Trials assessing dose - Neonatal Intensive Care Drug Manual

Trials assessing dose: Punyawattanaporn et al[3], in 70 preterm infants with each eye randomly allocated, reported the pupil size was larger after three drops of cyclopentolate 0.2% + phenylephrine 1.0% than after a single drop. However, a dilated pupil diameter ≥ 6 mm, adequate for the peripheral retina examination, was not obtained at 60 minutes in 21.4% of eyes after 1 drop and only 1.4% after 3 drops [LOE II]. Vincente et al [4], in 64 eye examinations performed on 15 enrolled infants, with the left eye randomly allocated to receive to receive either 0, 1 or 2 drops of cyclopentolate 0.2% and phenylephrine 1%, reported that effective mydriasis was achieved in the test eye with 1 or 2 drops and sustained to 120 minutes. Retinal examinations could be completed by 90 minutes in most infants with the use of 1 drop [LOE II].
Side effects
Isenberg et al [1] showed no clinically significant effect on systolic blood pressure or pulse rate [LOE III-2]. Chew et al [2], in 39 infants, reported a significant increase in mean blood pressure in infants allocated cyclopentolate 1% + phenylephrine 2.5% and the tropicamide 1% + phenylephrine 2.5% groups but not cyclopentolate 0.2% + phenylephrine 1%. They concluded the combination cyclopentolate 0.2% + phenylephrine 1% provided adequate pupillary dilation with the least systemic side effects [LOE II].
Mitchell et al [5], in infants given cyclopentolate 0.2% + phenylephrine 1% 3 drops at 0, 5 and 10 minutes, reported there was a significant association between cyclopentolate concentrations and gastric residuals in tube-fed infants not receiving oxygen (p = 0.01) [LOE IV].
There are several case reports of necrotising enterocolitis [6-8], seizures [9] and cyclopentolate toxicity [10] occurring after mydriatic instillation. Cyclopentolate toxicity occurred with cyclopentolate 1%, 1 drop x 6 instillations, and resolved with physostigmine infusion 0.02 mg/kg over 10 minutes.
Nefendorf et al[11] reported a cohort of 138 infants with 1246 eyes screened during 623 examinations using phenylephrine 2.5% + cyclopentolate 0.5% instilled 3 times, 5 minutes apart. Five infants of 623 (0.8%) having eye examinations had adverse events recorded in the 24-hour period after ROP screening [apnea and/or respiratory deterioration with 4 requiring ventilation]. One case of NEC occurred 1 week post-examination [LOE III-2]. Strube et al [12] reported in a controlled study that feeding infants 1 hour before compared with withholding feeding 2 or more hours before ROP examinations may reduce percentage crying during the examination, with no increased incidence of vomiting or gastric aspirates [LOE III-2].
Conclusion: Cyclopentolate 0.2% + phenylephrine 1% eye drops are an effective mydriatic with 1 to 3 drops producing adequate dilatation within 60 minutes sustained to 120 minutes. It is generally well-tolerated with minimal physiological effects reported at this dose. [LOE II GOR B]
Pharmacokinetics:
Mitchell et al[5], in infants given cyclopentolate 0.2% + phenylephrine 1% 3 drops at 0, 5 and 10 minutes, reported a cyclopentolate concentration range of 6–53 nanogram/mL in 15 of 18 infants, while phenylephrine was not detected. Concentrations of cyclopentolate were significantly higher in infants who were on oxygen (p = 0.01) [LOE IV]. Systemic absorption of the ophthalmic eye drops via conjunctival sac or nasolacrimal mucosa remains a potential cause of systemic effects of topical agents as the majority (up to 99%) of every drop is considered to be absorbed systemically. Several approaches have been advocated for reducing systemic absorption and the associated side effects. These include eyelid closure, digital occlusion of nasolacrimal duct for several minutes, wiping away excess drops during and after drug instillation and proper dilution or reduced volume of eye drops for use in children. [13]
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