Factors Associated with Short-Term Response after Systemic Corticosteroid Treatment in Invasively Ventilated Preterm Infants

Factors Associated with Short-Term Response after Systemic Corticosteroid Treatment in Invasively Ventilated Preterm Infants | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 1 July 2025 V1 Latest version Share on Factors Associated with Short-Term Response after Systemic Corticosteroid Treatment in Invasively Ventilated Preterm Infants Authors : Gyeong Eun Yeom 0000-0002-5713-569X , Seung Han Shin 0000-0002-7008-4073 , Han-Suk Kim 0000-0002-9777-3231 [email protected] , Ee- Kyung Kim , Ju Sun Heo , and Seh Hyun Kim Authors Info & Affiliations https://doi.org/10.22541/au.175138925.57072153/v1 169 views 117 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Objective: This study evaluated the factors affecting the short-term efficacy of systemic corticosteroid (CS) therapy, focusing on pulmonary hypertension (PH) and other clinical conditions in preterm infants with evolving or established bronchopulmonary dysplasia (BPD). Methods: A retrospective review was conducted on preterm infants (<32 weeks of gestation and/or <1,500 g birth weight) who received systemic CS therapy for BPD. Responders were defined as infants who were extubated within 14 days and/or achieved a ≥60% reduction in the respiratory severity score (RSS). Results: Of the 62 infants, 32 were classified as responders and 30 as non-responders. Non-responders had a significantly higher prevalence of PH requiring treatment (70.0% vs. 21.9%, p <0.001) and hemodynamically significant patent ductus arteriosus (hsPDA) at treatment initiation (30.0% vs. 3.1%, p = 0.005). Responders showed a greater reduction in RSS from day 1 to day 4 (33.8% vs. 11.7%, p = 0.002). In multivariate analysis, PH requiring treatment (adjusted odds ratio [aOR]: 6.66, 95% confidence interval [CI]: 1.39–31.92, p = 0.018) and hsPDA (aOR: 12.54, 95% CI: 1.16–135.05, p = 0.037) at treatment initiation were significant predictors of non-response. Conclusion: Identifying the vascular phenotypes of BPD, including PH and hsPDA, before initiating systemic CS therapy may improve patient selection and optimize treatment outcomes. Incorporating early changes in RSS from day 1 to day 4 enhanced the predictive accuracy for treatment failure and may facilitate the timely identification of non-responders. Introduction Bronchopulmonary dysplasia (BPD) remains a major cause of morbidity in preterm infants, primarily due to disrupted alveolar development during the critical period of lung growth 1 . This contributes to prolonged hospitalization, increased healthcare costs, and long-term pulmonary complications 2 . BPD affects approximately 36–75% of extremely preterm infants born before 28 weeks of gestation, with survival rates at discharge now exceeding 80% in developed countries 3-5 . It is associated with significant long-term morbidities, including chronic respiratory complications, increased susceptibility to pulmonary infections, frequent rehospitalization for respiratory issues, and adverse neurodevelopmental outcomes such as cerebral palsy (CP) and cognitive delays 6-10 . Traditionally, BPD has been considered the result of ongoing lung inflammation, which impairs tissue repair and disrupts lung development. However, recent studies have highlighted its heterogeneity, encompassing vascular, parenchymal, and airway abnormalities 11 . Pulmonary hypertension (PH), previously considered a complication of BPD, is now recognized as a distinct phenotype that reflects early pulmonary vascular disease in preterm infants 12,13 . Identifying the predominant BPD phenotypes in individual patients may allow for more targeted therapeutic interventions. Postnatal systemic corticosteroids (CS), particularly dexamethasone, are commonly used to prevent or treat BPD due to their potent anti-inflammatory effects. However, responses to CS therapy vary widely among studies. Extubation failure rates following the first course of CS range from 24% to 53%. Previous studies have identified lower gestational age, higher oxygen requirements, and elevated ventilator settings as risk factors for extubation failure. This study aimed to investigate whether PH and related conditions affect the short-term responses to systemic CS therapy in preterm infants with evolving or established BPD. Additionally, we examined whether the early treatment response observed during the first few days of therapy could enhance the prediction of treatment failure. 2. Materials and Methods 2.1 Study design and population This retrospective cohort study included preterm infants born at between January 2013 and December 2023. Infants were eligible if they received systemic CS therapy using a modified DART (Dexamethasone: A Randomized Trial) protocol (1.1 mg/kg over 10 days) for evolving or established BPD while on invasive mechanical ventilation 14 . Infants who completed a single course of systemic CS were included in this study. In cases involving multiple courses, only the first course was analyzed. Infants with major congenital anomalies such as congenital heart disease, chromosomal abnormalities, or structural airway anomalies confirmed by laryngoscopy were excluded. 2.2. Definition Hemodynamically significant patent ductus arteriosus (hsPDA) was defined as the presence of clinical or radiographic findings suggestive of cardiomegaly or pulmonary edema, combined with at least one echocardiographic criterion: (1) ductal diameter >1.4 mm/kg; (2) end-diastolic flow reversal in the descending aorta; or (3) a left atrium-to-aorta ratio ≥1.4 15 . The clinical manifestations of hsPDA included hypotension requiring inotropic support without other identifiable causes, persistent oliguria, or renal failure. Treatment options included ibuprofen (up to two courses) or acetaminophen. Surgical ligation or device closure was considered in refractory cases or when medical therapy was contraindicated. Primary surgical or device interventions were performed in cases of massive pulmonary hemorrhage due to PDA-induced left-to-right shunting. PH was suspected in cases of recurrent hypoxemia, prompting echocardiographic evaluation. PH was diagnosed when one or more of the following echocardiographic criteria were met: (1) peak tricuspid regurgitation velocity >2.8 m/s; (2) bidirectional or right-to-left shunting across any cardiac shunt; or (3) any degree of interventricular septal flattening 12 . In infants with suspected PH, the target peripheral oxygen saturation (SpO 2 ) was set at 95%, and the fraction of inspired oxygen (FiO 2 ) was adjusted accordingly. PH treatment was initiated when FiO 2 requirements were ≥0.6–0.7, and included inhaled nitric oxide, sildenafil (a phosphodiesterase-5 inhibitor), and treprostinil (a prostanoid analogue) 16 . 2.3. RSS-guided systemic CS administration The respiratory severity score (RSS), calculated as the product of mean airway pressure (MAP) and the FiO 2 , is a simple, noninvasive index of respiratory support. It is strongly correlated with the oxygenation index in mechanically ventilated neonates and does not require blood sampling 17 . Our unit previously demonstrated that RSS values on postnatal days (PND) 14, 21, and 28 were strongly associated with the subsequent development of severe BPD or death in extremely preterm infants. Specifically, an RSS ≥3.0 on day 14 and RSS ≥3.6 on day 21 were reliable cutoffs for predicting these outcomes 18 . These results are consistent with those of previous studies 19,20 . Based on these findings, we developed and implemented an institutional protocol for postnatal systemic CS administration guided by RSS (E-image 1). Preterm infants requiring mechanical ventilation beyond PND 14 were considered candidates for CS therapy. If the RSS was <4 or if ventilator settings had decreased, CS administration was deferred, and weekly RSS monitoring was continued. If the RSS was ≥4 or ventilator settings had increased, echocardiography was performed to assess for hsPDA or PH. When either condition was suspected and deemed likely to interfere with ventilator weaning, appropriate medical or surgical intervention was initiated. Simultaneously, laboratory tests were conducted to rule out infection. If no infection or other contraindications were identified, intravenous dexamethasone was administered according to a modified DART protocol, with a total dose of 1.1 mg/kg over 10 days 14 . The dosing schedule was as follows: days 1–2, 0.1 mg/kg every 12 h; days 3–4, 0.075 mg/kg every 12 h; days 5–7, 0.05 mg/kg every 12 h; day 8, no dose; day 9, 0.05 mg/kg every 12 h; and day 10 marked the end of treatment. 2.3. Data collection Medical records from the initiation of the first systemic dexamethasone course for BPD development were retrospectively reviewed. Prenatal variables included antenatal steroid administration, oligohydramnios, maternal diabetes mellitus (DM), preeclampsia, premature rupture of membranes (PROM), and histological chorioamnionitis. Neonatal variables included gestational age, birth weight, small-for-gestational-age (SGA) status, sex, respiratory distress syndrome (RDS), air leak, pulmonary hemorrhage, and culture-proven sepsis prior to the initiation of systemic CS therapy. BPD severity at 36 weeks’ postmenstrual age (PMA) was classified using the Jensen 2019 criteria 21 . Clinical data at the time of systemic CS initiation included PMA, PND, extubation outcomes, and concurrent medications. The RSS was calculated hourly using continuous vital sign data from the hospital’s electronic medical records. Daily RSS was defined as the average of hourly values. RSS monitoring was continued through day 14 to assess treatment response and extubation success. Echocardiography was performed by a pediatric cardiologist within 1 week of CS initiation to evaluate the presence of hsPDA or PH. 2.4. Study group allocation Infants were classified as responders if they met at least one of the following criteria: (1) successful extubation within 14 days of initiating systemic CS therapy, without re-intubation for at least 72 h; or (2) a ≥60% reduction in RSS from baseline at the time of treatment initiation. The 60% threshold was selected based on previous studies evaluating changes in RSS following systemic CS therapy in preterm infants 22 . Non-responders were defined as infants who did not achieve extubation within 14 days, required re-intubation within 72 h, or failed to show a ≥60% reduction in RSS from baseline. 2.5. Ethics approval and consent to participate statement The study was conducted in accordance with the principles of the Declaration of Helsinki. Ethical approval was obtained from the Institutional Review Board (IRB) of Seoul National University Hospital (IRB No. H-2408-016-1559). Due to the retrospective nature of the study, the requirement for informed consent was waived by the review board. 2.6. Statistical Analysis Descriptive statistics were used to summarize the clinical characteristics of the study population. Continuous variables were compared using the Student’s t -test or Wilcoxon rank-sum test, as appropriate. Categorical variables were analyzed using the chi-squared test or Fisher’s exact test. Multivariate logistic regression analysis was conducted to identify independent predictors of non-response to systemic CS therapy. Variables with a p -value of <0.05 in the univariate analysis, along with clinically relevant factors, were included in the regression models. Two models were constructed and compared: (1) Model 1 included gestational age, oligohydramnios, PMA at corticosteroid initiation, presence of hsPDA, use of any PH medication at the time of CS initiation, and baseline RSS at CS initiation. (2) Model 2 included all variables in Model 1, with the addition of the percentage change in RSS on day 4. Model performance was evaluated using the Akaike Information Criterion (AIC), McFadden’s R² , area under the receiver operating characteristic (ROC) curve (AUC), Hosmer–Lemeshow test, and likelihood ratio test. All statistical analyses were performed using R version 4.4.1 (2024; The R Foundation for Statistical Computing). 3. Results During the study period, 1,149 neonates born at <32 weeks of gestation and/or with a birth weight <1,500 g were admitted. Among them, 76 received systemic dexamethasone therapy for evolving or established BPD (Figure 1). Ten infants were excluded: six who received dexamethasone while on noninvasive ventilation, and four with significant airway abnormalities that precluded successful extubation (e.g., tracheomalacia, subglottic stenosis, or type C tracheoesophageal fistula). Additional exclusions included one case of congenital heart disease, two with genetic disorders, and one with incomplete data, yielding a final cohort of 62 infants. Of these, 32 were classified as responders and 30 as non-responders. 3.1. Demographic findings and neonatal morbidities No significant differences were observed between responders and non-responders in terms of gestational age (25.8 vs. 25.6 weeks, p = 0.616) or birth weight (745.4 vs. 706.9 g, p = 0.426) (Table 1). The proportion of SGA infants (15.6% vs. 16.7%, p = 1.000) and the rate of completed antenatal steroid courses (62.5% vs. 56.7%, p = 0.796) were also similar between groups. Other perinatal variables, including oligohydramnios, PROM, and histological chorioamnionitis, did not differ significantly between the groups. Apgar scores at 1 min (3.2 vs. 2.8, p = 0.278) and 5 min (5.3 vs. 5.8, p = 0.320) were comparable. The proportion of infants with grade 3 BPD was higher in the non-responder group than in the responder group (43.3% vs. 25.0%), although the difference did not reach statistical significance ( p = 0.131). BPD severity was classified based on the criteria proposed by Jensen et al. (2019) 21 . 3.2. Clinical characteristics at or prior to initiation of systemic dexamethasone Clinical characteristics at or before the initiation of systemic dexamethasone therapy are summarized in Table 2. Non-responders began systemic dexamethasone treatment at a younger PMA (29.4 ± 2.8 vs. 30.8 ± 3.6 weeks, p = 0.074) and earlier PND (28.1 ± 11.0 vs. 36.6 ± 18.3 days, p = 0.031). The proportion of infants receiving PH medication at treatment initiation was significantly higher in the non-responder group (70.0% vs. 21.9%, p < 0.001), as was the prevalence of hsPDA (30.0% vs. 3.1%, p = 0.005). The Day 1 RSS was significantly higher in non-responders (6.7 ± 3.1 vs. 4.7 ± 1.4, p = 0.007). The percentage reduction in RSS from Day 1 to Day 4 was significantly greater in responders (33.8% vs. 11.7%, p = 0.002). 3.3 Multivariate analysis for predicting non-responder to systemic dexamethasone Multivariate logistic regression analysis identified hsPDA (adjusted odds ratio [aOR]: 12.54, 95% confidence interval [CI]: 1.16–135.05, p = 0.037) and treatment for PH (aOR: 6.66, 95% CI: 1.39–31.92, p = 0.018) as independent predictors of non-response to systemic dexamethasone therapy in Model 1 (Table 3). Model 2, which additionally included the percentage change in RSS from Day 1 to Day 4, identified three significant predictors of non-response: hsPDA (aOR: 41.53, 95% CI: 2.13–811.53, p = 0.014), PH treatment (aOR: 10.06, 95% CI: 1.10–92.39, p = 0.041), and RSS change (%) from Day 1 to Day 4 (aOR: 0.91, 95% CI: 0.85–0.96, p = 0.001). Model 2 demonstrated improved predictive performance compared with Model 1, with a lower AIC (60.438 vs. 77.492), higher McFadden’s R 2 (0.476 vs. 0.237), and greater AUC (0.923 vs. 0.808) (E-table 1). Both models exhibited good calibration (Hosmer–Lemeshow, p > 0.05). A likelihood ratio test confirmed the superior fit of Model 2 (χ 2 = 19.054, p <0.001). 4. Discussion This study identified key clinical factors associated with a poor short-term response to systemic CS therapy in invasively ventilated preterm infants with evolving or established BPD. Our findings demonstrate that both PH and hsPDA at the time of systemic CS initiation were independent predictors of treatment non-responsiveness. These conditions may reflect a distinct “vascular phenotype” of BPD, which could attenuate the expected anti-inflammatory and lung maturation effects of corticosteroids. Furthermore, incorporating early changes in RSS within the first four days of therapy significantly improved the prediction of short-term treatment outcomes. Systemic CS reduces the incidence of BPD and improves respiratory outcomes in preterm infants 23-25 . Kristin et al. reported a 39% extubation failure rate following the first course of systemic dexamethasone in ventilator-dependent preterm infants, with lower gestational age, higher FiO₂, and elevated MAP at treatment initiation being significant predictors of treatment failure 26 . Similarly, a retrospective study reported a 21.6% extubation failure rate among preterm infants receiving systemic CS during invasive ventilation, with the use of high-frequency oscillatory ventilation and higher FiO₂ levels associated with treatment failure 27 . Data from the National Neonatal Research Database, which included 84,440 preterm infants born before 32 weeks of gestation, showed extubation failure rates ranging from 21.4% to 38%, depending on the timing of CS administration 28 . Unlike previous studies that primarily focused on ventilator parameters and the timing of CS administration, the present study highlights the significance of pulmonary vascular conditions—specifically hsPDA and PH—as key predictors of poor response to systemic dexamethasone. Severe BPD encompasses a spectrum of phenotypes, including homogeneous or heterogeneous lung disease, airway narrowing, and abnormal pulmonary vascular development 25 . When a specific phenotype predominantly contributes to disease severity, treatment strategies should be tailored to address the underlying pathology; conversely, targeting non-dominant features may offer limited therapeutic benefit. For example, airway abnormalities such as tracheobronchomalacia, which often impede successful extubation, may reduce the effectiveness of systemic CS, as these agents primarily act on parenchymal inflammation rather than on structural airway or vascular abnormalities. PH associated with BPD (BPD-PH) is a major complication of BPD, affecting approximately 25% of infants with moderate to severe disease. It adversely impacts both the cardiac and pulmonary systems and is associated with increased mortality in this population 29 . PH is now recognized as an early manifestation of pulmonary vascular disease that significantly contributes to adverse respiratory outcomes and overall morbidity in preterm infants. Its pathophysiology includes impaired alveolar-capillary gas exchange, abnormal vascular remodeling, and pulmonary vascular rarefaction—all of which lead to increased pulmonary vascular resistance and eventual right heart failure 30 . In infants whose BPD phenotype is predominantly characterized by pulmonary vascular disease, the response to dexamethasone may be diminished compared to those with parenchymal-dominant BPD and minimal pulmonary vascular abnormalities. The association between PDA and BPD is well established 31,32 . A persistent left-to-right shunt through the PDA increases pulmonary blood flow, disrupts pulmonary mechanics, and prolongs the need for mechanical ventilation—all of which adversely affect alveolar development and contribute to BPD-PH. Recent studies have shown that prolonged exposure to hsPDA is associated with the development of BPD-PH 33 . One case-control study demonstrated a significant association between moderate-to-large PDA and BPD-PH, even after adjusting for baseline characteristics 34 . Notably, a longer PDA exposure duration was correlated with BPD-PH 34 . These findings suggest that hsPDA may exacerbate pulmonary vascular disease in preterm infants with BPD, particularly in those with an underlying or evolving pulmonary vascular pathology. Early changes in RSS during the first 4 days of CS therapy emerged as a strong predictor of short-term treatment responses. Although early postnatal administration of systemic CS has been linked to adverse neurodevelopmental outcomes, including an increased risk of CP, leading to the discontinuation of routine CS use during the first week of life 35 . However, later administration still carries potential risks such as hypertension, hyperglycemia, gastrointestinal perforation, and gastrointestinal bleeding 8 . Therefore, early identification of infants unlikely to benefit from CS therapy may help minimize these risks by avoiding unnecessary exposure. The RSS, a simple, rapid, and noninvasive tool for assessing respiratory distress in newborns 36 , demonstrated substantial predictive utility in this study. By Day 4 of treatment, the responder group showed a 33.8% reduction in RSS compared to only 11.7% in the non-responder group. Incorporating the percentage change in RSS into the prediction model significantly improved its accuracy (E-table 1). This study has several limitations, including its retrospective design and relatively small sample size. Although dexamethasone is typically administered at our institution after hsPDA has been addressed, 33.1% of infants still had hsPDA at the time of CS initiation, indicating variability in clinical protocol adherence. In addition, the use of PH as a surrogate marker in our analysis may not have fully captured the severity of PH prior to therapy. Lastly, this study focused on short-term responses rather than the long-term efficacy in reducing the incidence of BPD. Nevertheless, the lower prevalence of severe BPD in the responder group supports the clinical relevance of our findings and suggests that BPD-PH may serve as a marker of greater disease severity. In invasively ventilated preterm infants, hsPDA and PH were significant predictors of poor response to systemic dexamethasone therapy, reflecting distinct BPD phenotypes. These findings emphasize the importance of careful patient selection and early management of pulmonary circulatory conditions to optimize treatment effectiveness. Incorporating early changes in the RSS improved the prediction of treatment failure, underscoring the need to refine the target population and consider early discontinuation of therapy in likely non-responders to minimize unnecessary steroid exposure and reduce potential neurodevelopmental risks. References 1. Jensen EA, Schmidt B. Epidemiology of bronchopulmonary dysplasia. Birth Defects Research Part A: Clinical and Molecular Teratology. 2014;100(3):145-157. 2. 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Journal of Perinatology. 2018;38(5):505-511. Figure legends Figure 1. RSS-guided postnatal systemic corticosteroid protocol implanted in the neonatal intensive care unit at Seoul National University Children’s Hospital. RSS, Respiratory severity score Figure 2. Flow chart of study population. BPD, bronchopulmonary dysplasia Supplementary Material File (tables_250606.docx) Download 26.77 KB Information & Authors Information Version history V1 Version 1 01 July 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords bronchopulmonary dysplasia dexamethasone pulmonary hypertension respiratory severity score Authors Affiliations Gyeong Eun Yeom 0000-0002-5713-569X Seoul National University Children's Hospital Department of Pediatrics View all articles by this author Seung Han Shin 0000-0002-7008-4073 Seoul National University Children's Hospital Department of Pediatrics View all articles by this author Han-Suk Kim 0000-0002-9777-3231 [email protected] Seoul National University Children's Hospital Department of Pediatrics View all articles by this author Ee- Kyung Kim Seoul National University Children's Hospital Department of Pediatrics View all articles by this author Ju Sun Heo Seoul National University Children's Hospital Department of Pediatrics View all articles by this author Seh Hyun Kim Seoul National University Children's Hospital Department of Pediatrics View all articles by this author Metrics & Citations Metrics Article Usage 169 views 117 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Gyeong Eun Yeom, Seung Han Shin, Han-Suk Kim, et al. 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