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1From the University of Calabar Teaching Hospital, Calabar, Nigeria; and the 2International Centre for Eye Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.
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METHODS. Two hundred thirty-three children aged 4 to 15 years attending outpatient eye clinics in Nigeria were randomized to (1) 1% cyclopentolate, (2) 1% cyclopentolate and 0.5% tropicamide, or (3) 1% atropine drops in each eye (instilled at home over 3 days). Ten children were lost to follow-up, nine from the atropine group. An optometrist measured the residual accommodation (primary outcome), dilated pupil size, pupil response to light, and self-reported side effects (secondary outcomes). Caregivers were interviewed about costs incurred due to cycloplegia (primary outcome). The incremental cost effectiveness ratios (ICERs) were calculated as the difference in cost divided by the difference in effectiveness comparing two agents. The 95% confidence intervals (CI) for ICERs were estimated through bootstrapping.
RESULTS. The atropine group had significantly lower mean residual accommodation (0.04 ± 0.01 D [SE]), than the combined regimen (0.36 ± 0.05 D) and cyclopentolate (0.63 ± 0.06 D) groups (P < 0.001). Atropine and the combined regimen produced better results for negative response to light and dilated pupil size than cyclopentolate. Atropine was more expensive, but also more effective, than the other agents. The ICER comparing atropine to the combined regimen was 1.81 (95% CI = –6.31–15.35) and compared to cyclopentolate was 0.59 (95% CI = –3.47–5.47). The combined regimen was both more effective and less expensive than cyclopentolate alone.
CONCLUSIONS. A combination of cyclopentolate and tropicamide should become the recommended agent for routine cycloplegic refraction in African children. The combined regimen was more effective than cyclopentolate, but not more expensive, and was preferable to atropine, since it incurred fewer losses to follow-up.
6/12 in the better eye) ranged from 1.2% in South African children aged 5 to 15 years,2 up to 10.1% in Malaysian children aged 7 to 15 years.3 Uncorrected significant refractive error was the main cause of visual impairment in all RESC settings, and provision of correct spectacles would have reduced considerably the prevalence of visual impairment, for instance, to only 0.3% in South African and 1.4% in Malaysian children.2 3 These data show that uncorrected significant refractive error in children is a substantial, yet avoidable, problem that could have adverse effects on academic performance and professional development in later life. The provision of spectacles to children with uncorrected refractive error has therefore been made a priority of VISION 2020: The Right to Sight, the global initiative of the World Health Organization (WHO) and the International Agency for Prevention of Blindness, for the elimination of avoidable blindness by the year 2020.4 Cycloplegic refraction is needed to measure refractive error accurately in children, as it inhibits accommodation during refraction and thereby prevents the overestimation of myopia and the underestimation of hyperopia.5 Atropine, cyclopentolate, and tropicamide are the most commonly used cycloplegic agents.6 7 Atropine produces the greatest amount of cycloplegia, making it the gold standard, but it has logistic drawbacks, as it can produce severe side effects, requires prolonged recovery, and necessitates the examination of the child a few days after administration.6 7 In contrast, cyclopentolate and tropicamide have a relatively short duration of action and so are used widely in clinical practice, and cycloplegic refraction with cyclopentolate eye drops was used in all RESC studies.1 6 There is concern, however, that cyclopentolate and tropicamide on their own are less effective cycloplegic agents in children with dark irides than in those with light irides8 9 and could lead to underestimation of the prevalence and severity of hyperopia in African and Asian populations.10 As an example, the RESC in South African children reported that approximately half of the children whose eyes were dilated with cyclopentolate had inadequate cycloplegia,2 and inadequate cycloplegia was also reported in the RESC in Malaysia and in India.3 11 Tropicamide 1% on its own is not a suitable alternative cycloplegic agent in an African setting as it is less effective than cyclopentolate in inhibiting accommodation,12 and its effectiveness seems to vary with ethnicity.13 Another drawback of tropicamide is that its maximum cycloplegic effect lasts less than 1 hour, making it impractical for use in a busy African outpatient clinic.6 Tropicamide in combination with cyclopentolate may increase cycloplegia in children with dark irides, while remaining fast acting, and this may provide the best alternative to atropine.14 15
The purpose of this study was to compare the cost and effectiveness of three cycloplegic drug regimens (atropine, cyclopentolate, and a combination of cyclopentolate and tropicamide) in a randomized controlled trial in Nigerian children aged 4 to 15 years.
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Ethical Considerations
Ethics approval was granted by the ethics committees of the University of Calabar Teaching Hospital, Nigeria, and of the London School of Hygiene and Tropical Medicine. The study was explained to the children and their parents. Written consent was obtained from all parents and verbal assent from all children who agreed to participate. All data were kept confidential throughout the study. The research adhered to the tenets of the Declaration of Helsinki.
Interventions
There were three treatment arms in the trial:
Objectives
The objectives of this study were:
Outcomes
Costs.
The parents or guardians of eligible children who had agreed to participate were interviewed by trained hospital personnel. They were asked about their out-of-pocket expenses, both direct and productivity costs, incurred as a result of the cycloplegic refraction. Direct costs are those that arose directly from delivering the intervention, including travel costs and any other costs such as accommodation and food directly attributable to the cycloplegic refraction. Productivity costs, refer to changes in productivity on account of the intervention, including (as applicable) the carer’s wages lost because the carer had to accompany the child to the clinic, the children’s wages lost, or the children’s school fees lost because the child was at the clinic for the cycloplegic refraction. The parents/guardians were also questioned about their sociodemographic status and their child’s ocular and general medical history.
Ophthalmic Examination before Cycloplegia.
VA of the children was tested by an ophthalmic assistant using a logMAR E-chart at 4 m illuminated with two fluorescent strip bulbs. VA results were converted and reported in 6-m equivalents. The anterior segment was examined by an optometrist and an ophthalmologist using a pen torch and a slit lamp (Haag Streit, Wedel, Germany), and ocular motility was measured by assessing the corneal reflex and neutralization with prisms.
The children were refracted in a dark room by an optometrist (AE) using a streak retinoscope (Keeler, Windsor, UK) at a measuring distance of 66 cm, equivalent to 1.5 D fixating an object at 6 m. This was followed by subjective refraction and direct ophthalmoscopy of the posterior pole (Keeler). Refractive errors were described by using spherical equivalents for the right eye, since there was a high correlation between VA for the right and left eyes. A child was classified as myopic if the spherical equivalent was –0.5 D or worse and as hyperopic if the spherical equivalent was +1.0 D or worse. Children with a spherical equivalent between –0.5 D and +1.0 D were classified as emmetropic.
Ophthalmic Examination with Cycloplegia.
After cycloplegia, children had their pupil dilatation and response to light measured by two independent optometrists who were not aware of their colleague’s measurement. Pupil dilation was assessed by measuring the pupillary diameter with a ruler to the nearest millimeter and pupillary reaction to light was graded as "response to light" or "no response to light." For five children there was a 
1-mm difference in pupillary diameter between the optometrists and/or disagreement on pupillary reaction to light, and so an ophthalmologist repeated the examination. In all five cases, the ophthalmologist agreed with one of the optometrists’ assessments, and so the consensus measurement was recorded. Cycloplegic objective refraction was performed by distance retinoscopy by the same technique as was used for noncycloplegic refraction. Dynamic near retinoscopy was performed while children moved fixation from a distance object at 6 m to a near object at 40 cm. All retinoscopies were performed by the same optometrist (AE). The study ophthalmologist examined the anterior and posterior segment with a slit lamp and by direct ophthalmoscopy. After the examination, the children (or parents of young children) were asked by a trained optometrist or auxiliary nurse whether they had experienced any side effects from the agent. The children were classified as having side effects if they complained about pain, stinging, profuse tearing, or discomfort or if tearing was observed.
Primary and Secondary Outcomes.
The primary outcome measures were the mean residual accommodation and the mean total cost for each regimen. Residual accommodation was determined by subtracting the cycloplegic near retinoscopy results from the cycloplegic distance retinoscopy results.
Secondary outcome measures were (1) the proportion of children whose pupils were dilated to 6 mm (2) the proportion of children whose pupils did not contract when exposed to the light of a pen torch, and (3) the proportion of children who reported side effects from the agent.
Sample Size
A sample size of 78 children in each of the three intervention arms was necessary, to detect a difference of at least 0.25 D in residual accommodation between the interventions, with 80% power and a 5% confidence level and allowing for 10% loss to follow-up.
Randomization and Masking
Children were randomly assigned to one of the three intervention arms. The intervention group was concealed in numbered, opaque envelopes which were contained in a box. Each child selected one envelope and gave it to the nurse, who opened the envelope. If the child was assigned to the cyclopentolate or combined-regimen group, then the nurse administered the appropriate cycloplegic agent at that time. If the child was assigned to the atropine group, then the nurse gave verbal instructions in the native dialect to the parents on how to administer the atropine drops at home and gave the parents an instruction leaflet and application chart. The parents of the children in the atropine group were instructed to bring the child back to the dilation room on the third day with the used bottle of atropine. The nurse recorded the child’s name, identification number and type of drug on a form that was not available to the study optometrist. Children who had been given short-acting cycloplegic drugs were examined after 30 minutes and children given atropine were examined after 3 days. The masking of the optometrist was incomplete, because children in different treatment groups were examined at different time intervals.
Statistical Methods
All data were checked for consistency and completeness at the end of each day. Data were entered onto computers (EpiData; EpiData Association, Odense, Denmark) and verified against the paper copy. Range and consistency tests were performed before the data were analyzed (SPSS ver. 11.6; SPSS, Chicago, IL).
Statistical analysis was performed in only the right eye, because the results in the left and right eyes were similar. Continuous data were described using means and standard errors for normally distributed data, whereas medians, quartiles, and ranges were used for data that were not normally distributed. Categorical data were described using frequencies and percentages. Normally distributed continuous data were tested for significance using the Student’s t-test or the analysis of variance (ANOVA). The Wilcoxon rank sum test was used for continuous data that did not follow a normal distribution, and the Pearson’s 
2 test was used for categorical data.
Mean and median costs incurred as a result of the intervention were calculated for the three regimens. For children who had extremely high costs (i.e., in the 99th percentile), the costs of children’s school fees lost were truncated at £1 per day (three children) and transport costs were truncated at £4 (two children). The incremental costs and effectiveness of the three treatments were compared in a cost-effectiveness analysis.16 The mean difference in effectiveness (i.e., residual accommodation) and costs were calculated comparing two cycloplegic agents in turn. The incremental cost-effectiveness ratio (ICER) was calculated as the difference in cost between the two agents divided by the difference in effectiveness. This gives the additional cost per 1-D decrease in residual accommodation for one agent compared to another. It is assumed that the mean additional cost for a 1-D reduction in residual accommodation is twice the mean additional cost of a 0.5-D reduction. A sampling distribution of the incremental costs and effectiveness was estimated through nonparametric bootstrapping with 1000 replications, a simulation method for statistical inference.17 Each bootstrap sample was obtained by repeated random sampling with replacement from the original data points. A bootstrap ICER was calculated for each of the 1000 bootstrap replicates. The 95% CIs for the ICERs comparing two cycloplegic agents were calculated from the 2.5 and 97.5 percentile of the ICERs. The bootstrapped ICERs were graphically represented on a cost-effectiveness plane, which shows the relative costs and effectiveness of the two agents.18 All costs and benefits were measured at the present time and were not discounted (i.e., when we reduce the value given to future costs and future benefits in relation to how far in the future they are measured).
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Our results support those in other studies that show the superior effectiveness of atropine in suppressing accommodation in children with dark irides. In a study of 50 Japanese children, the average refractive error obtained by autorefractor was 0.7 D higher in children after instillation of atropine drops (0.5% or 1% twice daily over 7 days) compared with cyclopentolate 1% (instilled three times every 5 minutes).19 In 25 Chinese children with pigmented irides, atropine 1% (applied twice daily over 3 days) detected a higher degree of hyperopia (+5.7 D) compared with a combined regimen of cyclopentolate 1% and tropicamide 1% (+5.3 D).15 The main disadvantage of atropine; however, is that it requires examination of children a few days after administration, and this may have contributed to the high loss to follow-up experienced in the atropine group in our study. Atropine can also produce severe side-effects (mainly due to its anticholinergic action), although longer term side effects (e.g., ultraviolet light damage to the lens and the retina as a result of chronic pupillary dilatation from long-term use of atropine) are unlikely to occur if atropine is used only for diagnostic purposes.20 The inadequate cycloplegia attained by cyclopentolate shown by other studies2 8 9 is consistent with our findings, in which 15% of children had a residual accommodation of >1 D. Tropicamide may boost mydriasis in cyclopentolate in children with dark irides, and this may be the best alternative to atropine,14 as shown by the present study. No previous cost-effectiveness study has been conducted on these agents in a low-income setting to allow comparison of results.
Study Limitations
This study was too small to find statistically significant differences in ICERs or to assess differences in the effectiveness of the cycloplegic agents between age groups. The hospital costs were not recorded (except for the direct costs of the drugs), since the time spent with the child by the ophthalmologist and optometrist was assumed to be the same for all three intervention arms. Masking of the optometrist was incomplete, because the cyclopentolate and combined-regimen groups were examined 30 minutes after instillation of drops, whereas the atropine group was examined after 3 days. Side effects for cyclopentolate and the combined regimen were assessed on the same day as the instillation of drops, whereas the atropine group was questioned about side effects after 3 days, which may have contributed to the difference in reported side effects. The duration of side effects was also not assessed, although side effects tended to be mild and apparent mainly on instillation of drops.
Study Strengths
We used a randomized controlled trial to assess the effectiveness of the cycloplegic agents, a question that has not been answered previously for an African population. We used the trial as a framework for economic evaluation and this allowed us to collect and analyze patient-specific resource use data. The same optometrist performed all the refractions. This was an effectiveness study rather than an efficacy study, as we did not use expensive equipment so that our study results would reflect the real-world circumstances of the African hospital. The CONSORT (Consolidated Standards of Reporting Trials) guidelines were adhered to for the trial.21
Public Health Implications
Inadequate cycloplegia may result in overdiagnosis of myopia and underdiagnosis of hyperopia, and a distortion of the magnitude of refractive errors among African children. Accurate cycloplegia is therefore important, but until now no randomized controlled trials have been undertaken in African children to identify the most cost-effective cycloplegic agent. This study confirms that atropine is more effective than cyclopentolate or the combined regimen, although it is not ideal for use in routine clinical practice because of the high loss to follow-up, and the prolonged impaired near vision produced by atropine may also reduce participation in trials, cohort studies, and surveys. Cyclopentolate was less effective but not cheaper than the combined regimen of cyclopentolate and tropicamide and may yield unreliable data on examinations in children. This implies that the combination of cyclopentolate and tropicamide should become the recommended cycloplegic agent of choice for routine cycloplegic refraction and large-scale studies of refractive error in African children. Atropine may remain the agent of choice, however, when a very accurate refraction is needed, such as for children with esotropia. Relative costs and effectiveness of the three regimens may vary between populations, and therefore more studies are needed before assessing whether the results are generalizable to other populations, although this may be less of an issue on the African continent.
Summary
Atropine was the most effective cycloplegic agent, but had practical limitations due to its requirement for examination after 3 days of treatment and consequent high loss to follow-up. A combination of cyclopentolate and tropicamide was more effective than cyclopentolate alone, but not more expensive, and should become the recommended cycloplegic agent of choice for routine cycloplegic refraction in African children.
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Submitted for publication June 5, 2006; revised August 25, October 20, and November 9, 2006; accepted January 15, 2007.
Disclosure: A. Ebri, None; H. Kuper, None; S. Wedner, None
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 
1734 solely to indicate this fact.
Corresponding author: Hannah Kuper, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK; hannah.kuper{at}lshtm.ac.uk.
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