelopmental impairment at 22 to 26 months of corrected age. RESULTS: We enrolled 800 infants (mean [±SD] birth weight, 715±167 g; mean gestational age, 24.9±1.5 weeks). Survival without moderate or severe bronchopulmonary dysplasia at 36 weeks occurred in 66 of 398 infants (16.6%) in the hydrocortisone group and in 53 of 402 (13.2%) in the placebo group (adjusted rate ratio, 1.27; 95% confidence interval [CI], 0.93 to 1.74). Two-year outcomes were known for 91.0% of the infants. Survival without moderate or severe neurodevelopmental impairment occurred in 132 of 358 infants (36.9%) in the hydrocortisone group and in 134 of 359 (37.3%) in the placebo group (adjusted rate ratio, 0.98; 95% CI, 0.81 to 1.18). Hypertension that was treated with medication occurred more frequently with hydrocortisone than with placebo (4.3% vs. 1.0%). Other adverse events were similar in the two groups. CONCLUSIONS: In this trial involving preterm infants, hydrocortisone treatment starting on postnatal day 14 to 28 did not result in substantially higher survival without moderate or severe bronchopulmonary dysplasia than placebo. Survival without moderate or severe neurodevelopmental impairment did not differ substantially between the two groups. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01353313.).

Novel Ventilation Strategies to Reduce Adverse Pulmonary Outcomes.

Extremely preterm infants who must suddenly support their own gas exchange with lungs that are incompletely developed and lacking adequate amount of surfactant and antioxidant defenses are susceptible to lung injury. The decades-long quest to prevent bronchopulmonary dysplasia has had limited success, in part because of increasing survival of more immature infants. The process must begin in the delivery room with gentle assistance in establishing and maintaining adequate lung aeration, followed by noninvasive support and less invasive surfactant administration. Various modalities of invasive and noninvasive support have been used with varying degree of effect and are reviewed in this article.

Ventilatory Strategies in Infants with Established Severe Bronchopulmonary Dysplasia: A Multicenter Point Prevalence Study.

We performed a point prevalence study on infants with severe bronchopulmonary dysplasia (BPD), collecting data on type and settings of ventilatory support; 187 infants, 51% of whom were on invasive positive-pressure ventilation (IPPV), from 15 centers were included. We found a significant center-specific variation in ventilator modes.

Decision to extubate extremely preterm infants: art, science or gamble?

In the modern era of neonatology, mechanical ventilation has been restricted to a smaller and more immature population of extremely preterm infants. Given the adverse outcomes associated with mechanical ventilation, every effort is made to extubate these infants as early as possible. However, the scientific basis for determining extubation readiness remains imprecise and primarily guided by clinical judgement, which is highly variable and subjective. In the absence of accurate tools to assess extubation readiness, many infants fail their extubation attempt and require reintubation, which also increases complications. Recent advances in the field have led to unravelling some of the complexities surrounding extubation in this population. This review aims to synthesise the available knowledge and provide a more evidence-based approach towards the reporting of extubation outcomes and assessment of extubation readiness in extremely preterm infants.

Sustained Inflation Versus Intermittent Positive Pressure Ventilation for Preterm Infants at Birth: Respiratory Function and Vital Sign Measurements.

OBJECTIVE: To characterize respiratory function monitor (RFM) measurements of sustained inflations and intermittent positive pressure ventilation (IPPV) delivered noninvasively to infants in the Sustained Aeration of Infant Lungs (SAIL) trial and to compare vital sign measurements between treatment arms. STUDY DESIGN: We analyzed RFM data from SAIL participants at 5 trial sites. We assessed tidal volumes, rates of airway obstruction, and mask leak among infants allocated to sustained inflations and IPPV, and we compared pulse rate and oxygen saturation measurements between treatment groups. RESULTS: Among 70 SAIL participants (36 sustained inflations, 34 IPPV) with RFM measurements, 40 (57%) were spontaneously breathing prior to the randomized intervention. The median expiratory tidal volume of sustained inflations administered was 5.3 mL/kg (IQR 1.1-9.2). Significant mask leak occurred in 15% and airway obstruction occurred during 17% of sustained inflations. Among 34 control infants, the median expiratory tidal volume of IPPV inflations was 4.3 mL/kg (IQR 1.3-6.6). Mask leak was present in 3%, and airway obstruction was present in 17% of IPPV inflations. There were no significant differences in pulse rate or oxygen saturation measurements between groups at any point during resuscitation. CONCLUSION: Expiratory tidal volumes of sustained inflations and IPPV inflations administered in the SAIL trial were highly variable in both treatment arms. Vital sign values were similar between groups throughout resuscitation. Sustained inflation as operationalized in the SAIL trial was not superior to IPPV to promote lung aeration after birth in this study subgroup. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02139800.