Cardiorespiratory Monitoring Data to Predict Respiratory Outcomes in Extremely Preterm Infants.

Rationale: Immature control of breathing is associated with apnea, periodic breathing, intermittent hypoxemia, and bradycardia in extremely preterm infants. However, it is not clear if such events independently predict worse respiratory outcome. Objectives: To determine if analysis of cardiorespiratory monitoring data can predict unfavorable respiratory outcomes at 40 weeks postmenstrual age (PMA) and other outcomes, such as bronchopulmonary dysplasia at 36 weeks PMA. Methods: The Prematurity-related Ventilatory Control (Pre-Vent) study was an observational multicenter prospective cohort study including infants born at <29 weeks of gestation with continuous cardiorespiratory monitoring. The primary outcome was either "favorable" (alive and previously discharged or inpatient and off respiratory medications/O2/support at 40 wk PMA) or "unfavorable" (either deceased or inpatient/previously discharged on respiratory medications/O2/support at 40 wk PMA). Measurements and Main Results: A total of 717 infants were evaluated (median birth weight, 850 g; gestation, 26.4 wk), 53.7% of whom had a favorable outcome and 46.3% of whom had an unfavorable outcome. Physiologic data predicted unfavorable outcome, with accuracy improving with advancing age (area under the curve, 0.79 at Day 7, 0.85 at Day 28 and 32 wk PMA). The physiologic variable that contributed most to prediction was intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <90%. Models with clinical data alone or combining physiologic and clinical data also had good accuracy, with areas under the curve of 0.84-0.85 at Days 7 and 14 and 0.86-0.88 at Day 28 and 32 weeks PMA. Intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <80% was the major physiologic predictor of severe bronchopulmonary dysplasia and death or mechanical ventilation at 40 weeks PMA. Conclusions: Physiologic data are independently associated with unfavorable respiratory outcome in extremely preterm infants.

Intermittent hypoxemia and oxidative stress in preterm infants.

Intermittent hypoxemia events (IH) are common in extremely preterm infants and are associated with many poor outcomes including retinopathy or prematurity, wheezing, bronchopulmonary dysplasia, cognitive or language delays and motor impairment. More recent data in animal and rodent models have suggested that specific patterns of IH may increase the risk for morbidity. The pathway by which these high risk patterns of IH initiate a pathological cascade is unknown but animal models suggest that oxidative stress may play a role. This review describes early postnatal patterns of IH in preterm infants, their relationship with morbidity, oxidative stress biomarkers relevant to the newborn infant and the relationship between IH and reactive oxygen species.

Pre-Vent: the prematurity-related ventilatory control study.

BACKGROUND: The increasing incidence of bronchopulmonary dysplasia in premature babies may be due in part to immature ventilatory control, contributing to hypoxemia. The latter responds to ventilation and/or oxygen therapy, treatments associated with adverse sequelae. This is an overview of the Prematurity-Related Ventilatory Control Study which aims to analyze the under-utilized cardiorespiratory continuous waveform monitoring data to delineate mechanisms of immature ventilatory control in preterm infants and identify predictive markers. METHODS: Continuous ECG, heart rate, respiratory, and oxygen saturation data will be collected throughout the NICU stay in 500 infants < 29 wks gestation across 5 centers. Mild permissive hypercapnia, and hyperoxia and/or hypoxia assessments will be conducted in a subcohort of infants along with inpatient questionnaires, urine, serum, and DNA samples. RESULTS: Primary outcomes will be respiratory status at 40 wks and quantitative measures of immature breathing plotted on a standard curve for infants matched at 36-37 wks. Physiologic and/or biologic determinants will be collected to enhance the predictive model linking ventilatory control to outcomes. CONCLUSIONS: By incorporating bedside monitoring variables along with biomarkers that predict respiratory outcomes we aim to elucidate individualized cardiopulmonary phenotypes and mechanisms of ventilatory control contributing to adverse respiratory outcomes in premature infants.

Neonatal intermittent hypoxemia events are associated with diagnosis of bronchopulmonary dysplasia at 36 weeks postmenstrual age.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a chronic lung disease and major pulmonary complication after premature birth. We have previously shown that increased intermittent hypoxemia (IH) events have been correlated to adverse outcomes and mortality in extremely premature infants. We hypothesize that early IH patterns are associated with the development of BPD. METHODS: IH frequency, duration, and nadirs were assessed using oxygen saturation (SpO2) waveforms in a retrospective cohort of 137 extremely premature newborns (<28 weeks gestation). Daily levels of inspired oxygen and mean airway pressure exposures were also recorded. RESULTS: Diagnosis of BPD at 36 weeks postmenstrual age was associated with increased daily IH, longer IH duration, and a higher IH nadir. Significant differences were detected through day 7 to day 26 of life. Infants who developed BPD had lower mean SpO2 despite their exposure to increased inspired oxygen and increased mean airway pressure. CONCLUSIONS: BPD was associated with more frequent, longer, and less severe IH events in addition to increased oxygen and pressure exposure within the first 26 days of life. Early IH patterns may contribute to the development of BPD or aid in identification of neonates at high risk.

Myo-inositol Effects on the Developing Respiratory Neural Control System.

Myo-inositol is a highly abundant stereoisomer of the inositol family of sugar alcohols and forms the structural basis for a variety of polyphosphate derivatives including second messengers and membrane phospholipids. These derivatives regulate numerous cell processes including gene transcription, membrane excitability, vesicular trafficking, intracellular calcium signaling, and neuronal growth and development. Myo-inositol can be formed endogenously from the breakdown of glucose, is found in a variety of foods including breastmilk and is commercially available as a nutritional supplement. Abnormal myo-inositol metabolism has been shown to underlie the pathophysiology of a variety of clinical conditions including Down Syndrome, traumatic brain injury, bronchopulmonary dysplasia (BPD), and respiratory distress syndrome (RDS). Several animal studies have shown that myo-inositol may play a critical role in development of both the central and peripheral respiratory neural control system; a notable example is the neonatal apnea and respiratory insufficiency that manifests in a mouse model of myo-inositol depletion, an effect that is also postnatally lethal. This review focuses on myo-inositol (and some of its derivatives) and how it may play a role in respiratory neural control; we also discuss clinical evidence demonstrating a link between serum myo-inositol levels and the incidence of intermittent hypoxemia (IH) events (a surrogate measure of apnea of prematurity (AOP)) in preterm infants. Further, there are both animal and human infant studies that have demonstrated respiratory benefits following supplementation with myo-inositol, which highlights the prospects that nutritional requirements are important for appropriate development and maturation of the respiratory system.

S-Nitrosoglutathione Attenuates Airway Hyperresponsiveness in Murine Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is characterized by lifelong obstructive lung disease and profound, refractory bronchospasm. It is observed among survivors of premature birth who have been treated with prolonged supplemental oxygen. Therapeutic options are limited. Using a neonatal mouse model of BPD, we show that hyperoxia increases activity and expression of a mediator of endogenous bronchoconstriction, S-nitrosoglutathione (GSNO) reductase. MicroRNA-342-3p, predicted in silico and shown in this study in vitro to suppress expression of GSNO reductase, was decreased in hyperoxia-exposed pups. Both pretreatment with aerosolized GSNO and inhibition of GSNO reductase attenuated airway hyperresponsiveness in vivo among juvenile and adult mice exposed to neonatal hyperoxia. Our data suggest that neonatal hyperoxia exposure causes detrimental effects on airway hyperreactivity through microRNA-342-3p-mediated upregulation of GSNO reductase expression. Furthermore, our data demonstrate that this adverse effect can be overcome by supplementing its substrate, GSNO, or by inhibiting the enzyme itself. Rates of BPD have not improved over the past two decades; nor have new therapies been developed. GSNO-based therapies are a novel treatment of the respiratory problems that patients with BPD experience.

The Effect of Continuous Positive Airway Pressure in a Mouse Model of Hyperoxic Neonatal Lung Injury.

BACKGROUND: Continuous positive airway pressure (CPAP) and supplemental oxygen have become the mainstay of neonatal respiratory support in preterm infants. Although oxygen therapy is associated with respiratory morbidities including bronchopulmonary dysplasia (BPD), the long-term effects of CPAP on lung function are largely unknown. We used a hyperoxia-induced mouse model of BPD to explore the effects of daily CPAP in the first week of life on later respiratory system mechanics. OBJECTIVE: We wanted to test the hypothesis that daily CPAP in a newborn-mouse model of BPD improves longer-term respiratory mechanics. METHODS: Mouse pups from C57BL/6 pregnant dams were exposed to room air (RA) or hyperoxia (50% O2, 24 h/day) for the first postnatal week with or without exposure to daily CPAP (6 cm H2O, 3 h/day). Respiratory system resistance (Rrs) and compliance (Crs) were measured following a subsequent 2-week period of RA recovery. Additional measurements included radial alveolar and macrophage counts. RESULTS: Mice exposed to hyperoxia had significantly elevated Rrs, decreased Crs, reduced alveolarization and increased macrophage counts at 3 weeks when compared to RA-treated mice. Daily CPAP treatment significantly improved Rrs, Crs and alveolarization and decreased lung macrophage infiltration in the hyperoxia-exposed pups. CONCLUSIONS: We have demonstrated that daily CPAP had a longer-term benefit on baseline respiratory system mechanics in a neonatal mouse model of BPD. We speculate that this beneficial effect of CPAP was the consequence of a decrease in the inflammatory response and resultant alveolar injury associated with hyperoxic lung injury in newborns.

Hypoxic Episodes in Bronchopulmonary Dysplasia.

Hypoxic episodes are troublesome components of bronchopulmonary dysplasia (BPD) in preterm infants. Immature respiratory control seems to be the major contributor, superimposed on abnormal respiratory function. Relatively short respiratory pauses may precipitate desaturation and bradycardia. This population is predisposed to pulmonary hypertension; it is likely that pulmonary vasoconstriction also plays a role. The natural history has been well-characterized in the preterm population at risk for BPD; however, the consequences are less clear. Proposed associations of intermittent hypoxia include retinopathy of prematurity, sleep disordered breathing, and neurodevelopmental delay. Future study should address whether these associations are causal relationships.

A higher incidence of intermittent hypoxemic episodes is associated with severe retinopathy of prematurity.

OBJECTIVE: Retinopathy of prematurity (ROP), a vasoproliferative disorder of the retina in preterm infants, is associated with multiple factors, including oxygenation level. We explored whether the common intermittent hypoxemic events in preterm infants are associated with the development of ROP. STUDY DESIGN: Oxygen desaturation events were quantified in 79 preterm infants (gestational age, 24 to 27-6/7 weeks) during the first 8 weeks of life. Infants were classified as requiring laser treatment for ROP versus having less severe or no ROP. A linear mixed model was used to study the association between the incidence of intermittent hypoxia and laser treatment of ROP, controlling for gestational age, sex, race, multiple births, and initial severity of illness. RESULTS: For all infants, hypoxemic events increased with postnatal age (P<.001). Controlling for all covariates, a higher incidence of oxygen desaturation events was found in the infants undergoing laser therapy for ROP (P<.001), males (P<.02), and infants of younger gestational age (P<.003). CONCLUSIONS: The incidence of hypoxemic events was higher in infants with ROP requiring laser therapy. Therapeutic strategies to optimize oxygenation in preterm infants should include minimization of desaturation episodes, which may in turn decrease serious morbidity in this high-risk population.