Pulmonology · Medical Literature
Bronchodilator Responsiveness in Preterm-Born Children With Chronic Lung Disease: Importance of Individualized Testing.
Abstract
Children born preterm with chronic lung disease of Immaturity (CLDI) frequently present with obstructive lung function, yet optimal bronchodilator therapy remains uncertain. Previous studies focused on β2-agonists, while evidence for muscarinic antagonist therapy is limited. We conducted a prospectively planned cross-sectional study of preterm-born children (< 35 weeks) with CLDI and obstructive spirometry (FEV1 z-score < -1.64). Of 73 screened, 64 were enrolled, and 55 completed the protocol. Each attended three randomized crossover visits with salbutamol, ipratropium bromide, or fenoterol/ipratropium combination. Spirometry was performed before and after administration. Overall, 48 children demonstrated bronchodilator responsiveness to at least one agent. Response rates were 56.4% for salbutamol (95% CI 43-70), 58.2% for ipratropium (95% CI 45-71), and 65.5% for the combination (95% CI 53-78), with no significant differences (McNemar's test, p = 0.45). Exclusive responses were observed in 9.1% to salbutamol (95% CI 3.0-20.0), 5.5% to ipratropium (95% CI 1.1-15.1), and 9.1% to the combination (95% CI 3.0-20.0). Among children with reversibility, repeated-measures ANOVA showed no significant difference in the effect of drugs (F = 0.1, p = 0.9), phenotype (F = 2.46, p = 0.12), or their interaction (F = 1.1, p = 0.34). In our cohort, 87% of preterm-born children with CLDI exhibit reversible bronchial obstruction, with a substantial subset responding exclusively to a single bronchodilator. Due to the fact that single-drug testing may underestimate reversibility, individualized bronchodilator testing should be incorporated into care, and its long-term implications merit further study.
Clinical relevance
In school-aged children born preterm (<35 weeks) with chronic lung disease of immaturity (CLDI) and obstructive spirometry, do salbutamol, ipratropium bromide, and their combination differ in rates of bronchodilator responsiveness, and does response pattern vary by spirometric phenotype? __SNAPSHOT__ {"studyDesign":"Prospectively planned, randomized crossover, cross-sectional study","setting":"Charles University, Prague, Czech Republic; single-institution","sampleSize":"n=64 enrolled; n=55 completed the full protocol (73 screened)","population":"School-aged children born preterm (<35 weeks gestational age) with chronic lung disease of immaturity (CLDI) and obstructive spirometry defined as FEV1 z-score < −1.64; mean age 12.6 years; 34 male","intervention":"Each participant received three inhaled bronchodilators in randomized sequence across three separate visits: (1) salbutamol 4 × 100 µg, (2) ipratropium bromide 4 × 20 µg, and (3) fenoterol/ipratropium combination 4 × 50 µg/20 µg, all administered via metered-dose inhaler with spacer","comparator":"Within-subject crossover comparison of three active bronchodilator agents; no placebo arm","primaryOutcome":"Bronchodilator responsiveness (BDR), defined as an increase in FEV1 greater than 10% of the child's predicted value following each agent; exclusive response to a single agent was also assessed","followUp":"Three crossover visit structure; duration between visits not reported","fundingSource":"Not reported"}
Key findings
Of 55 children who completed the protocol, 48 (87%) demonstrated a positive bronchodilator response to at least one agent. Response rates were 56.4% for salbutamol (95% CI 43–70%), 58.2% for ipratropium bromide (95% CI 45–71%), and 65.5% for the fenoterol/ipratropium combination (95% CI 53–78%), with no statistically significant difference among agents (McNemar's test, p = 0.45). Approximately one in four children responded to only a single agent: exclusive response rates were 9.1% for salbutamol alone (95% CI 3.0–20.0%), 5.5% for ipratropium alone (95% CI 1.1–15.1%), and 9.1% for the combination alone (95% CI 3.0–20.0%). Subgroup analysis by spirometric phenotype revealed that ipratropium bromide response was significantly more frequent in children with the prematurity-associated obstructive phenotype compared to those with the prematurity-associated preserved-ratio impaired spirometry (PRISm) phenotype (67.4% vs. 25.0%; p = 0.008). Salbutamol and combination response rates did not differ significantly across phenotypes. Children with the PRISm phenotype tended to favor the combination, though this trend was not statistically significant. NNT and NNH were not reported and cannot be calculated from available data. No clinically important adverse events were reported in the abstract.
Practice implications
This study establishes that the large majority (87%) of school-aged children with CLDI and confirmed obstructive spirometry demonstrate reversible airway obstruction to at least one inhaled bronchodilator, supporting the biological plausibility of bronchodilator therapy in this population. Crucially, the study did not establish superiority of any single agent: no significant difference was found between salbutamol, ipratropium, or their combination at the group level. However, the finding that approximately 23.7% of responders (9.1% + 5.5% + 9.1% exclusive rates, acknowledging overlap is not fully reported) responded exclusively to one agent reinforces that a universal, uniform bronchodilator approach would miss a clinically meaningful subset of patients. The differential response of ipratropium across spirometric phenotypes (obstructive vs. PRISm) suggests that phenotype-guided agent selection may be warranted, although this is a subgroup finding and should be interpreted cautiously. The findings apply to school-aged children (mean age 12.6 years) born before 35 weeks with confirmed obstructive spirometry; they do not apply to preterm children with normal spirometry, those with the PRISm phenotype exclusively, infants, adolescents, or adults. Longer-term clinical outcomes (symptom burden, exacerbation rate, quality of life, lung function trajectory) were not assessed. This summary is based on the published abstract only; full-text review is required before implementation in clinical protocols. __LIMITATIONS__ Abstract-only review: full methods, covariate adjustment, and complete results tables are unavailable for critical appraisal.,Small sample size (n=55 completers) limits statistical power, especially for subgroup analyses by phenotype; confidence intervals for exclusive response rates are wide (e.g., 3.0–20.0%), reflecting substantial imprecision.,No placebo arm: observed improvements in FEV1 may include a component of regression to the mean or effort-related variability.,Cross-sectional design precludes assessment of long-term treatment benefit, sustained reversibility, or clinical outcomes such as exacerbation frequency or quality of life.,Spirometry-only assessment: absence of impulse oscillometry (a sensitive method for small airway function) may underestimate the full scope of bronchodilator response in peripheral airways.,Single-center study (Prague, Czech Republic) limits geographic and ethnic generalizability.,Participants were restricted to children with FEV1 z-score < −1.64 (obstructive pattern); findings are not applicable to preterm children with normal or non-obstructive lung function.,Funding source not reported, precluding assessment of potential industry influence.,Duration between crossover visits and washout procedures not fully described in the abstract, raising the possibility of carryover effects. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ In school-aged children born preterm with CLDI and obstructive spirometry, 87% responded to at least one bronchodilator, but no single agent was superior, and approximately one in four responders reacted exclusively to a single drug—underscoring the inadequacy of a one-size-fits-all approach. Ipratropium bromide showed a significantly higher response rate in children with the classical obstructive phenotype compared to PRISm, supporting phenotype-stratified testing. Individualized bronchodilator responsiveness testing across agent classes appears warranted in this population, though confirmation in larger, multi-center studies with clinical outcome measures is needed before formal practice change.