Association of Racial Disparities With In-Hospital Outcomes in Severe Bronchopulmonary Dysplasia.

Importance: Bronchopulmonary dysplasia (BPD) is the most common serious morbidity of preterm birth. Short-term respiratory outcomes for infants with the most severe forms of BPD are highly variable. The mechanisms that explain this variability remain unknown and may be mediated by racial disparities. Objective: To determine the association of maternal race with death and length of hospital stay in a multicenter cohort of infants with severe BPD. Design, Setting, and Participants: This multicenter cohort study included preterm infants enrolled in the BPD Collaborative registry from January 1, 2015, to July 19, 2021, involving 8 BPD Collaborative centers located in the US. Included patients were born at less than 32 weeks' gestation, had a diagnosis of severe BPD as defined by the 2001 National Institutes of Health Consensus Criteria, and were born to Black or White mothers. Exposures: Maternal race: Black vs White. Main Outcomes and Measures: Death and length of hospital stay. Results: Among 834 registry infants (median [IQR] gestational age, 25 [24-27] weeks; 492 male infants [59%]) meeting inclusion criteria, the majority were born to White mothers (558 [67%]). Death was observed infrequently in the study cohort (32 [4%]), but Black maternal race was associated with an increased odds of death (adjusted odds ratio, 2.1; 95% CI, 1.2-3.5) after adjusting for center. Black maternal race was also significantly associated with length of hospital stay (adjusted between-group difference, 10 days; 95% CI, 3-17 days). Conclusions and Relevance: In a multicenter severe BPD cohort, study results suggest that infants born to Black mothers had increased likelihood of death and increased length of hospital stay compared with infants born to White mothers. Prospective studies are needed to define the sociodemographic mechanisms underlying disparate health outcomes for Black infants with severe BPD.

Outpatient Respiratory Management of Infants, Children, and Adolescents with Post-Prematurity Respiratory Disease: An Official American Thoracic Society Clinical Practice Guideline.

Background: Premature birth affects millions of neonates each year, placing them at risk for respiratory disease due to prematurity. Bronchopulmonary dysplasia is the most common chronic lung disease of infancy, but recent data suggest that even premature infants who do not meet the strict definition of bronchopulmonary dysplasia can develop adverse pulmonary outcomes later in life. This post-prematurity respiratory disease (PPRD) manifests as chronic respiratory symptoms, including cough, recurrent wheezing, exercise limitation, and reduced pulmonary function. This document provides an evidence-based clinical practice guideline on the outpatient management of infants, children, and adolescents with PPRD. Methods: A multidisciplinary panel of experts posed questions regarding the outpatient management of PPRD. We conducted a systematic review of the relevant literature. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of the clinical recommendations. Results: The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations were developed for or against three common medical therapies and four diagnostic evaluations in the context of the outpatient management of PPRD. Conclusions: The panel developed recommendations for the outpatient management of patients with PPRD on the basis of limited evidence and expert opinion. Important areas for future research were identified.

Established severe BPD: is there a way out? Change of ventilatory paradigms.

Improved survival of extremely preterm newborn infants has increased the number of infants at risk for developing bronchopulmonary dysplasia (BPD). Despite efforts to prevent BPD, many of these infants still develop severe BPD (sBPD) and require long-term invasive mechanical ventilation. The focus of research and clinical management has been on the prevention of BPD, which has had only modest success. On the other hand, research on the management of the established sBPD patient has received minimal attention even though this condition poses large economic and health problems with extensive morbidities and late mortality. Patients with sBPD, however, have been shown to respond to treatments focused not only on ventilatory strategies but also on multidisciplinary approaches where neurodevelopmental support, growth promoting strategies, and aggressive treatment of pulmonary hypertension improve their long-term outcomes. In this review we will try to present a physiology-based ventilatory strategy for established sBPD, emphasizing a possible paradigm shift from acute efforts to wean infants at all costs to a more chronic approach of stabilizing the infant. This chronic approach, herein referred to as chronic phase ventilation, aims at allowing active patient engagement, reducing air trapping, and improving ventilation-perfusion matching, while providing sufficient support to optimize late outcomes. IMPACT: Based on pathophysiological aspects of evolving and established severe BPD in premature infants, this review presents some lung mechanical properties of the most severe phenotype and proposes a chronic phase ventilatory strategy that aims at reducing air trapping, improving ventilation-perfusion matching and optimizing late outcomes.

Identifying and treating intrinsic PEEP in infants with severe bronchopulmonary dysplasia.

RATIONALE: Infants with severe bronchopulmonary dysplasia (sBPD) and airway obstruction may develop dynamic hyperinflation and intrinsic positive end-expiratory pressure (PEEPi ), which impairs patient/ventilator synchrony. OBJECTIVES: To determine if PEEPi is present in infants with sBPD during spontaneous breathing and if adjusting ventilator PEEP improves patient/ventilator synchrony and comfort. METHODS: Interventional study in infants with sBPD. PEEPi measured by esophageal pressure (Pes) and pneumotachometer, during pressure-supported breaths. PEEP i defined as the difference between Pes at start of the inspiratory effort minus Pes at onset of inspiratory flow. The set PEEP was adjusted to minimize PEEP i . "Best PEEP" was the setting with minimal wasted efforts (WE), an inspiratory effort seen on the Pes waveform without a corresponding ventilator breath. FiO 2 and SpO 2 measured pre- and post-PEEP adjustment. Sedation requirements evaluated 72 hours preprocedure and postprocedure. RESULTS: Twelve infants were assessed (gestational age, 24.9 ± 1.4 weeks; study age, 48.8 ± 1.5 weeks, postmenstrual age). Mean baseline ventilator PEEP was 16.4 cm H2 O (14-20 cm H 2 O). Eight infants required an increase, one, a reduction, and three, no change in the set PEEP. For the eight infants requiring an increase in set PEEP, there was an 18.9% reduction in WE and a reduction in FiO 2 (0.084 ± 0.058) requirements in the subsequent 24 hours. Conditional sedation was reduced in five infants postprocedure. No adverse events occurred during testing. CONCLUSION: PEEPi is measurable in infants with sBPD with concurrent esophageal manometry and flow-time tracings without the need for pharmacological paralysis. In those with PEEP i , increasing ventilator PEEP to offset PEEP i improves synchrony.

Tidal Breathing Measurements at Discharge and Clinical Outcomes in Extremely Low Gestational Age Neonates.

RATIONALE: The relationship between respiratory function at hospital discharge and the severity of later respiratory disease in extremely low gestational age neonates is not well defined. OBJECTIVES: To test the hypothesis that tidal breathing measurements near the time of hospital discharge differ between extremely premature infants with bronchopulmonary dysplasia (BPD) or respiratory disease in the first year of life and those without these conditions. METHODS: Study subjects were part of the PROP (Prematurity and Respiratory Outcomes Program) study, a longitudinal cohort study of infants born at less than 29 gestational weeks followed from birth to 1 year of age. Respiratory inductance plethysmography was used for tidal breathing measurements before and after inhaled albuterol 1 week before anticipated hospital discharge. Infants were breathing spontaneously and were receiving less than or equal to 1 L/min nasal cannula flow at 21% to 100% fraction of inspired oxygen. A survey of respiratory morbidity was administered to caregivers at 3, 6, 9, and 12 months corrected age to assess for respiratory disease. We compared tidal breathing measurements in infants with and without BPD (oxygen requirement at 36 wk) and with and without respiratory disease in the first year of life. Measurements were also performed in a comparison cohort of term infants. RESULTS: A total of 765 infants survived to 36 weeks postmenstrual age, with research-quality tidal breathing data in 452 out of 564 tested (80.1%). Among these 452 infants, the rate of postdischarge respiratory disease was 65.7%. Compared with a group of 18 term infants, PROP infants had abnormal tidal breathing patterns. However, there were no clinically significant differences in tidal breathing measurements in PROP infants who had BPD or who had respiratory disease in the first year of life compared with those without these diagnoses. Bronchodilator response was not significantly associated with respiratory disease in the first year of life. CONCLUSIONS: Extremely premature infants receiving less than 1 L/min nasal cannula support at 21% to 100% fraction of inspired oxygen have tidal breathing measurements that differ from term infants, but these measurements do not differentiate those preterm infants who have BPD or will have respiratory disease in the first year of life from those who do not. Clinical trial registered with www.clinicaltrials.gov (NCT01435187).

Tracheobronchomalacia Is Associated with Increased Morbidity in Bronchopulmonary Dysplasia.

RATIONALE: Tracheobronchomalacia is a common comorbidity in neonates with bronchopulmonary dysplasia. However, the effect of tracheobronchomalacia on the clinical course of bronchopulmonary dysplasia is not well-understood. OBJECTIVE: We sought to assess the impact of tracheobronchomalacia on outcomes in neonates with bronchopulmonary dysplasia in a large, multi-center cohort. METHODS: We preformed a cohort study of 974 neonates with bronchopulmonary dysplasia admitted to 27 neonatal intensive care units participating in the Children's Hospital Neonatal Database who had undergone bronchoscopy. In hospital morbidity for neonates with bronchopulmonary dysplasia and tracheobronchomalacia (N=353, 36.2%) was compared to those without tracheobronchomalacia (N=621, 63.8%) using mixed-effects multivariate regression. RESULTS: Neonates with tracheobronchomalacia and bronchopulmonary dysplasia had more comorbidities, such as gastroesophageal reflux (OR=1.65, 95%CI 1.23- 2.29, P=0.001) and pneumonia (OR=1.68, 95%CI 1.21-2.33, P=0.002) and more commonly required surgeries such as tracheostomy (OR=1.55, 95%CI 1.15-2.11, P=0.005) and gastrostomy (OR=1.38, 95%CI 1.03-1.85, P=0.03) compared with those without tracheobronchomalacia. Neonates with tracheobronchomalacia were hospitalitized (118 ± 93 vs 105 ± 83 days, P=0.02) and ventilated (83.1 ± 91.1 vs 67.2 ± 71.9 days, P=0.003) longer than those without tracheobronchomalacia. Upon discharge, neonates with tracheobronchomalacia and BPD were more likely to be mechanically ventilated (OR=1.37, 95CI 1.01-1.87 P=0.045) and possibly less likely to receive oral nutrition (OR=0.69, 95%CI 0.47-1.01, P=0.058). CONCLUSIONS: Tracheobronchomalacia is common in neonates with bronchopulmonary dysplasia who undergo bronchoscopy and is associated with longer and more complicated hospitalizations.

Infant lung function tests as endpoints in the ISIS multicenter clinical trial in cystic fibrosis.

BACKGROUND: The Infant Study of Inhaled Saline (ISIS) in CF was the first multicenter clinical trial to utilize infant pulmonary function tests (iPFTs) as an endpoint. METHODS: Secondary analysis of ISIS data was conducted in order to assess feasibility of iPFT measures and their associations with respiratory symptoms. Standard deviations were calculated to aid in power calculations for future clinical trials. RESULTS: Seventy-three participants enrolled, 70 returned for the final visit; 62 (89%) and 45 (64%) had acceptable paired functional residual capacity (FRC) and raised volume measurements, respectively. Mean baseline FEV0.5, FEF75 and FRC z-scores were 0.3 (SD: 1.2), -0.2 (SD: 2.0), and 1.8 (SD: 2.0). CONCLUSIONS: iPFTs are not appropriate primary endpoints for multicenter clinical trials due to challenges of obtaining acceptable data and near-normal average raised volume measurements. Raised volume measures have potential to serve as secondary endpoints in future clinical CF trials.

Paediatric Tracheomalacia.

Intrathoracic tracheomalacia is characterized by increased compliance of the central airway within the thorax. This leads to excessive dynamic collapse during exhalation or periods of increased intrathoracic pressure such as crying. Extrathoracic tracheomalacia involves dynamic collapse of the airway between the glottis and sternal notch that occurs during inhalation rather than exhalation. The tone of the posterior membrane of the trachea increases throughout development and childhood, as does the rigidity of the tracheal cartilage. Abnormalities of airway maturation result in congenital tracheomalacia. Acquired tracheomalacia occurs in the normally developed trachea due to trauma, external compression, or airway inflammation. Although tracheomalacia can be suspected by history, physical examination, and supportive radiographic findings, flexible fiberoptic bronchoscopy remains the "gold standard" for diagnosis. Current treatment strategies involve pharmacotherapy with cholinergic agents, positive pressure ventilation, and surgical repair.

Pulmonary hypertension in giant omphalocele infants.

BACKGROUND: Pulmonary hypoplasia has been described in cases of giant omphalocele (GO), although pulmonary hypertension (PH) has not been extensively studied in this disorder. In the present study, we describe rates and severity of PH in GO survivors who underwent standardized prenatal and postnatal care at our institution. METHODS: A retrospective chart review was performed for all patients in our pulmonary hypoplasia program with a diagnosis of GO. Statistical significance was calculated using Fisher's exact test and Mann-Whitney test (p<0.05). RESULTS: Fifty-four patients with GO were studied, with PH diagnosed in twenty (37%). No significant differences in gender, gestational ages, birth weight, or Apgar scores were associated with PH. Patients diagnosed with PH were managed with interventions, including high frequency oscillatory ventilation, and nitric oxide. Nine patients required long-term pulmonary vasodilator therapy. PH was associated with increased length of hospital stay (p<0.001), duration of mechanical ventilation (p=0.008), and requirement for tracheostomy (p=0.0032). Overall survival was high (94%), with significantly increased mortality in GO patients with PH (p=0.0460). Prenatal imaging demonstrating herniation of the stomach into the defect was significantly associated with PH (p=0.0322), with a positive predictive value of 52%. CONCLUSIONS: In this series, PH was observed in 37% of GO patients. PH represents a significant complication of GO, and management of pulmonary dysfunction is a critical consideration in improving clinical outcomes in these patients.

Changes in gastric pressure and volume during mechanical in-exsufflation.

BACKGROUND/PURPOSE: A mechanical insufflator-exsufflator (MI-E) is used to replicate spontaneous cough in weak or neurologically impaired patients. Its use is often withheld after abdominal surgery because of concerns for potential wound dehiscence from abdominal distension or development of excessive abdominal positive pressure. We hypothesized that gastric pressure during MI-E use would not exceed usual pressures generated during a spontaneous cough. METHODS: Thirteen subjects 0.8-23.1 years (mean 10.5 years) with neuromuscular weakness, pre-existing gastrostomy tube, and established MI-E routine were studied. A pressure transducer through the gastrostomy tube measured gastric pressure (Pgas) during MI-E treatment. Chest and abdominal volume change was assessed by respiratory inductance plethysmography. In three subjects, the same measurements were made during spontaneous cough. RESULTS: The maximum Pgas was 24 cm with applied pressures of 20-40 cm. In the three subjects able to cough, the maximum Pgas achieved during the spontaneous maneuver was 25 cm, a value higher than they achieved with MI-E treatment. CONCLUSION: MI-E resulted in less positive abdominal pressure than has been described in healthy subjects during spontaneous coughing. As such, use of an MI-E device should be considered safe to use in the post-operative period following abdominal surgery in patients with neuromuscular weakness.

Assessment of early pulmonary function abnormalities in giant omphalocele survivors.

PURPOSE: Infants with giant omphalocele (GO) are at increased risk for persistent respiratory insufficiency, yet information regarding the systematic assessment of their lung function is limited. We performed a group of pulmonary function tests (PFTs) including spirometry, fractional lung volume measurements, assessment of bronchodilator responsiveness, and passive respiratory mechanics in GO survivors during infancy and early childhood to evaluate the nature and degree of pulmonary dysfunction. MATERIAL AND METHODS: Between July 2004 and June 2008, 30 consecutive GO survivors were enrolled in our interdisciplinary follow-up program. Forty-seven percent (14/30) underwent PFT during follow-up evaluation using the raised volume rapid thoracic compression technique to measure forced expiratory flows and bronchodilator responsiveness, body plethysmography to calculate lung volumes, and the single breath occlusion technique to measure passive mechanics of the respiratory system. RESULTS: The mean age at PFT assessment was 19.3 ± 19.7 months (range, 1.0-58). Mean forced vital capacity and mean forced expiratory volume in the first 0.5 second were significantly reduced compared with published normative values (P = .03 and P < .01, respectively). Total lung capacity was significantly reduced (P < .001), whereas functional residual capacity, residual volume, and residual volume to total lung capacity ratio were within the normative range (P = .21, P = .34, and P = .48, respectively). Among the 46% who demonstrated significant bronchodilator responsiveness, there were greater increases in the mean percentage changes in flow at 25% to 75% (P = .01), flow at 75% (P < .001), and flow at 85% (P < .001) compared with those participants that did not respond. Specific compliance was reduced, whereas specific conductance increased, compared with published normal results. CONCLUSIONS: Abnormalities of pulmonary function in GO survivors include lung volume restriction without airway obstruction, an increased likelihood of airway hyperresponsivness, and reduced respiratory system specific compliance. Early recognition of pulmonary functional impairment in GO survivors could help to develop targeted treatment strategies to reduce the risk of subsequent pulmonary morbidity.

Pulmonary outcomes in bronchopulmonary dysplasia.

The incidence of bronchopulmonary dysplasia (BPD), defined as oxygen need at 36 weeks of postmenstrual age, is about 30% for infants with birth weights <1000 g. BPD is associated with persistent structural changes in the lung that result in significant effects on lung mechanics, gas exchange, and pulmonary vasculature. Up to 50% of infants with BPD require readmission to the hospital for lower respiratory tract illness in the first year of life. Long-term measurements of lung function in BPD include normalization of pulmonary mechanics and some lung volumes over time as somatic and lung growth occur, whereas abnormality of small airway function persists. The majority of data reveals no long-term decrease in exercise capacity. Mild to moderate radiological abnormalities persist. BPD is a result of dynamic processes involving inflammation, injury, repair, and maturation. Infants with BPD have significant pulmonary sequelae during childhood and adolescence, and continued surveillance of young adults with BPD is critical.

Viral respiratory infections in children with technology dependence and neuromuscular disorders.

BACKGROUND: Viral acute respiratory infections represent a significant cause of morbidity and mortality across all ages, especially in patients with chronic underlying conditions. Although recognized anecdotally, the risks of viral infection to those children with chronic underlying conditions rendering them technology dependent, or to those children with neuromuscular disorders, have not been well studied. METHODS: Studies of children with underlying conditions that result in technology dependence and those with neuromuscular disorders who required hospitalization for respiratory syncytial virus infection are reviewed. Additionally surveys of physician perceptions toward risk factors for severe viral illness and prevention in this population of patients are reported. Possible mechanisms to explain the increased risk of disease severity with viral respiratory infections are explored as well. RESULTS: Current or recent use of supplemental oxygen is associated with more severe disease in children with chronic underlying conditions, especially bronchopulmonary dysplasia. Supplemental oxygen use may be a marker for several factors known to increase the severity of viral respiratory illnesses. Children with neuromuscular weakness are also likely to experience more severe disease, most likely resulting from compromised airway clearance. CONCLUSIONS: Although the number of children who are technology-dependent or have severe neuromuscular weakness is small, their risk of severe disease after viral respiratory infection may be similar to that of premature infants or other high risk groups. A better understanding of the factors responsible for severe viral disease in these children would help create better strategies for treatment and prevention.

Airway structure, function and development in health and disease.

Until they are fully mature, the airways are highly susceptible to damage. Factors that may contribute to vulnerability of immature airways and the occurrence of bronchopulmonary dysplasia (BPD) in preterm neonates include decreased contractility of smooth muscles of the airway, which leads to generation of lower forces, and immaturity of airway cartilage, leading to increased compressibility of developing airways. Mechanical ventilation has little effect on adult airways, but affects the dimensions and mechanical properties of preterm and newborn airways. Techniques for clinical evaluation of airway function include: (i). measurements of airway function during tidal breathing (airway resistance and reactivity are significantly elevated in infants with BPD); (ii). forced expiratory flow measurements [small-airway obstruction in infants with BPD is indicated by markedly reduced maximal volume measurements (Vmax)]; (iii). radiography procedures (plain radiographs, fluoroscopy, computed tomography and virtual bronchoscopy); and (iv). endoscopy procedures (rigid or flexible bronchoscopy, with or without measurement of oesophageal pressure). Imaging has demonstrated an excessively decreased airway cross-sectional area during exhalation in infants with BPD and acquired tracheomegaly in very preterm infants who had received mechanical ventilatory support. To further advance our understanding of how the airways develop, and to design less damaging protocols for mechanical ventilation in preterm neonates, basic laboratory studies of airway ultrastructure need to be performed and the results correlated with clinical pulmonary function studies.

Transtracheal oxygen catheters in a pediatric population.

This is the first report to evaluate transtracheal oxygen catheter (TTOC) use in a pediatric patient series. Seven pediatric patients (4 boys and 3 girls) received TTOCs in 2 tertiary care medical centers. The medical indications included bronchopulmonary dysplasia in 4 patients and tracheomalacia in the other 3. The average age at the time of placement was 22 months (range, 2 weeks to 37 months). Catheter placement for 4 patients was through an open tracheotomy stoma. In 3, placement was through a percutaneous technique. The follow-up ranged from 2 weeks to 5 years. There were no long-term complications. Transient needs for supplemental oxygen were all met by the TTOC system. In 4 patients, the catheter has been removed because of resolution of the supplemental oxygen requirements. Minor complications included skin site infection and mucus plugging. In 1 patient, accidental dislodging of the catheter led to its replacement in the operating room. In 1 percutaneous placement, a pneumothorax occurred and resolved without any persistent morbidity. We conclude that transtracheal oxygen delivery can be a reasonable alternative to a nasal cannula or formal tracheotomy in selected pediatric patients in whom long-term oxygen delivery, but not an alternate airway, is required. In order to avoid complications, meticulous technique must be adhered to in using the percutaneous approach for placement.

Pulmonary function in technology-dependent children 2 years and older with bronchopulmonary dysplasia.

Somatic and pulmonary growth coincide with resolution of hypoxemia by 2 years of age in most children with bronchopulmonary dysplasia (BPD). However, a distinct subgroup of children with BPD continue to require mechanical ventilation and/or supplemental oxygen beyond 2 years of age. This study tested the hypothesis that indices of pulmonary function would be significantly worse in children with BPD 2 years and older who remained technology-dependent secondary to hypoxemia, compared to those of age-matched children with BPD who were normoxemic. We measured pulmonary mechanics in 21 oxygen- or ventilator-dependent children with BPD 2 years and older (BPDO2 group; mean age+/-SD, 30.2+/-6.5 months) and in 19 children with BPD who had been weaned off mechanical ventilation and supplemental oxygen for at least 6 months (control group; mean age, 30.1+/-5.5 months). Respiratory rate and tidal volume were measured after sedation with chloral hydrate, and dynamic compliance and expiratory conductance were calculated using the esophageal catheter technique. Maximal flow at FRC (V'(maxFRC)) and ratio of forced-to-tidal flows at midtidal volume were obtained by the rapid thoracic compression technique. FRC was determined by nitrogen washout. There were no statistically significant differences in most measured indices of pulmonary mechanics between the BPDO2 and control groups. However, V'(maxFRC)/FRC was higher in controls compared to subjects in the BPDO2 group (0.81+/-0.40 sec(-1) vs. 0.34+/-0.21 sec(-1), P<0.003). We conclude that most indices of pulmonary function in children with BPD 2 years and older do not reflect the need for mechanical ventilation or supplemental oxygen. We speculate that measurements of lung elastic recoil and tests of distribution of ventilation and pulmonary perfusion may be more sensitive in differentiating normoxemic and hypoxemic children with BPD 2 years and older.