European Journal of Ophthalmology / Vol. 6/ no. 2, 1996/ pp. 192-196

Effects and side effects of mydriatic eyedrops In neonates

M.S. DGUT " N. BOZKURT " E. DZEK 2, H. BiRGEN 2 , H. KAZOKOGLU " M. DGUT 3

1 Departments of Ophthalmology and 2 Pediatrics 3 Marmara University Faculty of Medicine, Haydarpasa Numune Hospital, Istanbul - Turkey

ABSTRACT: The pupils of neonates and premature infants often need to be dilated for reti­nal examination. The drops used for this purpose have some known side effects. This study investigated the effects and side effects of these drops. In this prospective randomized study, 80 healthy neonates were randomly assigned to eight groups . In Group A 1 % cyclopentolate was used; in Group B 1 % tropicamide; in Group C

2.5% phenylephrine; in Group D 1 % cyclopentolate and 1 % tropicamide; in Group E 2.5% phenylephrine and 1 % tropicamide; in Group F 0.5% cyclopentolate, 0.5% tropicamide and 2.5% phenylephrine; in Group. G 1% cyclopentolate and 2.5% phenylephrine and in Group H 0.9% NaCI. Heart rate, systolic and diastolic blood pressures were recorded before, and 5, 10, 15, 30, 45, 60 minutes after instillation of the drops. Pupillary size was measured at baseline, 30 and 60 minutes. To stimulate the conditions of indirect ophthalmoscopic examination, the pupil sizes were measured under the intense beam of a halogen light. The results were analyzed statistically. Maximum side effects were seen in group C; the safest was group B and maximum mydri­asis was achieved in group F. (Eur J Ophthalmol 1996; 6: 192-6)

KEY WORD: Neonates, Mydriatic eye-drops

INTRODUCTION

The pupils of newborns often need to be dilated for fundoscopic examination in order to detect various pathologies including retinopathy of prematurity, con­genital infections, congenital cataracts, neurological syndromes and retinal abnormalities associated with dysmorphic syndromes. Maximum mydriasis is nec­essary for adequate indirect ophthalmoscopy, especially in premature infants, to allow the diagnosis and grad­ing of retinopathy of prematurity.

Drugs that are innocuous in adults and safe in chil­dren may be dangerous when administered to small in­tants. Cyclopentolate, phenylephrine and tropicamide are currently in use for mydriasis. There have been var­ious reports about effects and side effects of the eye drops (1-20). Drugs with anticholinergic and adrener-

1120-6721/192-05 $02.5010

gic effects have some cardiovascular side effects (1, 2). Arterial hypertension is a risk factor for intracranial hemorrhage, especially in premature infants (3, 4). Phenylephrine has been associated with adverse sys­temic effects such as hypertension, subarachnoid hem­orrhage, cardiac arrhytmias and death. Cyclopento­late has central nervous system side effects (5-11) .

The aim of this study was to propose a safe and ef­fective eye drop or combination of drops for clinical use.

MATERIALS AND METHODS

Groups

Eighty healthy neonates ranging in gestational age from 37-41 weeks (mean 39.4), birth weights 2950-

© by Wichtig Editore, 1996

Ogut et al

3600 g (mean 3150.5) were divided into eight groups of ten; 160 eyes of 80 neonates were examined for dilatation.

Mydriatic agents

Group A was given 1 % cyclopentolate; Group B 1 % tropicamide; Group C 2.5% phenylephrine; Group D 1 % cyclopentolate and 1 % tropicamide; Group E 2.5% phenylephrine and 1 % tropicamide; Group F 0.5% cy­clopentolate, 0.5% tropicamide and 2.5% phenyle­phrine; Group G 1 % cyclopentolate and 2.5% phenyle­phrine and Group H 0.9% NaCI.

In groups A, Band C, two drops were instilled, 5 minutes apart. In Group F one drop of each medica­tion was given 5 minutes apart. In the other groups one drop of each medication was placed in each eye at 5-min intervals. In group H two drops of 0.9% NaCI were placed in each eye at 5-rnin intervals . To minimize transcutaneous absorption any excess fluid was wiped away from the periocular area. Group H received on­ly saline solution and served as a control group.

Pupilla ry size

This measurement was carried out immediately be­fore the first instillation of mydriatics and then 30 and 60 minutes after the last drops. The lighting in the room was kept constant throughout the examination. Pupil sizes were measured with a small plastic ruler in ambient lighting for the first three measurements and under the intense beam of a halogen transillumi­nator at the 60-min measurement to simulate the con­ditions of indirect ophthalmoscopic examination.

Blood pressure and heart rate

For the calculations in this study, we used mean systolic and diastolic pressures. Blood pressures (BP) and heart rate (HR) were measured by oscillometry (Neonatal DINAMAP 8100, Critikon Inc.) starting 15 min­utes before the first instillation. In this period a total of four measurements were taken and their average was used as baseline. Later measurements were tak­en 5, 10, 15, 30, 45 and 60 minutes after the last in­stillation. No measurement was taken within the first 5 minutes after the last drop. It was thought that han­dling the babies in that time might give false results

and might lead to misinterpretations. The neonatal cuff was left in place throughout the study to ensure uniformity of measurement. Infants were handled as little as possible and all observations were made by one investigator in the same room.

Statistics

Differences in the mean BP and HR for the eight groups at baseline and 5, 10, 15, 30, 45 and 60 min­utes were evaluated with Kruskal-Wallis test. The same test was used for the seven groups other than the con­trol group, to analyze the differences in mean pupil sizes at baseline, 30 minutes, 60 minutes and with light.

RESULTS

Mydriatic effect

Table I shows the mean pupil sizes of each group at the beginning of the study, at 30 and 60 minutes and with light. Changes from baseline to 30 minutes were not significant. The mean net dilatation was 4.3 mm in group F at 60 min and this was the largest change. The mean net dilatation was 4.1 mm in group D, 4.0 mm in group G, 3.9 mm in group E, 3.8 mm in group A and 3.5 mm in group C. The smallest dilatation was in group B (mean 2.9 mm). The smallest pupillary size with light was also in group B (mean 4.2 mm). The differences between group B and groups E, F and G were significant.

Blood pressure and heart rate

Mean systolic and diastolic blood pressures are shown in Tables II and III and mean heart rates in Table IV. Baseline values were the same in all groups. There was a significant difference in systolic BP be­tween group C and the control group but no changes between the control group and groups B, D and F. Di­astolic BP in group C was significantly different from the control group but there were no differences be­tween controls and groups Band D. HR in group C was significantly different from controls but there was no difference between groups B, D, F and G.

Compared to the control group, Band D were the safest whereas group C showed the maximum side effects.

193

Effects and side effects of mydriatic eye drops in neonates

TABLE I - MEAN PUPILLARY DIAMETERS

Group A Group B Group C Group 0 Group E Group F Group G (20 eyes) (20 eyes) (20 eyes) (20 eyes) (20 eyes) (20 eyes) (20 eyes)

Baseline 2.1 ± 0.31 2.3 ± 0.48 2.2 ± 0.42 2.1 ± 0.31 2.3 ± 0.48 2.31 ± 0.31 2.3 ± 0.54

30 min 4.4 ± 0.51 4.2 ± 0.42 4.3 ± 0.48 4.5 ± 0.52 4.6 ± 0.51 4.7 ± 0.48 4.9 ± 0.73

60 min 5.9 ± 0.56 5.2 ± 0.63 5.7 ± 0.67 6.2 ± 0.63 6.2 ± 0.63 6.4 ± 0.69 6.3 ± 0.67

Light 5.2 ± 0.91 4.2 ± 0.78 4.7 ± 0.67 5.7 ± 0.94 5.8 ± 1.03 6.1 ± 0.99 6.1 ± 0.73

Group A: 1 % cyclopentolate; Group B: 1 % tropicamide; Group C: 2.5% phenylephrine ; Group 0: 1 % cyclopentolate and 1 % tropicamide; Group E: 2.5% phenylephrine and 1 % tropicamide; Group F: 0.5% cyclopentolate, 0.5% tropicamide and 2.5% phenylephrine; Group G: 1 % cyclopentolate and 2.5% phenylephrine; Group H: 0.9% NaCI

TABLE II - MEAN SYSTOLIC BLOOD PRESSURES

Baseline 5 min 10 min 15 min 30 min 45 min 60 min

Group A 65.4 ± 11 .8 68.5 ± 5.58 70 ± 2.82 69.2 ± 2.09 67 ± 2.21 61 ± 3.65 71.3 ± 3.97

Group B 65.5 ± 7.53 66.7 ± 4.42 64 ± 3.85 64.5 ± 2.87 61.1 ± 3.60 59.7 ± 3.23 70.9 ± 3.10

Group C 61 .5 ± 7.38 66.5 ± 5.54 73.2 ± 3.61 71.9 ± 3.03 69.2 ± 2.86 60.8 ± 3.08 70.7 ± 2.71

Group 0 64 .4 ± 6.62 64.6 ± 3.71 67.8 ± 2.25 68.2 ± 2.70 64.2 ± 3.25 58.3 ± 4.27 70.3 ± 4.32

Group E 61 .7 ± 4.66 67.3 ± 4.05 70.3 ± 4.05 - 69.1 ± 2.23 67.6 ± 1.95 60.9 ± 4.43 70.3 ± 3.09

Group F 65.3 ± 7.91 66.1 ± 5.48 67.1 ± 2.37 64.7 ± 3.02 61 .8 ± 3.49 57.8 ± 3.55 70.5 ± 3.65

Group G 62 ± 5.47 66.3 ± 3.56 68.4 ± 3.27 69.2 ± 2.97 62.1 ± 3.98 58.8 ± 3.12 70.9 ± 3.66

Group H 63.9 ± 5.32 65.3 ± 3.65 61 ± 5.67 61 .8 ± 4.46 57.1 ± 4.38 55.3 ± 3.80 57.9 ± 4.84

TABLE III - MEAN DIASTOLIC BLOOD PRESSURES

Baseline 5 min 10 min 15 min 30 min 45 min 60 min

Group A 33.2 ± 2.34 35.7 ± 1.70 38.9 ± 1.79 37.8 ± 2.39 34.5 ± 2.01 31 .8±1.39 34.1 ± 1.66

Group B 33.9 ± 3.41 35.1 ± 1.79 34.4 ± 2.17 31 .9 ± 1.72 30.9 ± 1.66 30.2 ± 1.22 32.5 ± 1.43

Group C 33.8 ± 2.53 36.5 ± 1.95 39 ± 2.58 38.7 ± 1.88 36.3 ± 1.88 33.6 ± 1.77 34.7 ± 1.33

Group 0 33 ± 2.30 35.9 ± 2.28 34.3 ± 2.00 34.2 ± 2.04 31 .1 ± 1.59 30.5 ± 1.26 33.5 ± 1.50

Group E 33.3 ± 2.83 35.5 ± 1.95 33.4 ± 3.34 35.7 ± 2.54 34.3 ± 2.05 33.2 ± 1.61 33.7 ± 1.70

Group F 35.2 ± 2.71 36.5 ± 1.50 36.6 ± 1.71 31 .9±1.85 33.1 ±2.18 30.7 ± 1.63 33.6 ± 1.57

Group G 37.5 ± 3.20 34.6 ± 2.63 35 ± 2.35 37.1 ± 3.54 34.3 ± 2.75 31 .1 ± 2.55 33.6 ± 2.41

Group H 34 .9 ± 3.38 30.9 ± 2.02 30.7 ± 1.49 30.9 ± 1.91 30.9 ± 1.85 29.6±1 .17 29.8 ± 1.39

TABLE IV - MEAN HEART RATES

Baseline 5 min 10 min 15 min 30 min 45 min 60 min

Group A 116 ± 7.61 117.9 ± 9.91 125 ± 10.04 118.8 ± 6.82 113 ± 4.34 111.7±3.46 123.2 ± 9.11

Group B 120.9 ± 9.65 119.2 ± 14.79 112.1 ± 6.74 108.6 ± 6.38 106.2 ± 3.29 106.2 ± 5.71 123 ± 7.55

Group C 114.2 ± 9.56 120 ± 8.27 129.8 ± 7.30 125.9 ± 7.01 117.4 ± 5.31 114.8 ± 3.82 125.9 ± 8.77

Group 0 115.4 ± 6.38 108.4 ± 13.12 112.2 ± 8.56 111.8 ± 5.13 107.8 ± 5.26 104.7 ± 4.21 125.3 ± 7.86

Group E 115 ± 8.91 123 ± 9.51 116.9 ± 3.07 117.7 ± 6.36 112.9 ± 3.84 110.4 ± 4.69 122.4 ± 7.19

Group F 112.7 ± 10.46 105.8 ± 4.79 105.8 ± 4.41 107.5 ± 5.06 106.2 ± 4.44 108.6 ± 6.88 123.1 ± 6.85

Group G 111 .6 ± 7.21 109 ± 6.63 109.3 ± 5.39 113 ± 7.14 107.3 ± 4.80 109.1 ± 5.46 116.7 ± 5.79

Group H 107.1 ±6.02 106.9 ± 6.57 104.2 ± 6.30 103.6 ± 4.06 104.9 ± 5.34 105.8 ± 6.12 103.4 ± 4.67

194

6giH et a/

DISCUSSION

Various eye drops can be used to dilate pupils in neonates. A sympathomimetic agent such as phenyle­phrine to stimulate the dilator pupillae muscle, a parasym­patholytic agent such as cyclopentolate or tropicamide to inhibit the sphincter pupillae muscle, or both can be used. Systemic effects of mydriatic eye drops have been described widely (1-20). These medications can enter the systemic circulation through the capillaries of the eye or the lacrimal drainage system. Absorption may occur through the nasal mucosa or the gastroin­testinal tract (1). The ideal eye drop should achieve maximal mydriasis with the greatest safety margin.

Intracranial bleeding is one of the leading causes of mortality in preterm infants and arterial hyperten­sion is regarded as a risk factor for intracranial hem­orrhage, especially in premature infants (12). Adren­ergic and anticholinergic mydriatic drugs may exert cardiovascular side effects (1). Cyclopentolate~ may induce central nervous system side effects such as psychotic reactions and epilepsy (5-11), and also gas­trointestinal side effects (13) .•

The first report on reactive hypertension after ap­plication of 10% phenylephrine (PE) in an adult was published in 1956 (14). According to Borromeo-Mc­Grail (2), with 10% PE a significant blood pressure rise was noted and the mydriatic effect of 2.5% and 10% PE was the same. Controversial res~lts have been re­ported about 2.5% PE as regards the cardiovasc~.Jar . side effects (15-18).

Our results showed that administration of 2 drops of 2.5% PE was followed by significant increases es-

REFERENCES

1. Davidson SI. Systemic effects of eye drops. Transac­

tions of the ophthalmologic society of the United King­

dom. 1974; 94 : 487-95.

2. Borromeo-McGrail V, Bordiuk JM, Keitel H. Systemic

hypertension following ocular administration of 10%

phenyleprine in the neonate. Pediatrics 1973; 51: 1032-

6.

3. Caputo AR, Schnitzer RE. Systemic response to mydri­

atic eyedrops in neonates. J Pediatr Ophthalmol Strabismus 1978; 15: 109-22.

pecially at the 10th minute when compared with the con­trol group (p<0.001). There were no real changes in group B but the least mydriasis was achieved in this group. Although tropicamide was safe, the mydriasis achieved would not be adequate for peripherial reti­nal examination since the pupil constricted under in­tense light.

Bolt et al found that effective mydriasis was achieved when 2.5% PE and 1 % tropicamide were used together (19). We obtained a similar result (group E), but mean HR and BP differed significantly from controls (p<0.001). Maximum mydriasis was achieved in group F (6.4 mm), but there were significant rises in BP and HR (p<0.01). This group, however, was not as safe as group B, and the instillation of three drops into the neonatal eye is not practical. As a result we concluded that sufficient mydriasis without significant systemic side effects was achieved in group D. Tropicamide has been said to have a synergistic effect with the cycloplegic action of cyclopentolate (20, 21). Our results too suggest that tropicamide increases the mydriatic effect of cy­clopentolate.

Reprint requests to: Mehdi S. OgOt, M.D. Department of Ophthalmology Marmara University Hospital 81190 Altunizade, Istanbul, Turkey

4. Fraunfelder FT, Meyer SM. Possible cardiovascular ef­

fects secondary to topical ophthalmic phenylephrine

2.5%. Am J Ophthalmol 1985; 99: 362-3.

5. Kennerdel JS, Wunder FP. Cyclosporine associated with

two cases of grandmal seizure. Arch Ophthalmol 1972;

87: 634-5.

6. Beswick JA . Psychosis from cyclopentolate. Am J Oph­

thalmol 1962; 53: 879-80.

7. Bauer CR, Trottier MCT, Stern L. Systemic cyclopento­

late (Cyclogyl) toxicity in the newborn infant. J Pediatr

1973; 83: 501-5. 8. Addock EW. Cyclopentolate (Cyclogyl) toxicity in pedi-

-----------

195

Effects and side effects of mydriatic eye drops in neonates

atric patients. J Pediatr 1971; 79: 127.

9. Binkhost RD, Weinstein GW, Baretz RM, et al. Psychotic

reaction induced by cyclopentolate (Cyclogyl). Am J

Ophthalmol 1963; 55: 1243-5.

10. Simcoe CWo Cyclopentolate (Cyclogyl) toxicity. Arch

Ophthalmol 1962; 61: 46. 11. Peaeger DL, Miller SN. Toxic effects of cyclopentolate

(cyclogyl). Am J Ophthalmol 1964; 58: 1060-1.

12. Armstrong D, Norman MC. Periventricular leucomalacia

in neonates. Complications and sequela. Arch Dis Child

1974; 49: 367-75 .

13. Hermansen MC, Sullivan LS. Feeding intolerance fol­

lowing ophthalmologic examination. Am J Dis Child 1985;

139: 367-8.

14. Mc Reynolds WV, Havener WH, Henderson JW. Haz­

ards in the use of sympathomimetic drugs in ophthal­

mology. Arch Ophthalmol 1956; 56: 176-9. 15. Rosales T, Isenberg S, Leake R, Everett SW. Systemic

effects of mydriatics in low weight infants. J Pediatr Oph-

196

thalmol Strabismus 1981; 18 (6): 42-4. 16. Isenberg SJ, Everett S, Parelhof E. A comparison of my­

driatic eyedrops in low birth weight infants. Ophthal­

mology 1984; 91: 278-9.

17. Isenberg SJ, Everett S. Cardiovascular effects of mydri­

atics in low birth weight infants. J Pediatr 1984; 105: 111.

18. Lees BJ, Cajal LA. Increased blood pressure following pupillary dilatation with 2.5% phenylephrine in preterm

infants. Pediatrics 1981; 68: 231-4.

19. Bolt B, Benz B, Koerner F, Bossi E. A mydriatic eye­

drop combination without systemic effects for prema­

ture infants: a prospective double-blind study. J Pediatr

Ophthalmol Strabismus 1992; 29: 157-62.

20. Miranda MN. Residual accommodation; a comparison

between cyclopentolate 1 % and tropicamide 1 %. Arch Oph­thalmol 1972; 87: 515-7.

21. Caputo AR, Lingua RW. The problem of cycloplegia in

the pediatric age group: a combination formula for refraction.

J Pediatr Ophthalmol Strabismus 1980; 17: 119-28.