Systemic Response to Mydriatic Eyedrops in Neonates: Mydriatics in Neonates

Anthony R. Caputo, M.D. Robert E. Schnitzer, M.D.

Newark, New Jersey

When a newborn is exposed to partial pressures of oxygen above the normal blood range, the result may be Retrolental Fibro­plasia} Most premature babies who have received oxygen are routinely examinated prior to hospital discharge. Of the more popular mydriatic agents employed, there have been various reports of systemic manifestations. Our study was conducted to confirm previous reports and to find an adequate combination for dilatation without the systemic effects. Our current protocol at United Hospitals Medical Center (UHMC) was included in the study.

MATERIAL AND METHODS

Forty-eight neonates of mixed races were studied during routine dilatation prior to fundu­scopic examination. In each case, the patient was stable. euthermic, supine, approximately one hour after feeding. Gestational ages, determined by physical and neurological char­acteristics in conjunction with menstrual his­tory, ranged from 30 to 45 weeks. Present weights were from 1040 to 4350 grams.

Blood pressures were obtained using i1 cuff with an ultrasound transducer* over the bra­chial artery. This concept was originally pre­pared by Ware 2 and Kirby/ and its accuracywas documented by Hochberg et al.4 The cuffs remained in placethroughoutthe entire record­ing period. Apical heart rates were obtained by

From the Department of Ophthalmology. New Jersey Medical School.

This work was made possible by a grant from Fight for Sight, Inc. New York City. to the Fight for Sight Children'S Eye Center of the Eye Institute of New Jersey.

Requests for reprints should be addressed to Dr. A.R. Caputo, 15 S. 9th Street. Newark. New Jersey 07107.

*Roche Arteriosonde 10TO Prototype. Hoffman­LaRoche. Inc.

ascultation of the precordium. In all cases, heart rates and blood pressures were recorded for three intervals at five minutes apart. An average of these fig ures provided control levels.

Eye drops were instilled three times: one drop in each eye at five minute intervals. Excess tearing or overflow was wiped away imme­diately with a clean gauze. Heart rates and blood pressures were recorded at five minute intervals for the first 15 minutes and then every 15 minutes. After one hour, ey~lid retractors were applied and pupil sizes were measured with a small, clear plastic "ruler. Sizes before and after a high intensity spotlight were noted. Routine funduscopic examination then pro­ceeded.

To eliminate the possibility of subjective variation, the same investigator applied the drops, recorded pressures and heart rates, and measured pupil sizes.

The study was divided into four groups: Group I: Six neonates ranging from 34 to 40

weeks and weighing from 1530 to 4060 grams comprised this group. They were given an open trial of 10 percent aqueous phenylephrine.

Group II: We subdivided a total of 19 cases into six subgroups. In a double blind fashion, we randomly administered ten percent aqueous phenylephrine, one percent cyclopentolate, one percent tropicamide, and as our control, normal saline. These infants ranged from 32 to 45 weeks and weighed 1040 to 4350 grams.

Group III: A group of 12 infants, with ages from 30 to 42 weeks and weights from 1280 to 2460 grams, received the protocol fordilatation used at UHMC Intensive Care Nursery. This protocol is a com bi nation of drops of 2.5 percent aqueous phenylephrine, one percent cyclo­pentolate, and one-half percent tropicamide. One drop of each was placed in both eyes and repeated at five-minute intervals for three

JOURNAL OF PEDIATRIC OPHTHALMOLOGY AND STRABISMUS 109

instillations, i.e., nine drops in each eye. Group IV: To facilitate the administration of a

combination of drops, our pharmacy prepared a mixed solution. By combining 7 cc of one percent cyclopentolate, 7 cc of one percent tropicamide and .625 cc of ten percent aqueous phenylephrine in a 15 cc dropper bottle, a solution containing one-half percent cyclo­pentolate, one-half percent tropicamide, and 2.5 percent phenylephrine was prepared. We divided 11 neonates into two subgroups:

Subgroup A-four infants from 36 to 38 weeks and weighing 2200 to 3000 grams received a total of three drops in each eye. Subgroup B-seven infants from 37 to 44 weeks and weighing 1769 to 3800 grams received just one drop ofthe solution in each eye.

RESULTS

Group I

Approximately ten minutes following ocular application of 10 percent aqueous phenyleph­rine, there was blanching of the skin around the eyes in all cases (Fig. 1). The blanching was most intense between 20 and 30 minutes. This phenomenon has been previously reported.5r6

Our data, recorded on Table I and Graph I, shows a consistent but variable rise in blood pressure ranging from 10 to 26 mm Hg systolic and 2 to 14 mm Hg diastolic. The effects on heart rates were variable. !n four of the six cases, we observed a drop in heart rate, perhaps explained on the basis of a rise in blood pressure causing a reflex slowing of the hean.1

This is further discussed in the section to follow.

Pupil sizes ranged from 4 to 6 mm (average 5.0 mm) and did not vary with direct light stimulation. It is worth noting that in patients no. 5 and no. 6, both with dark irises, there was minimal dilatation and yet considerable cha nge in blood pressure. The blue-eyed baby, patient no. 2, had a maximum dilatation in this series. This phenomenon has been previously reported by Haddad et al.8

Group II: Double Blind Study.

Subgroup /I-A: This series involved three infants who received one percent cyclopen­tolate. (See Table and Graph II-A.) We observed no significant variation in blood pressure. Patient No.3 presented an interesting finding in that there was a steady rise in heart rate. This may represent the action of the anticholinergic

110

Fig. 1. Blanching of the periorbital area from phenylephrine.

agent on the heart.9 Maximum dilatation was 5 mm in all three cases; however. in the presence of a high intensity lamp, two of the pupils dropped to 4 mm.

Subgroup /I-B: Four patients received 10 percent aqueous phenylephrine in the second series of cases. (See Table and Graph II-B.) Three of the infants developed blanching of the skin around the eyes. Curiously, the 35-week­old, 1860 gram black infant was the exception. In two patients, No. 1 and No.4, there was a consistent rise in blood pressure. A drop in heart rate was also observed in patient No.4. Dilatation was from 3.0 to 5.0 mm (average 4.4 mm). Maximum dilatation was observed in tbe blue-eyed infant. It was interesting to note that there was greater dilatation in the white, though more mature babies.

Subgroup /I-C: Group II-C comprised three patients who received our control solution of normal saline. (See Table and Graph II-C.) As expected. pressures and heart rates were stable. There was no dilatation.

Subgroup 1/-0: This series of three patients received 10 percent viscous phenylephrine. This agent was included in order to compare its effects with the 10 percent aqueous solution. (See Table and Graph II-D.) One of the infants displayed a steady and consistent elevation in blood pressure with an associated fall in heart rate. (Note that the weight of this infant was only 1040 grams.) The other two infants showed no significant variation in pressure or heart rate. Dilatation ranged between 4 and 5 mm (average 4.7 mm) and light reflexes remained active in two of the patients. Blanch­ing occurred on the skin around the eyes in two cases.

Subgroup I/-E: Three babies received one

MARCH/APRIL, VOLUME 15. NUMBER 2

insti lations, i.e., nine drops in each eye. Group IV: To facilitate the administration of a

combination of drops, our pharmacy prepared a mixed solution. By combining 7 cc of one percent cyclopentolate, 7 cc of one percent tropicamide and .625 cc of ten percent aqueous phenylephrine in a 15 cc dropper bottle, a solution containing one-half percent cyclo­pentolate, one-half percent tropicamide, and 2.5 percent phenylephrine was prepared. VVe divided 11 neonates into two subgroups:

Subgroup A-four infants from 36 to 38 weeks and weighing 2200 to 3000 grams received a total of three drops in each eye. Subgroup 8-seven infants from 37 to 44 weeks and weighing 1769 to 3800 grams received just one drop of the solution in each eye.

RESULTS

Group I

Approximately ten minutes following ocular application of 10 percent aqueous phenyleph­rine, there was blanching of the skin around the eyes in all cases (Fig. 1). The blanching was most intense between 20 and 30 min utes. This phenomenon has been previously reported. 5

,6

Our data, recorded on Table I and Graph I, shows a consistent but variable rise in blood pressure ranging from 10 to 26 mm Hg systolic and 2 to 14 mm Hg diastolic. The effects on heart rates vvere variable. In four of the s~x

cases, we observed a drop in heart rate, perhaps explained on the basis of a rise in blood pressu re ca using a reflex slowing of the hea rt. 7

This is further discussed in the section to follow.

Pupil sizes ranged from 4 to 6 mm (average 5.0 mm) and did not vary with direct light stimulation. It is worth noting that in patients no. 5 and no. 6, both with dark irises, there was minimal dilatation and yet considerable change in blood pressure. The blue-eyed baby, patient no. 2, had a maximum dilatation in this series. This phenomenon has been previously reported by Haddad et a I. 8

Group II: Doubie Blind Study.

Subgroup /I-A: Th is series involved three infants who received one percent cyclopen­tolate. (See iable and Graph II-A.) We observed no significant variation in blood pressure. Patient No.3 presented an interesting finding in that there was a steady rise in heart rate. ihis may represent the action of the anticholinergic

110

Fig. 1. Blanching of the periorbital area from phenvlephrine.

agent on the heart.9 Maximum dilatation was 5 mm in all three cases; however, in the presence of a high intensity lamp, two of the pupils dropped to 4 mm.

Subgroup /1-8: Four patients received 10 percent aqueous phenylephrine in the second series of cases. (See Table and Graph II-B.) Three of the infants developed blanching of the skin around the eyes. Curiously, the 35-week­old, 1860 gram black infant was the exception. In two patients, No. 1 and No.4, there was a consistent rise in blood pressure. A drop in heart rate was also observed in patient No.4. Dilatation was from 3.0to 5.0 mm (average 4.4 mm). Maximum dilatation was observed in tbe blue-eyed infant. it was interesting to note that there was greater dilatation in the white, thoug h more mature babies.

Subgroup /I-C: Group II-C comprised three patients who received our control solution of normal saline. (See Table and Graph If-C.) As expected, pressures and heart rates were stable. There was no dilatation.

Subgroup I/-D: This series of three patients received 10 percent viscous phenylephrine. This agent was included in order to compare its effects with the 10 percent aqueous solution. (See Table and Graph II-D.) One of the infants displayed a steady and consistent elevation 1n blood pressure with an associated fall in heart rate. (Note that the weight of this infant was only 1040 grams.) The other two infants showed no significant variation in pressure or heart rate. Dilatation ranged between 4 and 5 mm (average 4.7 mm) and light reflexes remained active in two of the patients. Blanch­ing occurred on the skin around the eyes in two cases.

Subgroup II-E: Three babies received one

MARCHI APRIL, VOLUME 15, NUMBER 2

CASE WEEKS

WEIGHT

RACE

IRIS

(X)NI'R)L

5 MIN.

10 l-lIN.

15 l-lIN.

30 l-lIN.

A I: l..4"TlI.l --rJ r.L.L..l ....

60 l-ITN.

PUPIL

PUPIL E LIGHT

70

~ ~ 60

~ 50

~ u

~ ~

1 37

2000

Spanish

Bro ... n

B.P. H.R.

58/20 100

68/22 98

70/20 160

72/30 128

76/22 120

~o /<")1\ 11'L4 UOF ~v .LV"'I

58/24 98

5H1

Sl-IH

/ / 5 10

2 40

4060

hrute

Blue

B.P. H.R.

98/68 188

98/70 180

100/66 176

112/70 180

106/56 178

00/.,., It::n UV/ ,6. .LVU

108/62 164

6MM

eM

/ 15

/ 20

TABLE I

3 38

3800

White

Grey

B.P. B.R.

56/28 160

68/32 140

64/36.138

82/42 141

74/24 128

l:"l/~n l"Jn u",/...Ju J...J\J

68/28 128

Sl-M

Sl-lM

GRAPH I

/ 25

/ 30

4 5 6 40 34 34

3220 1530 1700

White White Black

GreY Br.Black Br. Black

B.P. H.R. B.P. H.R. B.P. H.R.

60/36 140 58/20 128 48120 168

62/38 142 68/22 122 58/20 184

60/42 132 68/28 140 68/22 156

62/40 120 68/28 136 68/24 154

68/50 120 68/32 132 66/22 152

.,., /c" "n .:,,/.,-, 1-'0 t::.t::/-,o 1 At::. '~/.,J..., J..J..\oI' VV/ ~L.. ..LL.U UU/ ' ..... ~'v

72/50 112 58/24 140 64/24 144

6r-M 4W1 4!-lM

6z"N 4M-i 4l-M

--.... CASE In

/ 35 40 45 50 55 60

percent tropicamide in this group. (See Table and Graph II-E.) No significant changes were observed. Dilatation ranged from 5 to 5.5 mm (average 5.3 mm).

Dilatation ranged from 4 to 5 mm (average 4.5 mm). Two patients retained a response to our light source with a.1 mm change. There was no blanching noted.

Subgroup II-F: This series consisted of three babies receiving aqueous phenylephrine. (See Table and Graph II-F.)There were no significant changes in blood pressures or heart rates.

Group 11/

A group of 12 infants received a combination of drops. (See Table and Graph III.) In two of the

JOURNAL OF PEDIATRIC OPHTHALMOLOGY AND STRABISMUS 111

TABLE II-A

CASE 1 2 3

WEEKS 38 36 35

WEIGHT 3840 2240 2000

PACE White White White

IRIS Gr.B1k BrO\-.n Lt. Brown

B.P. H.R B.P. H.R. B.P. H.R.

CCNZ'roL 76/32 156 78/26 146 56/20 144

5 MIN. 78/34 140 76/30 132 62/20 144

10 HIN. 78/34 152 84/24 152 60/20 148

15 MIN. 78/30 144 86/26 140 64/20 160

30 Mm. 78/26 146 83/30 160 56/20 160

45 HIN. 7Qn') lr:;') on!?/': l/,:') r:;o /?n l/':O • \J,..,_ .......... ..... .." ............. ...,- ..." .... , -...............

60 HIN. 78/28 152 78/20 172 58/20 152

PUPIL sr·N Sl--lM sr--r-l

PUPIL E LIGHI' 4l>M SI-1H 4M'1

GRAPH II·A

A

\ 160 -

~ 1150 .-_-._11"""

140 -

TIME

lHOUR

infants, there was a rise in both systolic and diastolic blood pressures. One of these was a blue-eyed 33-week-old baby; the other was a 37-week-old oriental with a grey iris. Heart rates did not vary significantly. The dilatation provided was from 7 mm to 8.5 mm (average 7.7 mm). There was no skin blanching.

112

I

TABLE I1-B *

1 2 3

35 41 36

1860 4350- 2400

Black h'hite Oriental

Br.Blk Blue Grey

B.P. H.R. B.P. H.R. ~_P. H.R.

48/20 168 80/20 178 ~6/20 126

58/20 180 78/30 132 156/20 132

60/20 180 78/32 160 52/20 120

~8/24 172 88/34 156 ~6/20 128

68/26 160 80/38 144 52/20 116

172/28 152 84/28 152 54/20 116

58/26.188 86/28 148 ~2/20 116

4-1/2M-l 51·1:-1 3!-M

1~-l/2l>M 4l>M 2l>M *-Skm Blanching

60

50

40

/ / /

TIME

Group IV

* 4

40

2760

White

Br.Grey

B.P. H.R.

50/20 154

46/20 128

48/20 124

56/20 116

62/20 108

r:;Q/')n 11 /': .."...,,- .... ----60/20 120

5}lM

4-1/2l>M

/ IHOOR

*

This final group of 11 infants received the premixed solution of 2.5 percent phenyleph­rine. one-half percent cyclopentolate and, one­half percent tropicamide. (See Table and Graph IV-A and B.)

Subgroup A: Three drops were administered

MARCH/APRIL, Vo"LUME 15, NUMBER 2

TABLE II-C

CASE 1 2 3

WEEKS 45 35 39

WEIGHT 3720 1680 2280

FACE Black "'!rite Spanish

IRIS Black Br.B1ack BrQl.o.n

B.P. H.R. B.P. n.li.. B.P. H.R.

CONIroL 70/24 172 42/20 134 40/20 160

5 MIN. 68/22 160 44/20 124 52/22 164

10 MIN. 68/24 176 48/20 126 44/20 160

15 MIN. 74/24 172 42/20 128 42/20 160

30 HIN. 68/24 164 46/20 128 38/20 164

45 MIN. 74/26 168 44/20 128 42/20 160

60 MIN. 74/28 164 46/20 124 38/20 158

PUPIL 3l-N Jr.N 21>!1-1

PUPIL E LIGHT 2. ... IM 2!--I1 1}I1

GRAPH II-C , CASE #2

50

40

~~ ~~ / / / /

1HOOR

TIME

in each eye of four infants at five minute intervals apart. There were no changes in heart rates or blood pressures. At one hour the average dilatation was 7.1 mm.

Subgroup B: This 9 roup of seven received just one drop in each eye. Therewere no changes in heart rates or blood pressures. Average dilata­tion at one hour was 7.0 mm.

I

TABLE II-D

1 2 3

36 36 37

1040 1440 2700

Spanish Black "l1ite

Brov.n Brov.n Blue

B.P. H.R. B.P. H.R. B.P. H.R.

44/20 166 54/20 122 62/26 134

36/20 170 58/20 120 62/22 120

38/20 158 56/20 116 58/20 116

44/20 142 46/20 120 64/28 124

54/20 132 46/20 116 68/30 132

54/20 132 54/20 ll6 64/28 132

48/20 138 46/20 120 66/32 132

9M 4M1 5NM

4J.f1..1 4!-N 4!-M

GRAPH 11-0

50 1

" • § CASE U

~ ~ 40 ~ V P.

t>

I 30

J J J J 1 HOUR

TIME

REVIEW OF THE LITERATURE

Phenylephrine: (NeD-Synephrine, IsophrinJ

Phenylephrine-HC1 (Ievo- -hydroxy -3-methylamino-3-hydroxyethyl-benzene-HC1 ) was first studied by Barger and Dale in 1910.10

It was not until 1936 when Health reported its use in op~thalmology.9

The difference chemically from epinephrine

JOURNAL OF PEDIATRIC OPHTHALMOLOGY AND STRABISMUS 113

TABLE II·E

CASE 1 2 3

WEEKS 37 32 39

WEIGBT 2280 1260 1780

RACE Spmish Black Black

IRIS Bra-m Grey Br.Black

B.P. H.R. B.P. B.R. B.P. H.R.

CONI'ROL 62/28 154 38/20 150 60/22 162

5 MIN. 64/28 152 34/20 140 62/22 164

10 MIN. 68/28 160 38/20 150 62/24 160

15 MIN. 66/28 160 40/20 140 62/22 160

30 MIN. 58/26 148 44/20 144 58/28 164

45 MIN. 68/26 144 40/20 150 54/26 160

60 MIN. 68/26 140 42/20 140 60/24 160

PUPIL s,r.M 5-1/2!-'M 5-l/2M1

PUPIL E LIGHT 5f.IH 5-l/2n1 5-1/2M-1

170 j GRAPH II·E

......

i 160

I CASE #3

150

/ / / / 1 HOUR

TIME

is that it lacks an OH group at the C-4 of the benzene ring, It is a white crystalline. relatively stable compound, readily soluble in water and alcohol. It has been following chemical struc­ture:7

@,"56

HO 4 c=J 1 l(-C-N

HO ~ 2 OH @, ~ C·C·N

I I HO OH C

Epinephrine Phenylephrine

114

TABLE II·F

1 2 3

36 35 34

1860 1800 1720 - .

Black Black Black

Brown BrQ\o,n Br. Black

B.P. H. R. B.P. H.R. B.P. H.R.

42/26 126 52/20 140 52/20 160

46/20 144 56/20 132 56/20 156

42/22 136 58/20 136 54/20 152

44/24 140 60/20 128 52/20 152

38/22 132 56/20 128 54/20 160

38/20 128 56/20 124 50/20 156

40/22 128 50/20 132 50/20 160

5f.1l1 4-l/2M1 4M1

Sl-M 3-1/2!-M 3lli

GRAPH II·F

60

~ ~ til

50

~ CASE #2 u

e ~

40

/ / / / 1 HOOR

TIME

Having almost a pure alpha adrenergic effect, the heart, which contains beta receptors, is not directly stimulated. Mechanism of action is mostly by direct stimulation at the alpha receptor sites, There seems to be some ability to liberate stored nor-epinephrine. The main effects of phenylepinephrine are within the cardiovascular system by contraction of smooth muscle within the walls of arterioles. This vasoconstriction results in an increased pe-

MARCH/APRIL, VOLUME 15, NUMBER 2

<­o C ::0 Z ~ r o ." LI m o ~ ::0 n o "0 :I: ~ :I: ~ r $: o r o G)

-< ~ Z o en -i :0 ~ OJ in s: c en

--Ul

CASE

WEEKS

WEIGHT

RACE

IRIS

CONI'ROL

5 MIN.

10 MIN.

15 MIN.

30 MIN.

45 MIN.

60 MIN.

PUPIL

PUPIL ,E_LIGHT

I 1

30

1280

Span.

Brown

BP HR

60/20 144

54/20 152

68/28 120

68/30 124

60/24 140

60/22 140

66/20 172

SMr-1

8MM

~ 80-

~ 70-P4 rO

-

~ SO-U)

" ., 36

2160

Black

Grey

BP HR

52/20 180

54/20 176

56/20 180

56/20 180

52/20 180

56/20 176

56/20 176

8-1/~1M

8-1/~'!'L

,--

I

TABLE III ,---3 4 5 6 7 8 9 10 11

36 33 37 36 38 42 39 37 37

1870 2040 2280 2000 2260 2460 2270 2260 2740

Black White White Black Span. White White , Black Oriental

Black Blue Brown Br.Blk Brown Brown Br.B1k Brown Grey

IBP HR :BP HR ,BP HR 'BP HR 'BP HR BP HR BP HR BP HR :BP HR

68/20 147 50/22 148 70/20 160 54/22 160 54/20 156 58/20 146 56/20 158 48/20 160 50/20 160

68/24 160 60/26 140 68/20 162 56/22 168 54/20 152 60/20 144 58/20 156 50/20 160 56/26 160

68/22 142 68/30 140 70/20 160 54/20 158 52/20 144 60/20 144 62/20 156 52/20 156 62/34 160

64/26 144 72/38 144 72/20 164 56/20 172 54/20 148 60/20 140 60/20 160 58/20 160 74/34 136

64/20 152 58/28 140 74/20 160 52/20 164 52/20 148 58/20 140 56/20 160 48/20 152 64/32 140

64/28 140 62/34 144 66/24 160 50/20 164 54/20 152 58/20 .1:3~f4/20 154 50/20 160 64/30 156

62/24 160 64/30 136 64/20 1S6 54/20 156 54/20 146 58/20 136! 54/20 154 50/20 156 58/28 152 -.

7M4 8MM 8MM 7-l/2M-f 7-1/2MM 8MM 7MM 7MM 8M>1

I 7M4 8MM --- 8MM 7-1/2MM __ 7-1/2M-1 __ 8~ 7MM 7MM 8M>1 _._---_.-

/ / TIME

-

/ 1 HOUR

GA:APH 111 (CASE #5)

170 -

160 -I~"'"

~ I ·150-

I ---y----;- - --; TIME 1 HOUR

12

39

340

Sp:m.

Brown

BP HR

80/30 158

74/32 156

74/28 152

82/30 160

82/30 156

88/30 144

81/32 156

7-1/2!-'IM

7-:1/~

TABLE IV-A

CASE

I

1

I

2

I

3

I

4

WEEKS 37 36 38 38

\=.t"'EIGHr 2200 3000 2170 2960

RACE White Oriental Black White -

IRIS Blue Grey ErcN.n Brov.n

B.P. B.R. B.P. B.R. B.P. H.R. B.P. H. R.

CCNI'ROL 52/22 164 70/30 156 64/28 164 60/20 144

5 MIN. 50/24 172 70/28 156 60/24 160 56/20 140

10 HIN. 48/22 168 70/30 156 74/32 160 58/20 144

15 MIN. 54/22 164 74/32 156 64/30 164 60/20 148

30 l-ITN. 48/22 160 68/30 152 64/28 160 60/20 152

45 BIN. 52/20 160 72/28 148 64/30 160 62/20 140

60 MIN. 54/20 160 74/26 156 66/24 156 64/20 144

PUPIL 71'N 7l-M 8M-! 6-1I2r-1M

PUPIL E LIGHT 71'N 7l-N 81-M 6-1/2r-M

GRAPH IV-A (CASE #3)

~ Ul

~ 50 ~

u

~ ~

/ / / / IHCUR

TIME

ripheral resistance, hence, eievation of systoiic and diastolic blood pressure. In an intact subject, this usually results in a reflex slowing of the heart rate via the parasympathetic system. This reflex bradycardia is consider­able.1,11

When the drug reaches the eye, either via the blood st~eam or by ocular instillation, it relaxes the sphincter muscle of the iris and strongly contracts the radial muscle fibers. It lowers intraocular pressure by slowing the infl ux of

116

170-

~ i

150-

/ / / / IHCUR

TIME

aqueous humoi. U a 10 p6icent solution is used, there is occasionally light cycloplegia .9,12

In the normal human eye, the effects on pressure and accommodation are slight, if any, However, in patients with open angle glau­coma, it may raise or lower pressure."1t may precipitate angle closure glaucoma in patients with narrow anterior angles and shallow anterior chambers. 13

Clinical uses of phenylephrine in ophthal­mology were described by Heath in 1949.lt may

MARCH/APRIL, VOLUME 15. NUMBER 2

TABLE IV-B

CASE 1 2 3 4 5 6 7

~"lEEKS 37 43 37 38 40 40 44

WEIGHT 2100 3400 1850 1760 2330 3000 3860

RACE Black Mute Black Black White hbite Spi:mish

IRIS Bro"n B~n Grey ~n Blue Blue Bra.m

B_P. H.R_ B.P. H.R. B.P. H.R. B.P. H.R. B.P. H.R. B.P. H.R. B.P. H.R.

CCNl'ROL 78/38 132 44/20 144 42/20 166 62/18 160 64/20 160 76/30 152 68/28 152

5 MIN 80/40 140 44/20 144 44/20 166 64/22 160 68/24 164 78/32 156 72/32 156

10 MIN. 80/38 136 46/20 148 40/20 162 66/22 164 66/20 160 80/32 152 70/32 152

15 MIN. 76/36 132 44/20 148 44/20 166 62/20 160 62/22 164 76/30 148 70/28 152

30 MIN. 76/40 132 46/20 144 42/20 162 60/20 156 64/20 160 74/20 144 68/28 152

45 HIN. 78/40 132 46/20 148 42/20 162 62/20 160 66/20 160 76/30 152 68/30 148

60 l-llN. 78/40 132 44/20 144 42/20 166 62/20 160 64/22 160 76/28 154 68/30 152

PUPIL 6-l/2}.N 7!-M 6-l/2r-N 7m 7-1/2!-N 7-1/2!-~1 7!-M

PUPIL ELIgHI 6-1/2!-i·l 7l-Jt.l 6-l/2!-M 7m 7-l/2!-N 7-l/2.\jt..l 7!-N

GRAPH IV-B

80

§ U)

~

8: u

~ 70

~

/

TTI1E

/ /

(CASE U)

/ 1HOOR

hn I.~~"" '!"'II~. 11 \ ~ rlnr-n.nnCt.t'-ti,,1""'I. ...... _n_+. I"", _ .......... LlV" U.:J-IIOJU U~. \ " U '-4I"". .... VIl~v,,;:)lIV~ c;JI~wIU, \'1 (]~ a

value for infiltrative anesthesia 9; and (3) as a

vasoconstrictor in the conjunctival sac.l-t A fourth use is a mydriatic for breaking adhe­sions. for refraction, for cyclosplegia, for over­coming extreme myosis in glaucoma, prior to intraocular surgery, for provocative testing for glaucoma, and as a mydriatic supplement when there is sensitivity to the mydriatic being used.

A drug applied to the conjunctival sac may become absorbed in varying amounts and may

~ ~

140

A \

130

/

E

/

TIME

/ I IHCUR

haVe clinically evident systemic reactions not due to hypersensitivity or idiosynchratic reac­tion. 1I There have been a number of articles written about such events with the ocular use of 10 percent phenylephrine. In 1956, Mc" Reynolds et ailS used 10 percent phenylephrine ophthalmic solution in 100 hypertensive pa­tients and there were no significant systemic reactions. In six of his cases, there was an elevation of no more than 10 mm Hg. He then reported a case of a subarachnoid hemorrhage

JOURNAL OF PEDIATRIC OPHTHALMOLOGY AND STRABISMUS 117

in a 35-year-old man following usage of a cotton wick soaked with the 10 percent solution. Previously, one percent atropine sulfate drops had been used every hour. It seems possible that the atropine was absorbed and blocked any vagal stimulus, thus allowing an exaggerated phenylephrine effect.

In a case described by Lansche in 1966,16 a 57-year-old diabetic male with rubeosis iridis developed a blood pressure of 220 mm Hg following one drop of 1 0 percent phenylephrine in an anesthetized eye. His pulse rose to 120. He turned pale, became faint, began to sweat profusely and developed a severe occipital headache without chest pain. Here, the situa­tion was one of combining a topical anesthetic with 10 percent phenylephrine in the presence of conjunctival hyperemia. Apparently, this allows a greater amount of absorption of the drug into the blood stream, as if given by subcutaneous injection.

In 1972, Solosko et al 17 reported three cases of severe hypertension following the use of ocular solutions. Two of the cases were in their sixties and in combination with either atropine or anesthesia. His third case was a three­month-old female weighing 12 pounds, who also received atropine both in her conjunctival sac and intramuscularly. SystemiC absorption of cutaneous and ocular use of atropine is known to occur.1S

-21

In 1973, Borromeo-McGrail et al5 studied the effects of 10 percent phenylephrine eye drops in neonates and reported significant hyper­tension in low birth-weight infants. In a double­blind study it was given to three infants, and in an open trial it was given to eight. The double­blind revealed a rise of 12-16 mm Hg systolic and 10-14 mm Hg diastolic pressures. There was no change in pulse rate. All infants tested apparently had a "full" pupillary dilatation in 25-30 minutes. Blanching was consistently observed. Their recommendation of using only one drop of 2.5 percent phenylephrine is certainly safe. but impractical for ophtha!­mology.

In 1949, Heath claimed that he had never noted or reported damaging effects on ocular tissues or blood vessels. Sensitivity or delayed healing have not thus far been reported.9

However, there have been several articles written on the direct toxic effects on the eye. In 1961, Mitsui and Takagi,22 using a five percent solution in older patients, observed occasional pigment floaters in the aqueous. These dis-

118

appeared in 12-24 hours and they were similar to the melanin of the pigment epithelium of the iris. Lowenfeld, in a personal communication with Haddad et al,8 observed an occasional rebound miosis in the elderly. and that sub­sequent use of the drug produced less mydria· sis in the elderly than that of the initial instillation. In a separate study of 32 patients, Haddad et al8 reported one case of rebound miosis in a 50-year-old subject. He also observed occasional pigmented floaters, pri­marily in older patients with dark irises. He described the phenomenon of rebound miosis as age-related.

PhYSiologically. when dropped in aqueous form into the conjunctival sac, a drug enters the aqueous humor mainly byway of penetration of the cornea. and in many cases, its effects are limited to the anterior chamber. 2

] Systemic absorption from the anterior chamber is slow and ·limited in degree. If the lens is absent, a minor amount may distribute posteriorly and if the quantity is great enough. macular damage may occur.9 By placing the drug under a contact lens or in cotton or using a greater drop viscosity, prolonged contact with corneal epi­thelium is permitted. This allows greater penetration. This is also true if the cornea is diseased or damaged. Such is the case also with local anesthetics, wetting agents, mas­sage, and abrasions. Theoretically, a compound must be lipid soluble to penetrate the corneal epithelium and water soluble, to cross the corneal stroma.2]

Possible mechanisms for rapid systemic absorption would be via the capillaries within the conjunctiva. As the drug passes over the surface of the eye and on through the lacrimal drainage system, it may be absorbed via the nasal mucosa. If it reaches the oropharynx or gastrointestinal tract after swallowing, this could be another means of absorption. Hyper­emia of the mucosa and lacrimal duct obstruc­tion would tend to increase absorption and conversely, excessive tearing would decrease absorption. It is worth mentioning that since the majority of the drug is absorbed prior to reaching the stomach, it therefore escapes any metabolic degradation by gastric enzymes. II

In January 1974, the British Medical'Jour­naf4 discussed other factors which could explain systemic reactions in our study and in the previous studies: (1 )the dose to body weight ratio is greater in infants; '(2) the muscosa to which it is accessible is readily permeable to

MARCH/APRIL, VOLUME 15. NUMBER 2

the drug; and (3) the route of administration bypasses any physiologic transformation of the drug. Furthermore. in a study on preterm infants less than 21 days postnatal life, Nachman et al6 showed an increased skin permeability by observing degrees of skin blanching from topically applied 10 percent phenylephrine. He observed that infants from 38 to 42 weeks failed to exhibit the response. It was postulated that the barrier function of the epidermis in preterm infants is also immature. It has been shown that absorption of chemicals does occur in nurseries.6

Cyclopentolate: (Cyclogyl)

Cyclopentolate (B-dimethylaminoethyl-(l-hydroxycyclopentyl)-p henyl . acetate hyd ro­chloride)25 is an anticholinergic mydriatic cy­cloplegic drug which belongs chemically to the class of basic esters of substituted phenyl acetic acids. It is a white. water-soluble

Clrystall~hose str:cture fOIlOWS:~

. / J, o O-(CH!)N-(CH!b.HCl

Cyclopentolate Hydrochloride Its effect on the eye is rapid and it has a short

duration of action. IJ•28 In normal subjects. it

does not alter intraocular pressure signifi­cantly.2S,26.~9 However, it may produce acute angle closure glaucoma in susceptible indivi­duals.

This drug has been studied extensively and had previously been devoid of toxic reactions from its ocular usage. Stolzar36 reported a study of 180 cases without any evidence of general or local toxicity in human subjects and in test animals. Other researchers have shown similar concl usions. 25.26

In 1951. Priestly et al 26 found that when two drops of 0.5 percent cyclopentolate was drop­ped in each eye five minutes apart. there was "complete" mydriasis of average size 7.0mm at about one-half hour in Caucasians and at 60 minutes in Negroes.

There have si nee been several reports of toxic effects with instillation of these eyedrops. In 1962, SimcoeJl reported an eight-year-old black female who. following two drops of one percent tropicamide and four drops of one percent cyclopentolate. developed "marked ataxia." dysarthria and incoherent speech along with other evidence of altered cerebellar function. There was no hyperactivity. nor did

the patient show changes in temperature. pulse. respiration or become flushed with drug skin and mucous membranes. This incident was duplicated by readministration of six drops of 1 percent solution on a later occasion. He noted also that children with brain damage were even more susceptible to similar reac­tions. That same yea r, Beswick~~ reported a case of a nine-year-old white boy. who upon receiving four drops of two percent cyclopen­tolate. began to hallucinate and actually tried to hide beneath the waiting bench in fear. His reaction lasted about three hours. Following recovery. the child was unable to recall the incident.

In 1963, Mark~J reported four cases and claimed that side effects to the drug did occur. but infrequently. Reactions consisted of a schizophrenia-like behavior pattern with ataxia. Three of his patients were fourteen years old and younger. and they all had received varying amounts of the one percent solution. Also in 1963. Binkhorst et alB conducted a study using two percent cyclopentolate in 40 children and adolescents and a second study of 35 cases using a double-blind approach. He included one percent and two percent cyclopentolate and reported that the two percent solution produced a statistically significant incidence of psychotic reactions characteristic of an acute brain syndrome. There were no significant changes with the one percent solution.

In 1964. Praeger et alH reported a case of a seven-year-old white male who. after use of four drops of the two percent solution. mani­fested signs and symptoms of cerebellar dys­function and visual hallucinations.

In 1967. CarpenterJ5 reported toxicity from four drops of a 0.2 percent solution in an 82-year-old white male who responded by de­compensation of a previously compensated chronic dementia. The patient did not return to the "status quo ante." as was the case in all previous reports of toxicity.

In 1970, Adcock J6 reported a four and one­half year-old male Caucasian who received six drops of a two percent solution. The child became markedly flushed and his mucous membranes became dry. This continued over the next hour and was accompanied by periods of wretching. hallucinations. gross' ataxia. incoherent babbling. confusion. somnolence. episodes of hyperactivity. an inability to recog­nize fa mily members. and an acute tachycardia. Central nervous system toxicity lasted about

JOURNAL OF PEDIATRIC OPHTHALMOLOGY AND STRABISMUS 119

seven hours, but the tachycardia was noted for 36 hours.

Kenderdell et al 37 reported two cases of grand mal seizures associated with two percent cyclopentolate eyedrops in 1972. One case was an 11-month-old white male who received one drop in each eye. The other was a 12-year-old known epileptic.

In 1973, Bauer et al3s reported systemic toxicity in newborns. A pair of premature black twins, after eight days of perinatal life, received one drop in each eye of ten percent phenyleph­rine and one percent cyclopentolate repeated twice at five~minute intervals. Symptoms in­cluded vomiting abdominal distention and ileus. After both had apparently recovered. one subsequently died from necrotizing entero­colitis and an intestinal perforation. Intoxica­tion by the drug was confirmed by blood analysis of the infant.

In 1974, a six-year-old girl was reported to have tripped several times on the way home from the office where she had received one percent cycJopentolate and 0.25 percent hyo­scine eyedrops. She apparently became very aggressive and said odd things. She was subsequently brought to the accident depart­ment actively hallucinating. By the following morning, she had recovered completely with­out recall of the incident.39

Tropicamide: (Mydriacyl)

Tropica m ide (N-ethyl- 2-p hen Iy-N -(4-pyridylmethyl)-hydracrylamide) is an anti­cholinergic mydriatic cycloplegic agent which has become known for its short latency period and its excellent pupillary dilatation. It is very short acting and produces greater mydriasis in subjects with lightly pigmented irises.4O--

43

Its structure is as follows:

@- C-OH -@ <==:) . ~-C-N.C <==:) N

II I o c-c -

Tropicamide

Being an anticholinergic agent, as is cyclo­pentolate, the mechanism of action in the eye is to block the effects of parasympathetic innerva­tion as well as to block cholinergic drugs acting on the ciliary body and the blood vessels of the eye.9 ln normal eyes, it rarely causes significa nt alteration of intraocular pressure. However, in

120

open angle glaucomatous eyes, it may cause the pressure to rise. As with cyclopentolate, it may precipitate acute angle closure glaucoma in subjects with shallow anterior chambers and abnormally narrow angles. In animal testing, there have been no detectable histologic abnormalities. Since the drug is not intended for long-term usage, one is not likely to encounter a chronic toxicity. If the drug is absorbed systemically, one would observe classical signs which would include redness and dryness of the skin. dry mouth, increased pulse and body temperature, and disorientation with visual hallucinations.9

,1l

The only report found in the literature of adverse effects following ocular administration was by Wahl et al.44 In 1969, he reported an incident, perhaps best described as an acute hypersensitivity to the 0.5 percent solution in a ten:year-old white boy. which read as follows:

Immediately following instillation of one drop of 0.5 percent tropicamide in each eye, he fell from his chair to the floor unconscious.~~

There was no bowel or bladder incontinence, no psychotic behavior. ataxia, flushing or state of hyperactivity, all of which would be an indication of anticholinergic toxicity.9,13t2I M

-I

Simcoe3\ reported that he has used up to ten drops of the one percent solution over a 30-minute period without producing toxic effects.

It is generally agreed that in order to permit adequate examination of the fundus and a thorough examination by slit lamp, a mydriatic agent should produce at least 7 mm dilatation. The most suitable drug would be one which opens the pupil rapidly and painlessly without untoward symptoms. If a problem should occur, as in precipitating acute glaucoma in sus­ceptible individuals, it should be easily counter­acted by a mild miotic.41~s In studying the mydriatic effect of 10 percent phenylephrine, Cambill et al 40 measured the responses to a variety of agents by means of an infrared electronic pupillograph. They observed that in adults there is a latency period of approximately 21 minutes with a maximal effect at 65 to 72 minutes. It produced less dilatation than tropicamide.1t has also been demonstrated that dilatation varies with eye color. The least dilatation was observed in hazel-eyed subjects and the greatest was noted in those with blue irises. It was further demonstrated that there was almost identical mydriasis produced with both 10 percent and 2.5 percent phenylephrine solutions.s

MARCH/APRIL. VOLUME 15. NUMBER 2

CONCLUSION Many drugs used as drops are absorbed

systemically and cause changes in vital signs. We have shown this to be the case with several of the more common mydriatics. If an agent has the potential to cause an elevation in blood pressure, it may well do so after ocular instillation. In a newborn especially if preterm, such an occurrence could precipitate or further a cerebral hemorrhage. It would seem impera­tive that blood pressures be known prior to the use of such ·agents and if they are elevated, then use should be avoided.

Ten percent aqueous and viscous phenyleph­rine causes blanching of the skin around the eyes of newborns. In most cases, it ra ises both systolic and diastolic blood pressures.

Ten percent aqueous or viscous phenyleph-rine, one percent cyc!opentolate, one percent tropicamide and 2.5 percent phenylephrine, when used alone in our study for a total dosage of three drops in each eye, did not provide adequate dilatation to view the periphery or the retina. This is essential for identifying the early changes seen in retrolental fibroplasia. 2J

Our "combination drop" protocol is effective in providing ari average dilatation equal to or greater than 7.0 mm in the presence of a high intensity spotlight. Using separate dropper bottles and placing a total ofthree drops in each eye of 2_5 percent phenylephrine, one percent cyclopentolate, and one-half peiCent tiOpica­mide we obtained an average dilatation of 7.7 mm. In two cases of this series, there was an elevation of blood pressures with no variation of heart rate. Cyclopentolate may cause an elevation of heart rate when used as a one percent solution for eyedrops.

In an attempt to facilitate the application of drops and to lessen the concentrate of cyclo­pentC!late, we prepared a 15 cc droppersolution containing 2.5 percent phenylephrine, one-half percent cyclopentolate and one-half percent tropicamide. With one drop in each eye repeated twice at five minute intervais for a total of six drops we observed average dilata­tion of 7.1 mm without any skin blanching or changes in pressures or heart rates. With a second group of seven babies we then applied only one drop in each eye. There were no changes in pressures or heart rates. After one hour the average dilatation was 7.0 mm.

It is obvious from this study that the use of 2.5 phenylephrine alone is not adequate for proper examination of the retina with the .indirect

ophthalmoscope. The original protocol of nine drops, although safe by our testing, certainly may have toxic effects. Therefore, the single instillation of our combination drops proved to be very effective while safe and we recommend it highly in examination of newborns in the nursery.

SUMMARY

During routine dilatation of 48 newborns, systemic responses and pupil dilatation were monitored. Both 10 percent aqueous and viscous phenylephrine caused blanching around the eyes and produced considerable rise in blood pressure. Dilatation average 4.7 mm. I n a double blind study, a 2.5 percent solution caused no skin blanching and no change in pressure or heart rate. Average dilatation was 4.5 mm. . No blood pressure changes were observed

with either one percent cyclopentolate or one percent tropicamide. Average dilatations were 5.0 mm and 5.3 mm respectively.

The above agents, used individually for a total dosage of three drops in each eye did not provide adequate dilatation for a thorough funduscopic examinaton.

Our protocol at United Hospitals Medical Center is a safe combination of drugs and provides excellent dilatation averaging greater than 7 mm. No skin blanching or change in heart rate was observed.

REFERENCES

1. Nelson WE: The newborn infant. In Vaughan & McKay (eds): Nelson Textbook of Pediatrics. Philadelphia, London & Toronto, W.B. Saunders Co, 1975, p 368.

2. Ware RW: New approaches to the indirect measurement of human blood pressure. Pre­sented at the Third National Biomedical Sci­ences Instrumentation Symposium, (Instrument Society of America 8M-65), Dallas, April 19·21, 1965.

3. Kirby RR, Kemmerer WT, Morgan JC: Trans­cutaneous Doppler measurement of blood pres­sure. Anesth 31 :86-89, 1969.

4. Hochberg HM, Saltzman MB: Accuracy of ultrasound blood pressure instrument in neo­nates, infants and children. Curr Ther Res 13:482-487,1971.

5. Borromeo-McGrail V, Bordiuk JM, Keitel H: Systemic hypertension following ocular admin­istration of 10% phenylephrine in the neonate. Pediatr 51 :1032-1036, 1973.

6. Nachman RL, Esterly NB: Increased skin perme­ability in preterm infants. J Pediatr 79:628-632, 1971.

JOURNAL OF PEDIATRIC OPHTHALMOLOGY AND STRABISMUS 121

7. Innes lA, Nickerson M: Norephinephrine, epi­nephrine and the sympathominetic amines. In Goodman LS, Gilman A (eds): The Pharma­Cological Basis of Therapeutics, 5th ed. New York, Macmillan, 1975, pp 477-513, 526-529.

8. Haddad NJ, Moyer NJ, Riley FC Jr: Mydriatic effeci of phenylephrine hydrochloride. Am J Ophthalmol 70:729-733, 1970.

9. Heath P, Geiter CW: Use of phenylephrine hydrochloride (neo-synephrine hydrochloride) in ophthalmology. Arch Ophthalmol 41: 172-177. 1949.

10. Barger G, Dale HH: Chemical structure of sympathominetic action of amines. J Physiol (Lond) 41:19-59,1910.

11. Davidson SI: Systemic effects of eyedrops. Trans Ophthalmpl Soc UK 94:487-495, 1974.

12. Holland MG: Sympathominetic drugs. Ann Oph­thai mol 36:875-888, 1974.

13. Grant MW: Toxicology of the Eye, 2nd ed. Springfield, Charles C. Thomas, 1974, pp 144= 148, 344-345, 819-820, 1067-1068.

14. Heath P: Neosynephrine hydrochloride: some uses and effects in ophthalmology. Arch Oph­thalmol 16:839-846, 1936.

15. McReynolds WU, Havener WH, Henderson JW: Hazards in the use of sympathomineticdrugs in ophthalmology. Arch Ophthalmol 56:176-179, 1956.

16. Lansche RK: Systemic reactions to topical epinephrine and phenylephrine. Am J Ophthal­mol 61 :95·98, 1966.

17. Solosko D, Smith RB: Hypertension following 10% phenylephrine ophthalmic.Anesth 36: 187-189, 1972.

18. Heath WE: Death from atropine poisoning. Br Med J 2:608, 1950.

19. German E, Siddiqui N: Atropine toxicity from eye drops in children. N Engl J Med 282:689, 1970.

20. Hoefnagel D: Toxic effects of atropine and homatropine eyedrops. N Engl J Med 264:168, 1961.

21. Freund M, Merin S: Toxic effects of scopalomine eye drops. Am J OphthalmoI70:637-639, 1970.

22. Mitsui Y, Takagi Y: Nature of aqueous floaters due to sympathominetic mydriatics. Arch Oph­thalmol 65:626, 1961.

23. Newell FW, Ernest JT: Ophthalmology: Prin­ciples and Concepts, 3rd ed. S1. Louis, C.V. Mosby, 1974, pp 95-123, 278-279.

24. Babies' blood pressure raised by eye drops. Br Med J 1 :2-3, 1974.

25. Gordon OM, Ehrenberg MH: Cyclopentolate hydrochloride: a new mydriatic and cycloplegic

122

agent. Am J Ophthalmol 38:8317838, 1954. 26. Priestly BS, Medine MM: A new mydriatic and

cycloplegic drug. Am J OphthalmoI34:572·575, 1951.

27. Gettes BC, Leopold IH: Evaluation of five new cycloplegic drugs. Arch Ophthalmol 49:24-27, 1953.

28. Mark HH: Psychotogenic Properties of Cyclo­pentolate. JAMA 186:214-215, 1963.

29. Barbee RF, Smith WO Jr: Acomparative studyof mydriatic and cycloplegic agents. Am J Ophthal­mol 44:617-622, 1957.

30. Stolzar IH: A new group of cycloplegic drugs. Am J Ophthalmol 36: 110-112, 1953.

31. Simcoe CW: Cyclopentolate (cyclogyl) toxicity. Arch Ophthalmol 67:406-408, 1962.

32. Beswick JA: Psychosis from cyclopentolate. Am J Ophthalmol 53:879-880, 1962.

33. BinkhQrst RD, Weinstein GW, Baretz RM et al: Psychotic reaction induced by cyclopentolate (cyclogyl), Am J Ophtha!mo! 55: 1234~ 1245, 1963.

34. Praeger DL, Miller SN: Toxic effects of cyclo­pentolate (cyclogyl). Am J Ophthalmol 58: 1 060-1061,1964.

35. Carpenter WT Jr: Precipitous mental deteriora­tion following cycloplegia with 0.2% cyclo­pentolate HC1. Arch Ophthalmol 78:445-447, 1967.

36. Adcock EW: Cyclopentolate (cyclogyl) toxicity in pediatric patients. J Pediatr 79:127-129,1971.

37. Kennerdell JS, Wicher FP: Cyclopentolate asso­ciated with two cases of grand mal seizure. Arch Ophthalmol 87:634-635. 1972.

38. Bauer CR, Trottier MCT, Stern L: Systemic cyclopentolate (cyciogylJ toxicity in the newborn infant. J Pediatr 82:501-505, 1973.

39. Wang MK, Tatane JR: Other systemic effects of eye drops. Br Med J 1 :453·454, 1974.

40. Gambill HD, Ogle KN, Kearns TP: Mydriatic effect of four drugs determined with pupil­lograph. Arch Ophthalmol 77:740-746, 1967.

41. Gettes BC: Tropicamide: comparative mydriatic effects. Am J Ophthalmol 55:84-87, 1963.

42. Gettes BC: Tropicamide, a new cycloplegic mydriatic. Arch Ophthalmol 65:632-635, 1961.

43. GeUes Be, Belmont 0: Tropicamide: compara­tive cycloplegic effects. Arch Ophthalmol 66:336-340, 1961.

44. Wahl JW: Systemic reaction to tropicamide. Arch Ophthalmol 82:320-321, 1969.

45. Feldman JB: Mydriatics: a clinical observation. Arch Ophthalmol 41 :42-59. 1949.

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