Machine learning to predict late respiratory support in preterm infants: a retrospective cohort study.

Bronchopulmonary dysplasia (BPD) has been a critical morbidity in preterm infants. To improve our definition and prediction of BPD is challenging yet indispensable. We aimed to apply machine learning (ML) to investigate effective models by using the recently-proposed and data-driven definition to predict late respiratory support modalities at 36 weeks' post menstrual age (PMA). We collected data on very-low-birth-weight infants born between 2016 and 2019 from the Taiwan Neonatal Network database. Twenty-four attributes associated with their early life and seven ML algorithms were used in our analysis. The target outcomes were overall mortality, death before 36 weeks' PMA, and severity of BPD under the new definition, which served as a proxy for respiratory support modalities. Of the 4103 infants initially considered, 3200 were deemed eligible. The logistic regression algorithm yielded the highest area under the receiver operating characteristic curve (AUROC). After attribute selection, the AUROC of the simplified models remain favorable (e.g., 0.801 when predicting no BPD, 0.850 when predicting grade 3 BPD or death before 36 weeks' PMA, and 0.881 when predicting overall mortality). By using ML, we developed models to predict late respiratory support. Estimators were developed for clinical application after being simplified through attribute selection.

Surfactant protein D inhibits lipid-laden foamy macrophages and lung inflammation in chronic obstructive pulmonary disease.

Increased levels of surfactant protein D (SP-D) and lipid-laden foamy macrophages (FMs) are frequently found under oxidative stress conditions and/or in patients with chronic obstructive pulmonary disease (COPD) who are also chronically exposed to cigarette smoke (CS). However, the roles and molecular mechanisms of SP-D and FMs in COPD have not yet been determined. In this study, increased levels of SP-D were found in the bronchoalveolar lavage fluid (BALF) and sera of ozone- and CS-exposed mice. Furthermore, SP-D-knockout mice showed increased lipid-laden FMs and airway inflammation caused by ozone and CS exposure, similar to that exhibited by our study cohort of chronic smokers and COPD patients. We also showed that an exogenous recombinant fragment of human SP-D (rfhSP-D) prevented the formation of oxidized low-density lipoprotein (oxLDL)-induced FMs in vitro and reversed the airway inflammation and emphysematous changes caused by oxidative stress and CS exposure in vivo. SP-D upregulated bone marrow-derived macrophage (BMDM) expression of genes involved in countering the oxidative stress and lipid metabolism perturbations induced by CS and oxLDL. Our study demonstrates the crucial roles of SP-D in the lipid homeostasis of dysfunctional alveolar macrophages caused by ozone and CS exposure in experimental mouse emphysema, which may provide a novel opportunity for the clinical application of SP-D in patients with COPD.

Six-monthly palivizumab prophylaxis effectively reduced RSV-associated hospitalization rates of preterm infants in a subtropical area: a population-based cohort study.

BACKGROUND: To evaluate the effects of 6-monthly palivizumab on respiratory syncytial virus-associated hospitalization (RSVH) in preterm infants in an area without RSV seasonality. METHODS: RSV prophylaxis with 6-monthly palivizumab in infants born at gestational age (GA) ≤28 weeks or those born at GA 29-35 weeks with bronchopulmonary dysplasia (BPD) was implemented in Taiwan since 2010. RSVH, use of mechanical ventilation (MV), admission to intensive care unit (ICU), length of hospital stay, and annual mortality were compared between the historical control group (no prophylaxis, 2008-2009) and the prophylaxis group (2011-2013). RESULTS: The annual RSVH rates decreased in the target population and in subgroups of infants who received prophylaxis (all target infants: odds ratio [OR], 0.43; 95% confidence interval [CI], 0.29-0.65). No difference was observed in MV and ICU usage and 1-year mortality in the ≤28 weeks subgroup. In the GA 29-35 weeks with BPD subgroup, ICU usage and 1-year mortality rates were significantly reduced with palivizumab prophylaxis regimen. A significant decrease was noted in the annual mortality and ICU admission rates of infants who received prophylactic treatment. CONCLUSION: Six-monthly palivizumab treatment reduced the RSVH rate, ICU usage, and annual mortality rates of target infants in an area without RSV seasonality.

Seasonal peaks and risk factors of respiratory syncytial virus infections related hospitalization of preterm infants in Taiwan.

OBJECTIVES: To assess the nationwide seasonal peaks, risk factors, and utilization of medical resources of respiratory syncytial virus-associated hospitalization (RSVH) in preterm infants in Taiwan. STUDY DESIGN: A Taiwan nationwide birth cohort was extracted from the Birth Certificate Application Database during 2007-2009 and prospectively linked to the National Health Insurance database. We evaluated the seasonal peaks and risk factors (gestational age [GA], chronologic age [CA], and bronchopulmonary dysplasia [BPD]) associated with the RSVH of preterm infants. The length of hospital stays (LOS), care in intensive care unit (ICU), and use of mechanical ventilation (MV) were also analyzed. RESULTS: There is a total duration of 9 months of RSVH season in Taiwan, three seasonal peaks and two seasonal peaks of RSVH in preterm infants with BPD and without BPD, respectively. Preterm infants had significantly higher RSVH rate than term infants (2.6% vs 0.9%, p<0.0001). Preterm infants born at 29-35 weeks of gestational age (wGA) with BPD had significantly higher RSVH rate than those without BPD (p<0.0001). Preterm infants without BPD born at < 32 wGA had higher RSVH rate than those born at 33-35 wGA (p<0.0001). Overall, 56.4% of RSVH occurred within 9 months of CA. Preterm infants with BPD had significantly higher ICU admission rate within 18 months of CA (p<0.0001), MV usage within 12 months of CA (p<0.0001) and LOS within 18 months of CA (p<0.001) than those without BPD. RSVH occurred within 6 months of CA was significantly associated with higher ICU admission rate (p<0.0001), MV usage (p = 0.0002) and longer LOS (p<0.001) in preterm infants without BPD. CONCLUSIONS: There is a total duration of 9 months of RSVH season in Taiwan. Preterm < 32 wGA, BPD, and CA within 6 months were risk factors of RSVH which also contribute to higher utilization of medical resources.

Family-centered Care Improved Neonatal Medical and Neurobehavioral Outcomes in Preterm Infants: Randomized Controlled Trial.

BACKGROUND: Family-centered care for preterm infants in Western societies has yielded short- to medium-term benefits. However, the intervention effects have rarely been validated in Eastern societies. OBJECTIVE: The aim of this study was to examine whether a family-centered intervention program (FCIP) could improve the short-term medical and neurobehavioral outcomes in preterm infants with very low birth weight (VLBW; a birth weight of <1,500 g) in Taiwan over the outcomes seen with a usual care program (UCP). DESIGN: This was a multicenter, single-blind, randomized controlled trial study. SETTING: Three medical centers in northern and southern Taiwan were the locations for the study. PARTICIPANTS: The participants were 251 VLBW preterm infants without severe perinatal complications. INTERVENTION: The infants were randomly assigned to receive the FCIP or the UCP during hospitalization. MEASUREMENTS: Infant morbidities, feeding, growth, and neurobehavioral performance were evaluated during the neonatal period. Parental adherence to interventions was measured in the FCIP group. RESULTS: The FCIP promoted earlier full enteral feeding (ß = -1.1 weeks; 95% CI = -1.9 to -0.2 weeks) and hospital discharge (ß = -0.6 week; 95% CI = -1.1 to -0.1 weeks), greater weight gain (ß = 3.3 g/d; 95% CI = 0.1 to 6.6 g/d), and better neurobehavioral performance than the UCP (ß = 1.2 points; 95% CI = 0.2 to 2.3 points). Furthermore, a higher degree of parental motivation in interventions, goal attainment, and comprehensiveness of home activities was significantly associated with greater effects in infants' neurobehavioral performance and weight gain (r = .20-.31; all Ps < .05). LIMITATIONS: The findings may not be generalized to preterm infants with severe perinatal diseases and parents with a low level of interest in interventions. CONCLUSIONS: Family-centered care facilitated short-term medical and neurobehavioral outcomes in VLBW preterm infants in Taiwan; the effects were likely achieved through parental adherence to interventions. The designated strategies may be considered in a future launch of family-centered care in Taiwan.

Randomized Trial to Compare Renal Function and Ductal Response between Indomethacin and Ibuprofen Treatment in Extremely Low Birth Weight Infants.

BACKGROUND: A head to head comparison study on renal function and ductal response between indomethacin and ibuprofen has rarely been conducted in extremely low birth weight (ELBW) infants. OBJECTIVES: The aim was to compare renal function and ductal response between indomethacin and ibuprofen in ELBW infants. METHODS: We performed a double-blind randomized control trial to compare renal function and ductal response between indomethacin (0.2, 0.1, and 0.1 mg/kg i.v. every 24 h for 3 doses) and ibuprofen lysine (10, 5, and 5 mg/kg i.v. every 24 h for 3 doses) in ELBW infants with significant hemodynamic patent ductus arteriosus (cardiovascular dysfunction score >3 and LA/AO ratio ≥1.3). RESULTS: A total of 144 infants were enrolled: 73 received indomethacin and 71 received ibuprofen lysine. Significant decreases in urine output were seen in 30 infants (41%) in the indomethacin group and 15 (21%) in the ibuprofen group (p = 0.02). The indomethacin group was associated with a significantly higher chance of persistent ductal response than the ibuprofen group (66 vs. 49%, p = 0.046), but with a lower glomerular filtration rate on day 1, higher serum creatinine on days 1, 2, and 7, and lower urinary prostaglandin on days 2-7. Both groups were comparable in mortality and in bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, and retinopathy of prematurity morbidity. CONCLUSIONS: With the current dosage, ibuprofen had fewer renal side effects but was associated with a lower rate of persistent ductal closure in ELBW infants. The precise role of prostaglandin on renal tubular function in ELBW infants remains to be further investigated.

Lung density standard deviations obtained using high-pitch dual-source computed tomography are valid predictors of bronchopulmonary dysplasia in preterm infants.

PURPOSE: This study aimed to validate standard deviations of lung densities obtained using high-pitch dual-source computed tomography (DSCT) densitometry as indices of bronchopulmonary dysplasia (BPD) severity in premature infants. METHODS: Data of preterm, late preterm group, and early term groups were evaluated. Mean and median standard deviations (SDmean, SDmedian) of CT lung density (CTLD) were calculated from CT images. RESULTS: SDmean of CTLD in infants with severe BPD was significantly higher than that of infants without BPD (198.1 vs. 140.9, respectively; P=.002). CONCLUSIONS: Study results support using high-pitch DSCT for BPD diagnosis and quantitative evaluation in prematurity.

Hypotension Associated With Intravitreal Bevacizumab Therapy for Retinopathy of Prematurity.

Intravitreal bevacizumab therapy in preterm infants for retinopathy of prematurity (ROP) can be associated with hypotension. We report twin preterm infants who developed hypotension within 1 day after intravitreal bevacizumab therapy for ROP. Before receiving the medication, their clinical statuses were stable and similar. The dose, procedure, and premedication were the same; however, twin B presented with hypotension for 3 days. Although bevacizumab-related hypotension has been described in product information (incidence rate 7%-15%), this is the first case report of intravitreal bevacizumab for ROP inducing hypotension. Physicians should be aware of intravitreal bevacizumab therapy-related hypotension when treating ROP. We suggest conducting a postmarketing active surveillance on the systemic adverse effects of this regimen in preterm infants.

Eosinophilia in very low birth weight infants.

BACKGROUND: Eosinophilia is common in premature infants, though its clinical significance remains unknown. This study investigated the pattern of eosinophilia and related factors in very low birth-weight (VLBW) infants. METHODS: The medical records of VLBW infants (birth body weight < 1500 g) admitted to the neonatal intensive care unit of a tertiary care center of Cheng Kung University Hospital between January 2005 and June 2007 were analyzed. Complete blood counts (CBC) with differential leukocyte counts were performed weekly. Eosinophilia was defined as an eosinophil count of more than 0.700 x 10(9)/L. The possible related factors were analyzed. RESULTS: A total of 142 infants were recruited into the study. Those who did not survive after the first 28 days and those with less than four available CBCs were excluded, leaving 107 infants and 828 CBC measurements. Overall, 19.0% of CBCs (157/828) indicated eosinophilia and 69.0% of all infants had at least one instance of eosinophilia during their hospital stay. Eosinophilia mainly occurred in the third week of life (27.1%), with an average peak eosinophil count of 0.520 x 10(9)/L. There were 37.3% of patients with mild eosinophilia (0.700-0.999 x 10(9)/L), 50.7% with moderate eosinophilia (1.000-2.999 x 10(9)/L), and 12% with severe eosinophilia (> or =3.000 x 10(9)/L). The demographic data and perinatal characteristics of infants with and without eosinophilia were comparable. Medical treatments including mechanical ventilation, antibiotic administration, total parenteral nutrition, intravenous catheterization, transfusion, and body weight gains were similar between the two groups. The eosinophil counts in the first week of life were significantly higher in infants with bronchopulmonary dysplasia (p < 0.05). They were also greater in VLBW infants with sepsis at the first, the third, the fourth, the fifth and the seventh weeks (p < 0.05). CONCLUSION: Eosinophilia is common in VLBW infants and occurs mainly in the third week of life. Higher eosinophil counts were associated with sepsis and family history of atopic eczema. Bronchopulmonary dysplasia was associated with higher eosinophil counts in the first week of life.

Inhaled nitric oxide enhances distal lung growth after exposure to hyperoxia in neonatal rats.

Exposure of newborn rats to hyperoxia impairs alveolarization and vessel growth, causing abnormal lung structure that persists during infancy. Recent studies have shown that impaired angiogenesis due to inhibition of vascular endothelial growth factor (VEGF) signaling decreases alveolar and vessel growth in the developing lung, and that nitric oxide (NO) mediates VEGF-dependent angiogenesis. The purpose of this study was to determine whether hyperoxia causes sustained reduction of lung VEGF, VEGF receptor, or endothelial NO synthase (eNOS) expression during recovery, and whether inhaled NO improves lung structure in infant rats after neonatal exposure to hyperoxia. Newborn rat pups were randomized to hyperoxia [fraction of inspired oxygen (Fio(2)), 1.00] or room air exposure for 6 d, and then placed in room air with or without inhaled NO (10 ppm) for 2 wk. Rats were then killed for studies, which included measurements of body weight, lung weight, right ventricular hypertrophy (RVH), morphometric analysis of alveolarization (by mean linear intercept (MLI), radial alveolar counts (RAC), and vascular volume (Vv), and immunostaining and Western blot analysis. In comparison with controls, neonatal hyperoxia reduced body weight, increased MLI, and reduced RAC in infant rats. Lung VEGF, VEGFR-2, and eNOS protein expression were reduced after hyperoxia. Inhaled NO treatment after hyperoxia increased body weight and improved distal lung growth, as demonstrated by increased RAC and Vv and decreased MLI. We conclude that neonatal hyperoxia reduced lung VEGF expression, which persisted during recovery in room air, and that inhaled NO restored distal lung growth in infant rats after neonatal hyperoxia.

Inhaled nitric oxide attenuates pulmonary hypertension and improves lung growth in infant rats after neonatal treatment with a VEGF receptor inhibitor.

VEGF plays a critical role during lung development and is decreased in human infants with bronchopulmonary dysplasia. Inhibition of VEGF receptors in the newborn rat decreases vascular growth and alveolarization and causes pulmonary hypertension (PH). Nitric oxide (NO) is a downstream mediator of VEGF, but whether the effects of impaired VEGF signaling are due to decreased NO production is unknown. Therefore, we sought to determine whether impaired VEGF signaling downregulates endothelial NO synthase (eNOS) expression in the developing lung and whether inhaled NO (iNO) decreases PH and improves lung growth after VEGF inhibition. Newborn rats received a single dose of SU-5416 (a VEGF receptor inhibitor) or vehicle by subcutaneous injection and were killed up to 3 wk of age for assessments of right ventricular hypertrophy (RVH), radial alveolar counts (RAC), lung eNOS protein, and NOx production in isolated perfused lungs (IPL). Neonatal treatment with SU-5416 increased RVH in infant rats and reduced RAC. Compared with controls, SU-5416 reduced lung eNOS protein expression by 89% at 5 days (P < 0.01). IPL studies from day 14 rats demonstrated increased baseline pulmonary artery pressure and lower perfusate NOx concentration after SU-5416 treatment. Importantly, iNO treatment prevented the increase in RVH and improved RAC after SU-5416 treatment. We conclude that treatment of neonatal rats with SU-5416 downregulates lung eNOS expression and that iNO therapy decreases PH and improves lung growth after SU-5416 treatment. We speculate that decreased NO production contributes to PH and decreases distal lung growth caused by impaired VEGF signaling.