The Effect of Eyemasks on Neonatal Stress Following Dilated Retinal Examination, a Randomized Clinical Trial
Phase: NA
Conditions: Retinopathy of Prematurity, Pain, Premature Infant, Retinal Disease
Sponsor: Sunnybrook Health Sciences Centre

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The Effect of Eyemasks on Neonatal Stress Following Dilated Retinal Examination, a 
Randomised Clinical Trial    
(MASK-ROP)  
Research Protocol and Statistical Analysis Plan 
Andrei-Alexandru Szigiato MD1; Matthew Speckert MD1; Jeanne Zielonka2; Kathleen 
Hollamby2; Filiberto Altomare MD FRCSC3; Eugene Ng MD FRCPC4; Michael Sgro MD 
FRCPC2 
 
1U of T Faculty of Medicine, Toronto, Canada.  
2Department of Pediatrics, St Michael’s Hospital, Toronto, Ontario, Canada  
3Department of Ophthalmology and Vision Sciences, University of Toronto, Ontario, Canada 
4Department of Neonatology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada 
 
Date: Jan 23, 2019 
NCT Number: NA 
 
 
 

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Introduction 
Retinopathy of Prematurity (ROP) is a disorder of retinal vascular development of the low 
birthweight preterm infant that may lead to blindness if untreated (1). The long term visual acuity 
of infants with ROP detected by screening examination can be improved by peripheral retinal 
ablation therapy or injection of anti-VEGF agents (2,3). 
The screening examination for retinopathy of prematurity involves dilation with mydriatic eye 
drops, insertion of a lid speculum to retract the eyelids, and depression of the sclera to visualize 
the retina. These exams are routinely performed in Neonatal Intensive Care Units (NICUs) to 
facilitate early detection of ROP and guide treatment to prevent retinal detachment and blindness 
(3). However, infants undergoing this examination have shown elevations in heart rate, blood 
pressure, and desaturations at the time of the examination, and in the hours following (4). The 
frequency of apneic events experienced by these infants is increased in the 24-48 hour period 
after an examination (5). 
Several studies have looked at the pain response to mydriatic drops and speculum insertion 
(6,7,8) as well as the systemic effects of the mydriatic drops. However, the cause of apneic 
events in the later post-examination period is unknown (5). We postulate that photosenstivity 
related to mydriasis is distressing for infants in the period before and after the ROP exam, 
potentially contributing to stressful events, including apnea(9).  
We propose to test this hypothesis by applying a mask to cover the eyes of the infant after the 
instillation of mydriatic drops, leaving the mask on for 4 hours, the typical duration of mydriasis 
following a drop of cyclopentolate (10). We expect that this intervention will result in a 
significant reduction in the number of stressful events following an examination, and may reduce 
the amount of distress experienced by infants.(9) 
Methods 
A dual-centre, prospective parallel group trial with balanced randomization (1:1) will be 
conducted. Infants requiring ROP screening will be automatically identified as part of routine 
hospital protocols. Participants will be recruited from the NICUs at St. Michael’s Hospital and 

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Sunnybrook Health Sciences Hospital in Toronto, Ontario, Canada. Parents or caregivers of 
eligible infants will be approached and consented for participation in this study.  
Inclusion criteria: Infant with birthweight of ≤1500 g or less or a gestational age of ≤ 32 weeks 
with no prior ROP screening. Examinations will be performed starting at either 4 weeks 
chronological age or 31 weeks post menstrual age, whichever is later. 
Exclusion criteria: Pre-existing corneal abrasion/ulcers, ocular malformations that prevent 
dilation, and known neurological abnormalities that could affect response to pain. Not 
anticipating transfer to another institution were approached for participation. No prior ROP 
screening 
A computer generated block randomization schedule will be made by the primary investigators, 
with a block size of 50 for each site (https://www.randomizer.org/). Assistants enrolling infants 
will be blinded to the randomization schedule and infants placed in the schedule in chronological 
order by date that consent was obtained. 
Protocol for Eye Examination: 
Cyclopentolate 0.5% and Phenylephrine 2.5% drops are to be instilled in both eyes to achieve 
mydriasis. After approximately 30 minutes, topical anaesthetic drops are instilled and a 
Barraquer wire speculum is used to retract the eyelids. Sucrose is given to soothe the infant prior 
and during examination. Indirect ophthalmoscopy with scleral depression is then performed to 
visualize the retina.  
Infants in the treatment arm will have a standard phototherapy mask (Biliband, Natus, 
Pleasanton, California, USA) applied over the eyes after instillation of mydriatic drops. The 
masks will be removed 4 hours after the eye examination, when the pharmacologic effect of the 
mydriatic agents would have subsided. The mask will be removed for the examination but 
reapplied promptly afterward. Infants in the control arm received standard examinations with no 
masking.  
Neonates are continuously monitored in both NICUs according to the standard of care. Apneic 
events, desaturation and bradycardic events are recorded based on nursing observation of 
monitor alarms and clinical status of the infant at the time of the event. An apneic episode is 

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defined as a cessation of respiratory effort >20 seconds, or less if accompanied by bradycardia, 
cyanosis or pallor. Low heart rate alarms were set at <100bpm; low pulse oximetry alarms were 
at <88%. Heart rate, blood pressure, oxygen saturation and distressful/apneic events were 
recorded hourly and retrospectively assessed for up to 48 hours after the instillation of eye drops. 
Both NICUs employ variable lighting schemes, with lights turned down after ROP screening 
according to standard protocol. 
Outcomes 
The primary outcome will be the total count of desaturations, bradycardic events, and apneic 
events (all “stressful events”) occurring 12 hours after examination in the treatment group 
compared to control, adjusted by the baseline rate of stressful events 12 hours before 
examination. Desaturations are defined as episodes when oxygen saturation falls below 88%, 
measured by pulse oximetry. Bradycardia is defined as a heart rate less than 100 beats per 
minute. Apneic events are defined as a pause in breathing for at least 20 seconds.  
Secondary outcomes include  
1. A sub-analysis of the effect of masking on reducing either desaturations, bradycardic events or 
apneic events.   
2. Monitoring changes in heart rate, respiratory rate, and oxygen saturation in the 4 hours period 
after examination in both groups.  
3. An exploratory analysis of baseline variables affecting the number of spells 12 hours after 
examination, including birth weight, age at examination, gestational age, ventilation needed 
during examination, ROP stage, medical co-morbidities, and medications. 
Data Collection 
Data will be entered into each patient’s medical record as per standard of care by NICU nursing 
staff. All data collection and chart review will be done at each respective NICU >48 hours after 
ROP screening was performed, with data collectors blinded to treatment group.   
Sample Size 

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Mitchell et al. (5) showed an incidence of apnea of 9/23 (23%) in the first 24 hours after eye 
examination. Scenarios to compare the incidence between masked and control groups, given 
80% power and alpha of 0.05 predicted a need of n=169 to detect a 50% reduction in apnea. As 
our primary outcome was all stressful events, which occur more frequently than apnea, an 
analysis of outcomes at n=50 was planned as this initial pilot study.  
Statistical Analysis 
Descriptive statistics will be used to characterize patients at baseline and over time. We 
anticipate a low number of stressful events in each group as our primary outcome. Therefore, we 
plan to compare groups using a negative binomial regression model, adjusting for the total 
number of stressful events during the 12 hours pre-examination. Secondary analyses using 
negative binomial regression models will also be performed to assess differences between groups 
in desaturations and bradycardic events, and to examine the additional effect of baseline 
variables (i.e., including birth weight, age at examination, gestational age, ventilation needed 
during examination, ROP stage, medical co-morbidities, and medications) on the primary 
outcome, adjusting for total number of stressful events during the 12 hours pre-examination.  
Linear mixed models for repeated measures will be performed for heart rate and respiratory rate, 
including time, group and the interaction of time by group, and assuming compound symmetry 
covariance structure. Apneic events will be compared between the groups with a Fisher’s exact 
test.   
Non-parametric Wilcoxon rank sum test will be used to measure changes in Oxygen saturation at 
different time points. All statistical analyses will be conducted using SAS (version 9.4, Cary, 
NC, USA).  
Predicted Results and Potential Impact of Research 
We predict that infants that have had their eyes shielded from environmental light while dilated 
are less likely to experience distressful events in the 12 hour period following ROP screening. If 
this study shows decreased rates of distress using this therapy, it would be a very simple addition 
to current practice and be of benefit for premature infants undergoing an uncomfortable exam.  
 
 

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