Extracellular Vesicle ASC: A Novel Mediator for Lung-Brain Axis in Preterm Brain Injury.

Bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI) are among the most common morbidities affecting preterm infants. Although BPD is a predictor of poor NDI, it is currently uncertain how BPD contributes to brain injury in preterm infants. Extracellular vesicles (EVs) are involved in inter-organ communication in diverse pathological processes. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is pivotal in inflammasome assembly and activation of inflammatory response. We assessed expression profiles of alveolar macrophage (AM) markers, CD11b, CD11c, and CD206, and ASC in EVs isolated from the plasma of preterm infants at risk for BPD at 1 week of age. We found that infants on higher fraction inspired oxygen (FiO2) therapy (HO2, ≥30%) had increased levels of AM-derived EV-ASC compared with infants on lower FiO2 (LO2, <30%). To assess the function of these EVs, we performed adoptive transfer experiments by injecting them into the circulation of newborn mice. We discovered that mice that received EVs from infants on HO2 had increased lung inflammation, decreased alveolarization, and disrupted vascular development, the hallmarks of BPD. Importantly, these EVs crossed the blood-brain barrier and the EVs from infants on HO2 caused inflammation, reduced cell survival, and increased cell death with features of pyroptosis and necroptosis in the hippocampus. These results highlight a novel role for AM-derived EV-ASC in mediating the lung-to-brain crosstalk that is critical in the pathogenesis of BPD and brain injury and identify potential novel targets for preventing and treating BPD and brain injury in preterm infants.

Etiology and Mechanism of Intermittent Hypoxemia Episodes in Spontaneously Breathing Extremely Premature Infants.

OBJECTIVE: To evaluate the mechanisms leading to intermittent hypoxemia (IH) episodes in spontaneously breathing extremely premature infants at 32 weeks and 36 weeks postmenstrual age (PMA). METHODS: We studied spontaneously breathing premature infants born at 23-28 weeks of gestational age who presented with IH episodes while on noninvasive respiratory support at 32 or 36 weeks PMA. Daytime recordings of arterial oxygen saturation (SpO2), esophageal pressure, respiratory inductive plethysmography of the abdomen, chest wall, and their sum were obtained during 4 hours at 32 weeks and 36 weeks PMA. IH episodes (SpO2 <90% for ≥5 seconds) and severe IH episodes (SpO2 < 80% for ≥5 seconds) were classified as resulting from apnea, active exhalation and breath holding, reduced tidal volume (VT), or reduced respiratory rate (RR) during the preceding 60 seconds. RESULTS: Fifty-one infants with a mean gestational age of 25.9 ± 1.5 weeks and a mean birth weight of 846 ± 185 g were included. Of these, 31 and 41 were included in the analysis at 32 weeks and 36 weeks PMA, respectively. At both 32 weeks and 36 weeks PMA, greater proportions of all IH episodes and severe IH episodes were associated with active exhalation and breath holding than with apnea, reduced RR, or reduced VT. The severity and duration of the IH episodes did not differ between mechanisms. CONCLUSIONS: In this group of premature infants, the predominant mechanism associated with daytime IH was active exhalation and breath holding. This etiology is more closely associated with behavioral factors than abnormal respiratory control and can have implications for prevention.

Pulse oximetry reliability for detection of hypoxemia under motion in extremely premature infants.

BACKGROUND: Episodes of intermittent hypoxemia (IH) in extremely premature infants are detected by pulse oximetry (SpO2) but motion artifact can cause falsely low readings. OBJECTIVES: To evaluate the reliability of SpO2 during IH episodes associated with motion in premature infants of ≤28 weeks GA monitored with 2 pulse oximeters. METHODS: IH episodes (defined as SpO2 < 90%, >10 s and SpO2 < 80%, >10 s) were classified by an analytic tool based on distortion caused by motion in the pulse plethysmograph (Pleth) as: A (true hypoxemia), both SpO2 decreased (only one Pleth showed motion); B (false hypoxemia), one SpO2 decreased (Pleth showed motion) and the other didn't (Pleth didn't show motion); C (suspected hypoxemia), both SpO2 decreased (both Pleth showed motion); D (true hypoxemia-motion free), both SpO2 decreased (neither Pleth showed motion). RESULTS: In 24-72 h data from 20 infants of 25.4 ± 1.5 weeks GA, 14.1 ± 5.7 episodes with SpO2 < 90% and 7.9 ± 5.5 episodes with SpO2 < 80% per infant were identified. 29 ± 15% of episodes with SpO2 < 90% were type A, 1 ± 2% B, 43 ± 21% C and 27 ± 23% D, while 26 ± 22% of episodes with SpO2 < 80% were type A, 0.3 ± 1.2% B, 45 ± 29% C, and 19 ± 25% D [p < 0.001 type B vs. rest (GLM-repeated measures)]. CONCLUSION: In extremely premature infants SpO2 with motion artifact is more likely to indicate true- than false hypoxemia. IMPACT: Uncertainty on the effect of motion on SpO2 accuracy during hypoxemia episodes in premature infants can influence the caregiver's trust on SpO2 and influence their response. This study evaluated data from two pulse oximeters used simultaneously in different extremities to determine the reliability of SpO2 during motion artifact in premature infants. Data from this study showed that in extremely premature infants SpO2 is more likely to indicate true- than false hypoxemia during episodes of hypoxemia associated with motion artifact.

Effect of the Target Range on Arterial Oxygen Saturation Stability in Extremely Premature Infants.

OBJECTIVE: The aim of this study was to compare the effect of targeting arterial oxygen saturation (SpO2) in the high (93-95%) versus the low portion (90-92%) of the recommended range of 90-95% on oxygenation stability in extremely premature infants. METHODS: Premature infants of ≤28 weeks of gestational age who received a fraction of inspired oxygen (FiO2) > 0.21 after day 14 were eligible. FiO2 was adjusted by a dedicated investigator to keep SpO2 between 90-92% and 93-95% for 2 h each in random sequence. Episodes of intermittent hypoxemia (IH) were defined as SpO2 <90% for ≥10 s; severe IH episodes were defined as SpO2 <80% for ≥10 s. Hyperoxemia was defined as SpO2 >95% or >98%. RESULTS: Eighteen premature infants were enrolled. Their (mean ± SD) GA was 26 ± 1.5 w. Seven infants were on mechanical ventilation, 4 infants on nasal ventilation, and 7 infants on nasal cannula. They were on a mean FiO2 0.38 ± 0.12 at study entry. Episodes of IH and severe IH were more frequent during the low compared to the high target (36.6 [27.0-41.3] vs. 16.0 [7.8-19.0], p < 0.001; 8.4 ± 9.3 vs. 3.2 ± 4.3, p = 0.002). The proportions of time with SpO2 >95% and >98% were greater with the high target (13.9 ± 11 vs. 34.1 ± 15.4%, p < 0.001; 0.9 [0-5.7] vs. 3.4 [0.5-16.1]%, p = 0.002). CONCLUSION: In this group of extremely premature infants, targeting SpO2 at the lower portion of the recommended range resulted in more frequent episodes of IH. However, targeting the higher SpO2 range led to more hyperoxemia. This trade-off warrants further investigation.

Efficacy of late postnatal dexamethasone on weaning from invasive mechanical ventilation in extreme premature infants.

OBJECTIVE: To evaluate the short-term respiratory effects of PND in a cohort of ventilator-dependent premature infants. STUDY DESIGN: Clinical data from 106 infants 23-28 weeks gestation who received PND for weaning from MV during 2011-2017 were evaluated. PND was started at a dose of 0.1 mg/kg/d tapered over 5-7 d. Treatment success was defined as extubated and free from MV on d14 after start of treatment. RESULT: Treatment was successful in 83 (78%) infants. Demographics and age of treatment did not differ between groups. In the failure group, a higher proportion were on HFOV and FiO2 ≥ 0.50 before treatment, compared to the successful group. CONCLUSION: In most infants, PND resulted in successful weaning from MV. Reduced need for oxygen in infants not extubated may be beneficial, but it is unknown if this offsets the risks. The long-term effects PND in ventilator dependent infants need to be evaluated.