Jpn J Ophthalmol 2007;51:111–115 DOI 10.

1007/s10384-006-0400-7
© Japanese Ophthalmological Society 2007

CLINICAL INVESTIGATION

Cycloplegic Effect of 0.5%Tropicamide and

0.5%Phenylephrine Mixed Eye Drops: Objective
Assessment in Japanese Schoolchildren with Myopia
Ichiro Hamasaki, Satoshi Hasebe, Shuhei Kimura, Manabu Miyata,
and Hiroshi Ohtsuki

Department of Ophthalmology, Okayama University, Graduate School of Medicine, Dentistry,

and Pharmaceutical Sciences, Okayama, Japan

Abstract
Purpose: To evaluate the cycloplegic effect of mixed eye drops containing 0.5% tropicamide and 0.5%
phenylephrine in myopic children, and to determine whether their efficacy was associated with their
clinical characteristics.
Methods: Eighty-one myopic children (age, mean ± SD, 11.0 ± 1.5 years; mean spherical equivalent
refractive error, −4.27 ± 1.41 D; range, −1.57 to −8.66 D) were recruited. One drop of Mydrin-P was
administered to each eye twice, with an interval of 5 min between. Twenty-five minutes after the second
drop, accommodative responses were measured with an open-view autorefractometer, while the subject
was encouraged to accommodate by binocularly looking at a Maltese cross located at a distance of 33 cm.
The difference between the refractive reading and that obtained with a Maltese cross at 500 cm was
regarded as residual accommodation (RA). The repeatability of this measurement was also evaluated.
Results: The mean RA was 0.21 ± 0.29 D (range, −0.31 to 0.99 D). There was no association in RA
between the right and left eyes, between RA and age, or between RA and sex, but RA was weakly cor-
related with refractive error (r = 0.274, P = 0.019). The intersubject difference found in RA can be
explained mostly by the extent of repeatability (±0.71 D).
Conclusion: The insignificant magnitude of RA indicated that the mixed eye drop is an acceptable
and useful cycloplegic agent in Japanese schoolchildren with a wide range of myopic refractive
errors. Jpn J Ophthalmol 2007;51:111–115 © Japanese Ophthalmological Society 2007
Key Words: autorefractometer, cyclopegic effect, residual accommodation, myopia, children

Introduction periods of time to obtain maximum cycloplegia and for

Cycloplegia improves the test–retest repeatability of
the refractive measurement of eyes and thus has been
recommended for use in longitudinal and cross-sectional
investigations of refractive error.1 Tropicamide, cyclopen-
tolate hydrochloride, and atropine sulfate are widely used
as cycloplegic agents. Among them, tropicamide is most
convenient to use in clinics, because it requires shorter
Received: July 25, 2006 / Accepted: October 16, 2006
Correspondence and reprint requests to: Satoshi Hasebe, Depart-
ment of Ophthalmology, Okayama University, Graduate School of
Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho,
Okayama 700-8558, Japan
e-mail: shasebe@md.okayama-u.ac.jp
recovery from cycloplegia, and rarely induces systemic side
effects.2–4
However, early studies5,6 indicated that the cycloplegic
effect of tropicamide was much less than that of cyclopen-
tolate or atropine and was thus insufficient for refractive
measurement, especially in children. This conclusion was
drawn on the basis of subjective measurement of residual
accommodation (RA), that is, by the push-up method, after
application of cycloplegic agents, but there are many con-
founding factors that influence the results of this subjective
test. As a result, RA determined subjectively was reported
to be surprisingly larger than that determined objectively.6
Several researchers objectively measured the RA and
found that the difference in cycloplegic effect between trop-
112
icamide and cyclopentolate is much smaller than previously
suggested.7–9 Using an autorefractometer, Manny et al.10
reevaluated the cycloplegic effect of 1% tropicamide in 469
children enrolled in the Correction of Myopia Evaluation
Trial (COMET) and then concluded that 1% tropicamide
is an effective cycloplegic agent in myopic children. In
accordance with these findings, tropicamide has been used
more widely as a cycloplegic agent in longitudinal and cross-
sectional investigations of myopia.11–15
In Japan, 1% tropicamide is not commercially available.
Furthermore, COMET recruited ethnically diverse chil-
dren. If the effect of tropicamide differs among races or
iris colors,5,8 the reported cycloplegic effect might not be
obtained in Japanese children. In the present study, using
experimental conditions similar to those described by
Manny et al.,10 we objectively measured the cycloplegic
effect of mixed eye drops containing 0.5% tropicamide and
0.5% phenylephrine (Mydrin-P, Santen, Osaka, Japan),
that is, a commercially available substitute for 1% tropi-
camide, in Japanese schoolchildren with myopia and then
determined whether its efficacy was associated with age,
sex, or refractive errors.
Subjects and Methods
Subjects
We recruited 81 subjects from the 95 children enrolled in
the Myopia Control Trial with Progressive Addition Lenses
in Japanese Schoolchildren13 study [average age ± SD, 11.0
± 1.5 years; range, 7–14 years; boys, 43 (53%); mean spher-
ical equivalent of refractive errors, −4.27 ± 1.41 diopters (D)
(range, −1.50 to −8.19 D) in the right eye, and −4.37 ± 1.43 D
(range, −1.57 to −8.66 D) in the left eye]. All children met
the following criteria: best-corrected visual acuity equal to
or better than 20/20 in both eyes; astigmatism ≤ 1.50 D;
anisometria ≤ 1.50 D; no manifest strabismus; and no eye
disease except for refractive errors.
In accord with the Helsinki declaration, after an explana-
tion about the aim and procedure of this study, written
consent was obtained from both the children and their
guardians. This study received the approval of the ethics
panel of Okayama University Medical School (21 May
2002).
Procedures
In this study, similarly to the method described by Manny
et al.,10 RA was calculated from distance and near cyclople-
gic autorefraction to examine the depth of cycloplegia.
First, a drop of Midrin-P was administered to both eyes.
Subjects were requested to close their eyes for 30 s after the
instillation. A second eye drop was administered 5 min after
the initial instillation. Twenty-five minutes after the second
eye drop, cycloplegic refraction was measured with an infra-
red autorefractometer (ARK-2000; Nidek, Gamagori,
Jpn J Ophthalmol
Vol 51: 111–115, 2007
Japan). Four of the 81 (5%) children were excluded from
the following analysis because administration of the eye
drops was considered to be imperfect owing to exaggerated
winking or lacrimation.
Second, the refractive errors of both eyes were fully cor-
rected with spectacle lenses, the dioptric powers of which
were determined by the above-mentioned method, in a trial
frame. Refractive readings of the eyes were obtained
through the spectacle lenses with an open-view autorefrac-
tometer (WV-500; Grand Seiko, Fukuyama, Japan), while
the subjects were encouraged to accommodate by binocu-
larly looking at an accommodative target, or a high contrast
(>90%) Maltese cross (2° × 2° of visual angle) located 33 cm
or 500 cm in front of their eyes. For the 33-cm target, a large
panel (25° × 25° of visual angle) was placed behind it to
secure binocular fusion. During the measurement, the sub-
jects were instructed to try to look at the target as clearly
as possible. The measurement was performed in a well-lit
room, and the targets were identically illuminated. The pro-
cedure took 5 min at most. No subject reported diplopia for
the target. Under the same experimental conditions, it has
previously been shown that the average accommodative
response in myopic children under noncycloplegic condi-
tions is 1.61 ± 0.48 D.16
Five measurements were taken for each target and
averaged (spherical equivalent). The difference between
the averaged accommodative response to the 33-cm (3.00 D)
target and that to the 500-cm (0.20 D) target (the accom-
modative and vergence demand in this setting was 2.80 D
and 2.80 meter-angles, respectively) was regarded as the
RA. The accommodation reduction rate, [(2.80 D − RA)/
2.80 D] × 100%, was also calculated for comparison with the
previously reported data.
The measurement was performed again after a 5-min
rest, and the repeatability of the measurement was evalu-
ated by determining the interval over which 95% of the
differences between the 1st and 2nd measurements lie, which
was constructed as the mean of the differences ± 1.96 × SD
of the differences).1,17
Results
Because data for both eyes were similar, data are reported
for the left eye only except for comparisons between the
two eyes. The mean (± SD) accommodative response
remaining after the application of Mydrin-P was 0.21 ±
0.29 D (range, −0.31 to 0.99 D). The averaged reduction rate
of accommodation against the accommodative demand was
thus 91%. As shown in Fig. 1 (the regression line was
obtained by the Deming method, assuming equal variance
of the measurement errors for the two variables),18 no cor-
relation was found in RA between the right and left eyes (r
= 0.128, P = 0.28). The difference in RA between the right
and left eyes was not significantly different from 0 D (0.03
± 0.33 D, P = 0.37, paired t test). RA was ≥0.50 D in five eyes
(7%) (data from one eye was not available for some sub-
jects). The mean RAs for boys and girls were 0.22 ± 0.20 D
I. HAMASAKI ET AL.
CYCLOPLEGIC EFFECT OF 0.5% TROPICAMIDE
Figure 1. Relationship of residual accommodation between the right
and left eyes. No correlation was found between the two eyes (r = 0.128,
P = 0.28).
Figure 2. Relationship between residual accommodation and age (left
eye). Residual accommodation tended to decrease with age (y =
−0.021x + 0.444), but the correlation was not significant (r = −0.119, P
= 0.314). - - - -, mean residual accommodation.
and 0.21 ± 0.29 D, respectively, and again the difference was
not significant (P = 0.94).
As shown in Fig. 2, RA tended to decrease with age, but
the correlation between the two variables was not sig-
nificant. RA decreased as the degree of myopia increased
(r = 0.274, P = 0.019) (Fig. 3).
Repeatability of the RA measurement was analyzed in
a difference versus mean plot (Fig. 4).1,17 The difference
between the 1st and 2nd measurements was distributed ran-
domly regardless of the mean RA of the two measurements.
The mean difference was 0.01 ± 0.34 D and was not statisti-
cally different from 0 D (paired t test). Thus, the repeat-
ability (the mean difference between the 1st and 2nd
measurements ± 1.96 × SD of the differences) was ±0.71 D.
113
Figure 3. Relationship between residual accommodation and spherical
equivalent refractive errors. Residual accommodation tended to
decrease with the degree of myopia (y = 0.045x + 0.416, r = 0.274,
P = 0.019). - - - -, mean residual accommodation.
Figure 4. Test–retest repeatability of measurement of residual accom-
modation. The mean (± SD) difference between two measurements
obtained on different occasions was 0.01 ± 0.34 D. - - - -, repeatability
(95% limits of agreement of two measurements obtained on different
occasions).
Discussion
When presented with a combined demand of 2.80 D accom-
modation and 2.80 meter-angle convergence and encour-
aged to accommodate, the myopic children, on average,
demonstrated 0.21 D of accommodation (reduction rate of
92%) after the application of Mydrin-P. This result sug-
gested that considerably less than 0.21 D of accommodation
can be expected during routine clinical subjective refraction
or autorefraction performed after instillation of Mydrin-P,
where accommodation is discouraged by optical blurring of
the target (fogging) or by providing essentially a zero
114
accommodation demand with a distant target. Considering
this result together with the shorter period of time required
to obtain maximum cycloplegic effect and the rare inci-
dence of systemic side effects associated with Mydrin-P, we
can conclude that Mydrin-P is an acceptable and useful
cycloplegic agent for longitudinal or cross-sectional investi-
gations in Japanese schoolchildren with myopia.
Compared with RA subjectively measured after applica-
tion of tropicamide,5,6 the RA after application of Mydrin-P
objectively measured in this study was much smaller. Mutti
et al.8 measured the accommodation remaining after appli-
cation of 1% tropicamide using both subjective and objec-
tive techniques and found a surprisingly large difference
between the measurements: RA was 3.27 D when evaluated
by measuring the near-point of accommodation by the
push-up method, whereas it was 0.71 D when evaluated with
an autorefractometer.8 This finding has been supported by
another study comparing the cycloplegic effects of tropi-
camide and cyclopentlate.9
Although the push-up (subjective) test is frequently used
to evaluate accommodative function in clinics, many con-
founding factors influence the results. For example, the
depth of focus of the eye (roughly ± 0.5 D with the natural
diameter of the pupil)19 makes the subjectively measured
near-point of accommodation closer to the eye. In addition,
pupil dilation induced by tropicamide and phenylephrine
increases spherical aberration and probably increases the
extent of the depth of focus. Reportedly, tropicamide itself
increases high-order aberration of the eye in some patients.20
Even when measured through an artificial pupil, any small
misalignment of the artificial pupil to the center of the
entrance pupil would increase the high-order aberration. A
high-order aberration is considered to contribute to appar-
ent accommodation in pseudophakic, or basically no-
accommodation, eyes.21
When compared with RA after application of 1%
tropicamide reported in COMET children (0.30–0.38 D, an
accommodation reduction rate of 85%–89%),10 the RA
found in the present study, which was measured under
similar experimental conditions, was slightly smaller (0.26 D,
or an accommodation reduction rate of 92%), despite the
lower concentration (0.5%) of tropicamide in Mydrin-P.
Likewise, the percentage of eyes showing RA ≥ 0.50 D in
COMET children (23% or 29%)10 was greater than that
in our study (16%). These results can be explained by
several factors. First, the 0.5% phenylephrine contained in
Mydrin-P probably enhances the cycloplegic effect of trop-
icamide,22–24 although a low concentration of phenylephrine
itself has been reported to have little effect on accommoda-
tion in humans25 and other primates.26 Second, in the study
in COMET children, RA did not significantly differ among
races (probably due to the limited sample size of Asian
children), but the mean RA in Asian children (0.29 D on
average for the right and left eyes) was smaller than that in
black or Hispanic children (0.35 D or 0.52 D, respectively).10
Tropicamide may be a more effective cycloplegic agent in
Asian children, including Japanese children. Finally, the
timing of refractive measurement after administration of
Jpn J Ophthalmol
Vol 51: 111–115, 2007
tropicamide is considered to be crucial when anticipating
the maximum cycloplegic effect. Reportedly, the duration
during which the maximum effect persists is rather short:
the cycloplegic effect of tropicamide reaches its maximum
30 min after the initial application and then continues for
15 min.23,24,27 In the study in COMET children, RA was mea-
sured 25 min after the initial application,10 whereas it was
measured 30–35 min after the initial instillation in our study.
This small difference in timing of the measurement may be
another reason for the slightly smaller RA in our study,
although we did not perform sequential measurement of
RA.
A large RA close to 1 D was observed in several eyes
(Fig. 1). This finding is consistent with the results of the
study in COMET children: 6%–7% of the children showed
an RA > 1 D.10 That study also found that it is difficult to
predict which children might retain more accommodation
from these clinical parameters, because RA was not found
to be associated with sex, age, race, pupillary color, or
refractive errors. However, RA up to 1 D might be explained
by the sum of the repeatability (random errors) of the mea-
surement and the mean RA (0.21 D). Likewise, the random
measurement errors may explain the unrealistic negative
RA found in some children: the maximum amplitude of the
negative accommodation (−0.32 D) was within the repeat-
ability of the measurement.
Cycloplegic autorefraction is generally considered to
provide highest repeatability among all clinical examina-
tions for measuring refractive errors,1 and the repeatability
has been reported to be ±0.49 D in children when a WV-500
(SRW-5000) autorefractometer is used.28 To obtain RA,
two measurements for different levels of accommodative
demand are usually required, and thus the repeatability of
the RA measurement is estimated by multiplying the repeat-
ability of a single measurement (±0.49 D) by the square root
of 2, according to the error-propagation theory. The repeat-
ability of RA measurement found in this study (±0.71 D)
agrees with this prediction (±0.69 D). Furthermore, no cor-
relation was found in RA between the right eye and the left
eye (Fig. 1), indicating that the variation in RA is not neces-
sarily attributable to intersubject variation in chemosensi-
tivity to tropicamide.
Certainly, this study should be viewed in the light of
some limitations. First, RA did not show a significant asso-
ciation with age within the age range of our subjects (7–14
years), and so it is still questionable whether Mydrin-P is
an effective cycloplegic agent in younger children. In fact,
accommodation remaining after application of 1% tropi-
camide5 or a combination of 1% cyclopentolate and 1%
tropicamide29 has been reported to increase in younger sub-
jects. Second, RA slightly increased as the degree of myopia
decreased within the refractive range of −1.57 to −8.66 D
(Fig. 3). A similar tendency has been reported by Manny
et al.,10 although the correlation was not significant, prob-
ably because their refractive error range was limited (−1.25
to −4.50 D)10. In addition, it has been reported that, under
noncycloplegic conditions, myopic children show smaller
accommodative responses to accommodative demands than
I. HAMASAKI ET AL.
CYCLOPLEGIC EFFECT OF 0.5% TROPICAMIDE
emmetropic children.16,30 This relationship may contribute
partly to the small RA we found in myopic children; hence,
it is questionable whether Mydrin-P is still an effective
cycloplegic agent in hyperopic children. Finally, our study
did not directly compare RA or refractive measurements
among different cycloplegic agents. Strictly, a significant
bias may exist between refractive measurements obtained
with Mydrin-P and that obtained with other cycloplegic
agents such as cyclopentolate or atropine. The results of this
study indicate simply that the cycloplegic effect of Mydrin-
P in Japanese children with myopia is substantially equal to
that obtained with 1% tropicamide in the COMET study
of ethnically diverse children.10 It is reasonable to com-
pare refractive values in cross-sectional investigations in
Japanese children obtained with Mydrin-P with those
obtained with 1% tropicamide elsewhere.
In conclusion, the insignificant extent of RA objectively
measured in this study indicated that a mixed eye drop of
0.5% tropicamide and 0.5% phenylephrine (Mydrin-P) is an
acceptable and useful cycloplegic agent in Japanese school-
children with a wide range of myopic refractive errors.
Acknowledgments. This research was partly supported by the Tanaka-
Chain Optical Company (Hiroshima, Japan) and the Japanese Ministry
of Education, Culture, Sports, Science and Technology, Scientific
Research (C), Grant No. 15390532.
References
1. Zadnik K, Mutti DO, Adams AJ. The repeatability of measure-
ment of the ocular components. Invest Ophthalmol Vis Sci 1992;33:
2325–2333.
2. Gettes BC. Tropicamide, a new cycloplegic mydriatic. Arch Oph-
thalmol 1961;65:632–635.
3. Gettes BC, Belmont O. Tropicamide: comparative cycloplegic
effects. Arch Ophthalmol 1961;66:336–340.
4. Applebaum M, Jaanus SD. Use of diagnostic pharmaceutical
agents and incidence of adverse effects. Am J Optom Physiol Opt
1983;60:384–388.
5. Milder B. Tropicamide as a cycloplegic agent. Arch Ophthalmol
1961;66:70–72.
6. Lovasik JV. Pharmacokinetics of topically applied cyclopentolate
HCl and tropicamide. Am J Optom Physiol Opt 1986;63:787–803.
7. Egashira SM, Kish LL, Twelker JD, et al. Comparison of cyclo-
pentolate vs. tropicamide cycloplegia in children. Optom Vis Sci
1993;70:1019–1026.
8. Mutti DO, Zadnik K, Egashira S, et al. The effect of cycloplegia
on measurement of the ocular components. Invest Ophthalmol Vis
Sci 1994;35:515–527.
9. Lin LL, Shih YF, Hsiao CH, et al. The cycloplegic effects of cyclo-
pentolate and tropicamide on myopic children. J Ocul Pharmacol
Ther 1998;14:331–335.
10. Manny RE, Hussein M, Scheiman M, et al. Tropicamide (1%): an
effective cycloplegic agent for myopic children. Invest Ophthalmol
Vis Sci 2001;42:1728–1735.
115
11. Gwiazda J, Hyman L, Hussein M, et al. A randomized clinical trial
of progressive addition lenses versus single vision lenses on the
progression of myopia in children. Invest Ophthalmol Vis Sci
2003;44:1492–1500.
12. Kleinstein RN, Jones LA, Hullett S, et al. Refractive error and
ethnicity in children. Arch Ophthalmol 2003;121:1141–1147.
13. Hasebe S, Nonaka F, Nakatsuka C, et al. Myopia control trial with
progressive addition lenses in Japanese schoolchildren: baseline
measures refraction, accommodation, heterophoria. Jpn J Oph-
thalmol 2005;49:23–30.
14. Varughese S, Varughese RM, Gupta N, et al. Refractive error at
birth and its relation to gestational age. Curr Eye Res 2005;30:412–
428.
15. Phillips JR. Monovision slows juvenile myopia progression unilat-
erally. Br J Ophthalmol 2005;89:1196–1200.
16. Nakatsuka C, Hasebe S, Nonaka F, Ohtsuki H. Accommodative
lag under habitual seeing conditions: comparison between
myopic and emmetropic children. Jpn J Ophthalmol 2005;49:189–
194.
17. Blant JM, Altman DG. Statistical methods for assessing agreement
between two methods of clinical measurement. Lancet 1986;1(8476):
307–310.
18. Cornbleet PJ, Gochman N. Incorrect least-squares regression coef-
ficients in method-comparison analysis. Clin Chem 1979;25:432–
438.
19. Green DG, Powers MK, Banks MS. Depth of focus, eye size and
visual acuity. Vision Res 1980;20:827–835.
20. Tuan KA, Somani S, Chernyak DA. Changes in wavefront aber-
ration with pharmaceutical dilating agents. J Refract Surg 2005;5:
S530–534.
21. Oshika T, Mimura T, Tanaka S, et al. Apparent accommodation
and corneal wavefront aberration in pseudophakic eyes. Invest
Ophthalmol Vis Sci 2002;43:2882–2886.
22. Lovasik JV, Kergoat H. Time course of cycloplegia induced by a
new phenylephrine–tropicamide combination drug. Optom Vis Sci
1990;67:352–358.
23. Zetterstrom C. A cross-over study of the cycloplegic effects of a
single topical application of cyclopentolate–phenylephrine and
routine atropinization for 3.5 days. Acta Ophthalmol (Copenh)
1985;63:525–529.
24. Alimgil ML, Erda N. The cycloplegic effect of atropine in com-
parison with the cyclopentolate–tropicamide–phenylephrine
combination. Klin Monatsbl Augenheilkd 1992;201:9–11.
25. Culhane HM, Winn B, Gilmartin B. Human dynamic closed-loop
accommodation augmented by sympathetic inhibition. Invest Oph-
thalmol Vis Sci 1999;40:1137–1143.
26. Ostrin LA, Glasser A. The effect of phenylephrine on pupil diam-
eter and accommodation in Rhesus monkeys. Invest Ophthalmol
Vis Sci 2004;45:215–221.
27. Mine K, Hirai H, Uozato H, et al. A comparative study of
tropicamide and cyclopentolate concerning the onset of maximum
cycloplegia and its duration (in Japanese, with English abstract).
Ganka Rinsho Iho (Folia Ophthalmol Jpn) 1985;36:1766–
1769.
28. Chat SWS, Edwards MH. Clinical evaluation of the Shin-Nippon
SRW-5000 autorefractor in children. Ophthalmic Physiol Opt
2001;21:87–100.
29. Miranda MN, Juan S. Residual accommodation. A comparison
between cyclopentolate 1% and a combination of cyclopentolate
1% and tropicamide 1%. Arch Ophthalmol 1972;87:515–517.
30. Gwiazda J, Thorn F, Bauer J, et al. Myopic children show insuffi-
cient accommodative response to blur. Invest Ophthalmol Vis Sci
1993;34:690–694.