Efficacy and Safety of Mydriatic Microdrops for Retinopathy of Prematurity Screening: The MyMiROPS Randomized Clinical Trial.

Importance: Commercial mydriatics administered in preterm infants during retinopathy of prematurity (ROP) screening have been associated with various cardiorespiratory and gastrointestinal adverse events. Objective: To examine whether microdrops of a combined mixture of 1.67% phenylephrine and 0.33% tropicamide are noninferior to standard drops regarding mydriatic efficacy at 45, 90, and 120 minutes. The occurrence of systemic adverse events and systemic absorption of phenylephrine eyedrops were additional secondary outcomes. Design, Setting, and Participants: This randomized clinical trial with a double-masked, noninferiority, crossover design included infants undergoing ROP screening at a tertiary center in Northern Greece from September 2021 to January 2023. Eligible participants were infants with gestational age below 32 weeks and/or birthweight under 1501 g, or infants beyond these thresholds referred by an attending neonatologist due to comorbidities. Interventions: Either microdrops or standard drops of the diluted mixture were administered at a random allocation sequence with a 1-week washout period. Main outcomes and measures: The horizontal pupil diameter at 45, 90, and 120 minutes was measured using a customized ruler in 0.5-mm increments. Mixed-effects linear regression models were developed, and the confidence interval (CI) approach was used for assessing noninferiority. The predefined noninferiority margin was -0.4 mm. Heart rate; oxygen saturation; blood pressure measurements at 45, 90, and 120 minutes; 24-hour hypertensive episodes; and 48-hour systemic adverse events were assessed. Phenylephrine concentration in peripheral blood within 3 hours postinstillation was measured using hydrophilic liquid chromatography-tandem mass spectrometry. Pooled pharmacokinetic parameters were calculated based on a developed mathematical model. Results: A total of 83 infants were randomized (mean [SD] gestational age, 29.7 [2.0] weeks; mean [SD] birth weight, 1277 [374] g). Microdrops proved to be superior regarding mydriatic efficacy at 45 minutes (mean difference, 0.12; Bonferroni-corrected 95% CI, 0.01 to 0.23; P = .008) and noninferior at 90 minutes (Bonferroni-corrected 95% CI, -0.10 to 0.17) and 120 minutes (Bonferroni-corrected 95% CI, -0.18 to 0.14). Lower levels of oxygen saturation at 45 minutes (mean difference, 0.66; 95% CI, 0.09 to 1.24; P = .03) and 90 minutes (mean difference, 0.58; 95% CI, 0.03 to 1.14; P = .04) and higher percentage of 24-hour hypertensive episodes (median [IQR] percentage of hypertensive episodes: microdrops, 0.10% [0.02%-0.19%] vs standard drops, 0.14% [0.06%-0.40%]; P = .01) were observed after standard drops. A 1-compartment model with first-order absorption best described the pharmacokinetic data. Conclusion and Relevance: To our knowledge, this is the first study establishing noninferiority of microdrops compared with standard drops of a diluted mydriatic mixture, showing reduced systemic adverse events after microdrops and determining the pharmacokinetic profile of phenylephrine eyedrops in preterm infants. Trial Registration: ClinicalTrials.gov Identifier: NCT05043077.