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Efficacy and safety of mydriatic microdrops for retinopathy of prematurity screening: an external pilot crossover randomized controlled trial

Abstract

Objective

To study the efficacy and safety of mydriatic microdrops compared with standard drops for retinopathy of prematurity (ROP) screening.

Study design

Preterm infants undergoing ROP screening received microdrops and standard drops of phenylephrine 1.67% and tropicamide 0.33% in a random allocation sequence at two consecutive weekly examinations. Primary outcome was pupil diameter measured by two masked observers at 45 (T45) and 90 (T90) minutes after instillation.

Results

Twenty-five infants were randomized. No differences observed in mean pupil diameter after either administration technique at all time points (T45 Mean Difference: −0.14; 95% Confidence Interval: −0.38, 0.09; p = 0.23). Heart rate values at T120 were lower after microdrop instillation (p = 0.046). Otherwise, adverse events did not differ after either administration technique.

Conclusion

This pilot study provides evidence of microdrops mydriasis efficacy, while justifying a full-scale trial to confirm their non-inferiority compared with standard drops and provide more data about safety.

Trial registration

ClinicalTrials.gov: NCT04623684.

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Fig. 1: The microdrop instillation device and the ruler that were used in the present pilot study.
Fig. 2

References

  1. 1.

    Hellström A, Smith LE, Dammann O. Retinopathy of prematurity. Lancet. 2013;382:1445–57.

    Article  Google Scholar 

  2. 2.

    Kremer LJ, Reith DM, Medlicott N, Broadbent R. Systematic review of mydriatics used for screening of retinopathy in premature infants. BMJ Paediatr Open. 2019;3:e000448.

    Article  Google Scholar 

  3. 3.

    Shell JW. Pharmacokinetics of topically applied ophthalmic drugs. Surv Ophthalmol. 1982;26:207–18.

    CAS  Article  Google Scholar 

  4. 4.

    Frangie JP. Clinical pharmacokinetics of various topical ophthalmic delivery systems. Clin Pharmacokinet. 1995;29:130–8.

    CAS  Article  Google Scholar 

  5. 5.

    Xue K, Hildebrand GD. Deep periocular infantile capillary hemangiomas responding to topical application of timolol maleate, 0.5%, drops. JAMA Ophthalmol. 2013;131:1246–8.

    Article  Google Scholar 

  6. 6.

    Alcorn J, McNamara PJ. Pharmacokinetics in the newborn. Adv Drug Deliv Rev. 2003;55:667–86.

    CAS  Article  Google Scholar 

  7. 7.

    Seliniotaki AK, Prousali E, Lithoxopoulou M, Kokkali S, Ziakas N, Soubasi V, et al. Alternative mydriasis techniques for retinopathy of prematurity screening. Int Ophthalmol. 2020;40:3613–9.

    Article  Google Scholar 

  8. 8.

    Lynch MG, Brown RH, Goode SM, Schoenwald RD, Chien DS. Reduction of phenylephrine drop size in infants achieves equal dilation with decreased systemic absorption. Arch Ophthalmol. 1987;105:1364–5.

    CAS  Article  Google Scholar 

  9. 9.

    Wheatcroft S, Sharma A, McAllister J. Reduction in mydriatic drop size in premature infants. Br J Ophthalmol. 1993;77:364–5.

    CAS  Article  Google Scholar 

  10. 10.

    Elibol O, Alçelik T, Yüksel N, Caglar Y. The influence of drop size of cyclopentolate, phenylephrine and tropicamide on pupil dilatation and systemic side effects in infants. Acta Ophthalmol Scand. 1997;75:178–80.

    CAS  Article  Google Scholar 

  11. 11.

    Eldridge SM, Chan CL, Campbell MJ, Bond CM, Hopewell S, Thabane L, et al. CONSORT 2010 statement: extension to randomised pilot and feasibility trials. BMJ. 2016;355:i5239.

    Article  Google Scholar 

  12. 12.

    Dwan K, Li T, Altman DG, Elbourne D. CONSORT 2010 statement: extension to randomised crossover trials. BMJ. 2019;366:l4378.

    Article  Google Scholar 

  13. 13.

    Mataftsi A, Moutzouri S, Karagianni P, Ziakas N, Soubasi V, Brazitikos P, et al. Retinopathy of prematurity occurrence and evaluation of screening policy in a large tertiary Greek cohort. Int Ophthalmol. 2020;40:385–91.

    Article  Google Scholar 

  14. 14.

    Dionne JM, Abitbol CL, Flynn JT. Hypertension in infancy: diagnosis, management and outcome. Pediatr Nephrol. 2012;27:17–32.

    Article  Google Scholar 

  15. 15.

    Flynn JT. Neonatal hypertension: diagnosis and management. Pediatr Nephrol. 2000;14:332–41.

    CAS  Article  Google Scholar 

  16. 16.

    Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg. 1978;187:1–7.

    CAS  Article  Google Scholar 

  17. 17.

    Whitehead AL, Julious SA, Cooper CL, Campbell MJ. Estimating the sample size for a pilot randomised trial to minimise the overall trial sample size for the external pilot and main trial for a continuous outcome variable. Stat Methods Med Res. 2016;25:1057–73.

    Article  Google Scholar 

  18. 18.

    Bland JM, Altman DG. Measuring agreement in method comparison studies. Stat Methods Med Res. 1999;8:135–60.

    CAS  Article  Google Scholar 

  19. 19.

    Kremer LJ, Broadbent R, Medlicott N, Sime MJ, McCaffrey F, Reith DM. Randomised controlled pilot trial comparing low dose and very low- dose microdrop administration of phenylephrine and cyclopentolate for retinopathy of prematurity eye examinations in neonates. Arch Dis Child. 2021;106:603–8.

    Article  Google Scholar 

  20. 20.

    Mishima S, Gasset A, Klyce SD Jr, Baum JL. Determination of tear volume and tear flow. Invest Ophthalmol. 1966;5:264–76.

    CAS  PubMed  Google Scholar 

  21. 21.

    Walker J. Non-inferiority statistics and equivalence studies. BJA Educ. 2019;19:267–71.

    CAS  Article  Google Scholar 

  22. 22.

    Büyükcam A, Celik HT, Korkmaz A, Yurdakök M. Myoclonic seizure due to cyclopentolate eye drop in a preterm infant. Turk J Pediatr. 2012;54:419–20.

    PubMed  Google Scholar 

  23. 23.

    Poets CF. Apnea of prematurity: What can observational studies tell us about pathophysiology? Sleep Med. 2010;11:701–7.

    Article  Google Scholar 

  24. 24.

    Van Santvliet L, Ludwig A. Determinants of eye drop size. Surv Ophthalmol. 2004;49:197–213.

    Article  Google Scholar 

  25. 25.

    German EJ, Hurst MA, Wood D. Reliability of drop size from multi-dose eye drop bottles: is it cause for concern? Eye. 1999;13:93–100.

    Article  Google Scholar 

  26. 26.

    Craig EW, Griffiths PG. Effect on mydriasis of modifying the volume of phenylephrine drops. Br J Ophthalmol. 1991;75:222–3.

    CAS  Article  Google Scholar 

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Authors

Contributions

AKS, ML, EG, ABH, and AM contributed to the conception and design of the study. AKS was involved in the assignment of interventions. ML and AM were involved in the recruitment and screening of trial participants and data collection. AKS, PT, ABH, and AM performed data analysis. All authors (AKS, ML, PT, EG, ED, NZ, ABH, and AM) contributed to the interpretation of the data. AKS, PT and AM prepared the initial draft manuscript. All authors (AKS, ML, PT, EG, ED, NZ, ABH, and AM) were involved in the revision and edit of the manuscript. All authors (AKS, ML, PT, EG, ED, NZ, ABH, and AM) approved the final version to be published and are responsible for accuracy and integrity of all aspects of research.

Corresponding author

Correspondence to Asimina Mataftsi.

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Seliniotaki, A.K., Lithoxopoulou, M., Talimtzi, P. et al. Efficacy and safety of mydriatic microdrops for retinopathy of prematurity screening: an external pilot crossover randomized controlled trial. J Perinatol (2021). https://doi.org/10.1038/s41372-021-01229-w

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