Comparison of microdrop administration using a bottle adapter of 2.5% phenylephrine and 0.8% tropicamide with standard drop for ROP examination: a randomized controlled noninferiority trial

BACKGROUND: Pharmacologic mydriasis is essential for retinopathy of prematurity (ROP) screening; however, conventional ophthalmic drops substantially exceed neonatal conjunctival sac volume, leading to systemic absorption and potential adverse effects. Microdrop administration may reduce drug exposure while preserving adequate pupillary dilation. This study aimed to determine whether microdrop administration of phenylephrine and tropicamide is noninferior to standard drops in achieving adequate mydriasis for ROP screening via a bottle adapter. METHODS: This single-center, randomized, parallel-group noninferiority trial was conducted in a tertiary neonatal unit in Chennai, India. Preterm infants undergoing routine ROP screening were randomized to receive either microdrops (10.26 µL) or standard drops (26.58 µL) of 2.5% phenylephrine and 0.8% tropicamide. Three doses were administered at 10-minute intervals. The primary outcome was the mean pupil diameter at 45 min after the first instillation. The secondary outcomes included physiological parameters (heart rate, oxygen saturation, and blood pressure), systemic and local adverse events, and the adequacy of ROP examination. A noninferiority margin of - 0.5 mm was prespecified. RESULTS: Among the 127 infants assessed for eligibility, 102 were randomized (microdrop group, n = 52; standard group, n = 50), and all completed the study. Baseline characteristics were comparable between the groups. At 45 min, mean pupil diameter was 6.54 ± 0.52 mm in the microdrop group and 6.38 ± 0.63 mm in the standard-drop group (mean difference, 0.16 mm; 95% CI, - 0.07 to 0.38 mm; p for noninferiority < 0.001). As the lower bound of the 95% CI (- 0.07 mm) was above the prespecified noninferiority margin of - 0.5 mm, noninferiority was established. Physiological parameters, including heart rate, oxygen saturation, and blood pressure, remained stable and comparable between the groups. Systemic adverse events were rare and similar across groups, and no local ocular complications were observed. ROP examination was successfully completed in all infants. CONCLUSION: Microdrop administration of phenylephrine and tropicamide achieved mydriasis comparable to standard drops, with no significant difference in adverse effects between the groups. This approach may represent a safer, clinically feasible and more physiologically appropriate strategy for ROP screening by reducing drug exposure in vulnerable preterm infants. TRIAL REGISTRATION: The study protocol was approved by the Institutional Ethics Committee of Madras Medical College, Chennai (IEC No. MMC/Approval/12052025). The trial was registered with the Clinical Trials Registry of India (CTRI/REF/2025/03/101681)on 10-03-2025.