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 abovo the normal blood range. the result may be Rctro l cn1<l1 Fibro- plasia.! Most premature babies who have rccoived oxygen Dro r outine ly examinated prior to hospital discharge. Of the more popular mydriat ic . ugents employ ed, 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 Cenler (UHMC) was included in the study. MATERIAL AND METHODS Forty-eight neonates of mixed races we re studied during rou tine dila tati on prior to fundu- scopic examination. In each case, the patient was slable, euthermic, supine, approximate ly one hour after feed i ng. Gestationa l ages, determined by physical and n eurolog ical char- acteristics in conj unction w ith menstrua l his- tory, ranged from 30 to 45 weeks. Present weights were from 1040 to 4350 grams. Blood pressures were obtained using a cuff wilh an ultr asound transduce r· over 'the bra- chia l artery. This concept was or iginally pre- pared by Ware z and Kirby.' and its accuracy was documented by Hochberg et aI.' The cuffs remained in place throug h out the en tir e record- ing period . Apica l heart rales were obtained by From the Department of Ophthalmology, N I! IV Jersey Medical School. This work was made possible by a grant Irom Fight for Sight, Inc. New York CilY, (a the Fight for Sighl Children's Eye Center 01 the Eye Instiwte of New Jersey . Requests for reprints should be addressed to Dr. A.R. Capulo. 15 S. 91h Slreel, Newark. New Jersey 07107. ·Roche Artl) riQ$onde 1010 Protolype. Hoffm an · LaRoche. Inc. ascuhation of the precordium. In all cases, heart rates and blood pressures were recorded for th r ee intervals at f ive minutes apart. An average of these fi gures provided contro l levels. Eye dr ops were instilled three times : one dr op in each eye at fjye minute intervals . Excess tearing or overflow was wiped away i mme- dialOly with a clean gauze. Heart rales and blood pressures we re recorded at five minute intervals for the first 15 minutes and then every 15 minutes. After one hour, retractors were applied and pupi l were measured with a small, clear plastic ruler. Sizes before and afte r a high intensity spotli ght were nOle.Q. Routine fu nduscopic examination t hen pro· ceeded. To elimin ate the possibility of subjective variation, the same investigato r 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 1530to 4060 gr ams comprised t his group . They were given an open trial 01 10 percent aqueous pheny l eph rin e. Group II: We subdivided a total of 19 cases into six subgr oups . In a doub l e blin d fashion, we r andom ly admini stered ten per cent aqueous phenylephrine, one percent cyclopento l atc, one perce nt tropicamide, and as ou r control. normal saline. These inf ants ranged from 32 to 45 weeks and weighed 1040 to 4350 grams . Group III: A group of 12 infants, wi th ages from 30 to 42 weeks and weigh ts from 1 280 to 2460 grams , received the protocol fo r dilatation used at Ut-lMC Intensive Care Nursery. This protocol is a combination of drops of 2.5 percent aqueous phenylephrine, one percent cycle· pentolate, and one-half per cent tropicamide. One drop of each was placed in both eyes and repeated at five-m inut e int ervals for three JOURNAL OF PEDIATRI C OPHTHALMOLOGY AND STRABISMUS 10 9
Transcript
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 abovo the normal blood range. the result may be Rctrol cn1<l1 Fibroplasia.! Most premature babies who have rccoived oxygen Dro routinely examinated prior to hospital discharge. Of the more popular mydriatic .ugents 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 Cenler (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 slable, euthermic, supine, approximate ly one hour after feeding. Gestationa l ages, determined by physical and neurolog ical characteristics in con junction w ith menstrua l history, ranged from 30 to 45 weeks. Present weights were from 1040 to 4350 grams.
Blood pressures were obtained using a cuff wilh an ultrasound transducer· over 'the brachial artery. This concept was or iginally prepared by Warez and Kirby.' and its accuracy was documented by Hochberg et aI.' The cuffs remained in place throug hout the entire recording period. Apica l heart rales were obtained by
From the Department of Ophthalmology, N I! IV
Jersey Medical School. This work was made possible by a grant Irom Fight
for Sight, Inc. New York CilY, (a the Fight for Sighl Children's Eye Center 01 the Eye Instiwte of New Jersey.
Requests for reprints should be addressed to Dr. A.R. Capulo. 15 S. 91h Slreel, Newark. New Jersey 07107.
·Roche Artl)riQ$onde 1010 Protolype. Hoffman · LaRoche. Inc.
ascuhation of the precordium. In a ll cases, heart rates and blood pressures were recorded for th ree intervals at five minutes apart. An average of these f igures provided control levels.
Eye drops were instilled three times:one drop in each eye at fjye minute intervals. Excess tearing or overflow was wiped away immedialOly with a clean gauze. Heart rales and b lood pressures we re recorded at five minute intervals for the f i rst 15 minutes and then every 15 minutes. After one hour, ey~lid retractors were applied and pupi l siz~s were measured with a small, clear plastic ruler. Sizes before and after a high intensity spot light were nOle.Q. Routine f unduscopic examination t hen pro· ceeded.
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 1530to 4060 grams comprised this group. They were given an open trial 01 10 percent aqueous phenylephrin e.
Group II: We subdivided a total of 19 cases into six subg roups. In a double blind fashion, we randomly admini stered ten percent aqueous phenylephrine, one percent cyclopentolatc, one percent tropicamide, and as ou r control. normal saline. These infants ranged from 32 to 45 weeks and weighed 1040 to 4350 grams.
Group III: A group of 12 infants, w ith ages from 30 to 42 weeks and weigh ts from 1280 to 2460 grams, received the protocol fo r dilatation used at Ut-lMC Intensive Care Nursery. This protocol is a combination of drops of 2.5 percent aqueous phenylephrine, one percent cycle· pentolate, and one-half percent tropicamide. One drop of each was placed in both eyes and repeated at five-m inute intervals for three
JOURNAL OF PEDIATRIC OPHTHALMOLOGY AND STRABISMUS 109
instilla tions, i.e ., nine drops in each (lye. Group IV: To facil itate t he administ rat ion of <I
co mb ination of drops, ou r ph armacy prepared a mixed so lution. 9y combin i:"l g 7 cc of one percent cyc lopentol<lte, 7 cc of one percen t trooicamidc and .625 cc of re n oercem aqueous phenyl ephr i nE! in a 1 5 cc dr:.pper bo ttle, a solution coma ining one· half percent cycla· pentolate, one· half percent (ropicamide, and 2.5 percent pnEin yl e~ h fl ne was p repared. We divided 1 1 neonates in to two subgroups:
Subgr oup A - folJr iniants from 36 [0 38 v,'esks and w eighi ng 2200 to 3000 grams rece ived a total of th ree drops in each eye. Subgroup 8 - seven infants f rom 37 to 44 w eeks and we ig"i'lg 1769 10 3800 grams received j ust one drop o! the so luti on in each By£,.
RE SULTS
Croup I
Approx imately ten minu tes follOWing ocular apoli cat ion of 10 percent aqueous pheny leph· rine, there was blancn lng of the skm ,Hound th e eyes in al l cases (Fig. 1 ). The blanching wa s most intense between 20and 30 minutes. Thi s pheno menon has been previous ly reported.''''
Our dat a, recorded on Table I and Graph I, shows a co nsistent but vari able r ise in blood nressure ranging from 10 to 26 mm Hg systolic and 2 to 14 mm Hg diastoli c. The oftects on hear t rates were variable. !n fo ur of th e six cases. w e observed a drop in heart rate, perhaps explained on t he bOlS IS of a r ise in blood pre ssu re ca using a reflex slowing of the ~eart .
Th is is fu rther discu ssed in t he section to follow.
Pupi l sizes rang£'d from 4 to 6 mm (average 5.0 mm) and did no, vary With direct ligh t stimulati on. It i s vlorth noti ng t hat in patients no. 5 and no. 6, both w ith dark ir ises, there was min ima l dil atation and yet cons iderable change in blood pressure. The blue-eyed baby, pa tl ent no. 2, had a max imum dilat ation in this seri es. Th is ph enomenon has been previously rep orted by Haddad et a l. ;
Group //: Doubl f! Blind Study.
Subgroup If·A: Thi s series involved three infan ts who recei ved one pe rce nt cyc lopenlolat e. (See Table and Gra ph II-A.) We obs tlrved no signif icant varia tion in blood pressure. Pati ent No. 3 presented an Inte:es,Jng fi nding itl that Ihere w as a stead', r ise in heart rate. This m ay rep resent the ac!ion of the amicho linergic
110
Fig. 1. 81/lnchmg of the perIorbital arr-a 'rom phenyfeph rinl't
agont on the heart.' MaXimum dilat-Ol tlon W Cl S 5 mm in at! three cases: however, in th~ presence of a h igh imensity lamp, tw O of the pupils dro;:>ped to ". mr:1.
Subgroup 1/-8 : Fourp8tiems received 10 pe rcent (lque(lus phenylephrine in t he second :;;e tles o f c C! ~s . (S e.: Ta ble and Graph 11·8.) ·ih ree of the infa nt s de"eloped bl anchi ng o f the :;;.<i n aro und the eyes. Cur Io usly. the 35·weekold, 1860 gram black infant was th e exception. In tw o pati en ts, No. 1 and 1\l0. 4, the re w as a consistent rise in b lood pressure. A drop in heart ra te was also obse rved in pat ient No.4. Dilatatio n w as from 3.0 to 5.0 mm [average 4.4 mm ). Maximum di la tatl(H"l was observed in ,be blue·eyed in fa nt. It was interesting 10 note that there was greater dil atation in the while, though more matu re babie s.
Subgroup /I· e: Group H-C comprised three patients who received our control solution of normal sal ina. (See Table and Graph II- C. ) As expec ted, press ure~ and heart rates w er(l stab le. There was no dilateti on.
Subg roup " ·0: This seri es of three pati ents received 10 percent visco us phenylephr ine. Th is agent w as included in orde r to compare its effects with the 10 pereen! aqueous solu tion. (See Table and Graph 11 · 0 .) One of the infants disp layed a ste ady and co nsist !!nt elevat ion in blood pressure w i th an as sociated fall in heart rate. [Not e that t ne w eigt t oi , Mis infant w as onl'! 1040 grams.) The other two infants show ed no signifcam varia t ion in pres sure or heart r.at \'l . Di latat ion rang ed between 4 and 5 mm (a vereg e 4. 7 mm) and light ref lexes re mained active in two of the patien ts. Blanch· ing occ urred on tha skm around t he eye s in tw O cases.
Subgroup /I-E: Th ree babies rece ived one
MARCH/APRIL. VOLU VIE 1 5. NUM BER 2
CASE >=
h"EIGirr
RACE
IRIS
CmmlL
S I·IDI.
10 Hm.
15 ~ml .
30 HIN .
45 ~m1.
60 ~m1.
PUl'IL
PUPIL E LlQIT
70
I 60
SO
~
I ~
1 37
2000
Spanish
"""'n B.P. H.R.
58/20 100
68/22 98
70/20 160
72/30 128
76/22 120
68/20 104
58/24 98
~t·l
~N
/ / 5 10
, 40
4060
~Jtite
Blue
B.P . M.R.
98/68 188
98/70 180
100/66 176
112170 180
106/56 178
88/72 160
108/62 164
6:<:·t
6.' :-1
/ 15
/ 20
TABLE I
3 JS
3800
\":hite
Ccey
B.P . H.R.
56/28 160
68/32 140
64/36 138
82 42 141
74/24 128
62/30 130
68/28 128
5!·N
5!>:M
GRAPH I
/ 25
/ 3D
4 5 6 40 " "
3220 1530 1700
\':hitc hmtc Black.
Gm Br.Bl<lcK Br. Black
B.P. H.R. B. P . H. R. B. P . H.R.
60/36 140 58/20 128 48/20 168
62/38 142 69/22 122 58/20 184
60/42 132 6a/28 140 68/22 156
62/40 120 68/28 136 68/24 154
68/50 120 68/32 132 66/22 152
72/50 110 60/22 128 66/28 146
72/50 112 58/24 140 64/24 144
€'~'·1 4!·N 4.~:1
G.'N 4.t·t ·! 4.'t1
CASE 11
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).
Dilata tion ranged fr om 4 to 5 mm (average 4.5 mmJ. Two palient s retained a response to our light source with a 1 mm change. Th ere was no blanching noted.
Subgroup I/-F: This se ri es consisted of three babies receiving aqueous ph enylephrine. (S ee Tabl e and Graph II-F.JTherewere no significa nt changes in blood pressures or heart HItes.
Group III
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
C'"" 1 , 3
-= 38 J6 35
\,UG!!l' 3840 2240 2000
PACE hhlte ~;hlte l,hiOO
IRIS Gr.Blk oro.n Lt .Bro'\o.n
B.P. H. R B. P . II.R. B.P . H.R .
mnrox. 76/32 156 78/26 146 56/20 144
5 Hill. 78/34 140 76/30 lJ2 62/20 144
10 HDI . 78/34 152 84/24 152 60/20 148
15 ~UN. 78/30 144 86/26 140 64/20 160
30 ~IDI. 78/26 146 83/30 160 56/20 160
45 HIN. 78/32 152 80/26 162 58/20 168
60 ~ml. 78/28 152 78/20 172 58/20 152
PUPIL 5:·.1 S.'N S.~N
PUPIL E LIGrr 4m SN 4m
GRAPH II-A
170
16
~ CASE t3
~ 150 --14
1 flOOR
rolE
infants, th ere was a rise in both svstolic and diastolic blood pressures. One of these was a blue-eved 33-week-old baby; the other was a 37·week-old orienta l with a grey iris. Heart rates did not va ry significantly. The dilatation provided was from 7 mm to 8.5 mm (average 7.7 mm). There was no skin blanching.
112
TABLE II -B • • •
1 , 3 4
35 41 J6 " 1860 4350· 2400 2760
Black ~:hite iental "'hite
Ilr.Dlk Dl= "'oy Br .Grey
n.p. 1I . R. B . P . H.R. .P. II.R. B.P. H.R.
8/20 168 80/20 178 6/20 126 50120 154
sa/20 180 78/30 132 '6/20 132 46/20 1 28
0/20 180 78/32 160 2/20 120 48120 124
8/24 172 88/34 156 6/20 128 56/20 116
8/26 160 80/38 144 2/20 116 62/20 108
2/28 152 84/28 152 /20 116 58/20 116
58/26. 188 86/28 148 2/20 116 60/20 120
4-1/2'N 5.'t.! 3.'N S.'~l
-l/aN <eN 2foN 4-1/2,\~·\
*-Skin Bl anc
GRAPH 11 · 8
" C'\SE n
~ 50
~ 40
~ u
B ~
I I I 1 liOOR
rolE
Group IV
This f ina l group of 11 infants received the premi xed solution of 2.5 percent phenyleph· rine, one-half percent cyclopento!a tc and, one· hall percent tropicamide. (See Table and Graph IV·A and S.)
Subgroup A: Three drops were admin istered
MARCH/APRil. VO·LUME 15. NUMBER 2
TABLE !I -e
"""" 1 , 3
h"EEKS 45 35 39
"",em 3720 1680 2280
""'" Bl"'" \\hltc,. I """,,,, I RIS Bl""" Dr .Blact Bro'~-n
B.P. M.R. B.P . n.r.. D.P. II . R.
carrroL 70/24 172 42/20 13~ 40/20 160
5 HIN. 6S/22 160 44/20 124 52/22 164
10 HIN. 68/24 176 48/20 126 44/20 160
15 MIN. 74/24 172 42/20 128 42/20 160
30 }IDl' . 68/24 164 46/20 128 38aO 164
45 HnL 74/26 168 44/20 128 42/20 160
601-ml. 74/28 164 46/20 124 38120 158
PUPIL 3.':., 3., •. , 2.'r·1
roJ'IL E LIGirr 2':-' 2.':.1 ''''
GRAPH u·e 13
'" " ~ 12 #
i CASE "
50
40
n / / / / 1 I<lJR
mE
in each eVe of four infants at five minute intervals apart . Th ere were no changes in hea rt rates or blood pressures. A t one hour the average dilatation was 7. T mm.
Subgroup B: Th is group of seven received just one drop in each eye. Th erewere no cha nges in heart rates or blood pressures. Average di lata· tion at one hour w.as 7.0 mm.
TABLE 11-0
1 , 3
36 36 37
1040 1440 2700
I SPl-'1.is."I Black hllite
-~ .~n .'00 B.P. M.R. a.p. fi.R. B.P. H.R.
44/20 166 54/20 122 62126 134
36120 170 58/20 120 62122 120
38/20 158 56/20 116 5~/20 116
44/20 142 46/20 120 64/28 124
54/20 132 46/20 11 6 68/30 132
54/20 132 54/20 116 64/28 132
48120 138 46/20 120 66/32 132
5.'i·' 4~N s..'N
4~N 4.'N m'l
GRAPH 1/· 0
50 1 I
CASE 11
40
• u
~ 30
7 7 7 7 1 liooR
,.""
REVIEW OF THE LITERATURE
Phenylephrine: (Nco. Synephrine. Isophrin)
Phenylephrine·HC 1 (leva· .hydroxy ·3· methylamino·3·hydroxyethyl ·benzene·HC 1) was first studied by 8arger and Dale in 1910.10
It WllS not until 1936 when Hea lth repon ed i ls use in op~lharmology.·
The difference chemically from epinephrine
JOURNAL OF PEDIATRIC OPHTHALMOLOGY AND STRABISMUS
TABLE II -E
CASE 1 2 3
,= 37 32 39
~!EtQrr 2280 1260 1780
RIa Soo.nis.~ ruack Block
IRIS _n
Gr.v Dc .Black
B_P_ H_R_ B_P. II.R. B_P_ II_R_
""moL 62/28 154 38/20 150 60/22 162
5 HUI. 64{28 152 34/20 140 62/22 164
10 NUl_ 68/28 160 38/20 150 62/24 160
15 ~ml_ 66/28 160 40/20 140 62/22 160
30 HIN_ 58/26 148 44/20 144 58/28 164
45 MIN_ 68 /26 144 40/ 20 150 54/26 160
60 HnL 68/26 140 42/20 140 60/24 160
PUPIL 5.,:.\ 5-l/2..~N 5- l/Ut·t
PUPIL ELI"" 5.\~·1 5-112/1N 5- l/2..'N
GRAPH !I -E
170
~ 160
~ 150
/ /
CJISE 13
/ / 1 I<XJR
is that it lacks an OH group at t he C-4 of the benzene ring. It is a w hite crys talline, relative ly stable compound, readily soluble in water and alcohol. It has been following chemical structure:1
@- 56
HO 4 c=:) 1 y-C-N
HO 3 2 OH @-<=:> C-C-N , ,
HO OH C
Epinephrine Phenyleph rine
114
TABLE II -F
1 2 3
" 3S 34
1860 1800 1720
Block Block Block
B=.n _n
Sr _ Black
B_P_ H. R_ D_P. Il_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
38120 128 56/20 124 50/20 156
40/ 22 128 50/20 132 50/20 160
5..' •• \ 4-1/2':-1 4~:-·1
5!·t·\ 3-l/.2/I:~ 3I-N
GRAPH II-F
CIISE 12
/ / / / 1InJR
TIME
Having almost a pure alpha adrenergic effect, the heart. w hich conlOins beta receptors, is not directly stimulated. Mechan ism of action is most ly by direct stimu lation at the alpha receptor si tes. There seems lobe some ability to liberate stored nor· epinephrine. The main elfccls of phcnylepinephrinc arc withi n the cardiovascular system by contractio.n of smooth muscle withi n the walls of arterioles. Th is vasoconstriction results in an increased pe·
ripheral res istance. hence, elevation of systolic and diastoli c blood pressure. In an iniaci subject. this usually results in a reflex slowing of the hear! rate via the parasympathetic system. Th is reflex bradyca rdia is consider· able.l,1I
When the drug reaches the eye, ei ther via the blood st~cam or by ocular instillat ion, it relaxes the sphincter muscle of the iri s and stron gly contracts th e radial muscle fibers. It lowers intraocular pressure by slowing the in flux of
116
170-
~ ~
~ 150-
I 1 HOOR
TI>lE
aqueous humor. If a 10 percen l solution is used, there is occasionally l ight cycloplegia."':
In th e norm al human eye, the effects on pressu re and accommodation are slight, if any. However, in patients with open angle glau· coma, it may ra ise or lower pressur~. It may precipi tate angle closure glaucoma in pa tients with narrow anterior ang les and sha llow anterior chambers. II
Clinical uses of phenyleph rine in ophlhal. mology were descri bed byHealh in 1949. 11 may
PUPil. E LIGI 6-1 2.'1:-1 71-1'1 6- l/2a'l 7~N 7-1/2.':-1 7-1/2'1'1 7I-N
GRAPH IV· B (CASE til
••
I i 7. ~
I I I I 1 HOOR
be used as: (1) a decongestive agent; (2) as a va lue for in f ihralive anesthesia9
; and (3) as a vasoconstrictor in th e conjuncti val sac." A fourth use is a mydriat ic for breaking adhe· sions, for refraction. for cyclospleg ia. for over· coming extreme myosis in glaucoma. prior to intraocu lar su rgery, for provocative testi ng for glaucoma. and as a mydrialicsupplement when there is sensitivi ty to t he mydriat ic being used.
A drug appl ied to the conjunctiva l sac may become absorbed i n varying amounts and may
~ !
14.
13.
I I I / 1 HaIR
have cl inica lly evident systemic reacti ons n ot due to hypersensitivity or idiosynchratic reac· t ion.1I Th ere have been a number of ar tic les wr itten about such events w ith the ocul ar usc of 10 percent phenylephr ine. In 1956. McReynolds ct ailS used 10 perce nt phenylep hrine ophtha lmic solution in 100 hypertenSive pa· tients and there were no signi ficant systemic reactions. In six of his cases. there \vas an eleva tion of no more than 10 mm Hg. He then repon ed 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 sulfato drops had been used every hour . It seems possible that the atropine was absorbed and blocked any vaga l stimulus. thus allowing an exaggerated phenylephrine effect.
In a case described by Lansche in 1966, Ii a 57-year-old diabetic male wi th rub eosis iridis developed a blood pressure of 220 mm Hg following one drop all 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 w ith 10 percent phenylephrine in the presence of con junctiva l hyperemiC!. Apparently. this allows a greater amount of absorption of the drug into th e blood stream, as if given by subcutaneous injection.
In 1972. Solosko et alu 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 th ree· month·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.n ' l l
In 1973. Sorromeo·McGrail et all studied the effects of 10 percent phenylephrine eye drops in neonates and reported significant hyper· tension in low birth-weight infants. Ina double· blind study it was given to three infant s, and in an open trial it was given to eight. The doubleblind revealed a rise of 12-16 mm Hg systotic and 10·14 mm Hg diastolic pressures. There was no change in pulse rate. All infants tested apparently had a "fu ll" 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 impractica l for ophthalmology.
In 1949, Heath claimed that he had never noted or reported damaging effects on ocula r tissues or blood vessels. Sensitivity or delayed healing have not thus far been reported.9
However, there have been several articles wrillen on the direct toxic effects on the eye. In 196 1. Mitsui and Takagi': l using a five percent solution in older patients. observed occasional pigment floaters in the aqueous. These dis·
"8
appeared ;n 12- 24 hoursand they were similar to the melanin of the pigment epithe lium of th e iris. Lowenfeld, in a personal communication with Haddad et aI, ' observed an occasional rebound miosis in the elderly. and that sub· sequent use of the drug produced less mydria· sis in the elderly than that 01 the initial instillation. In a separate study of 32 patients, Haddad et al1 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 bywayof penetration of the cornea. and ;n many cases, its effects are limited to the anterior chamber. lJ Systemic absorption from the anterior chamber is slow and 'limited in degree. If the lens is absent, a minor amount may distribute posterior ly 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 grea ter drop viscosity, prolonged contact with corneal epi· theli um is permitted. This allows greater pen.et ration. This is also tru e if the cor-nea is diseased or damaged. Such is the case also with loca l anesthetics, weuing agents, mas· sage, and abrasions. Theoretically, a compound must be lip id solublo to penetrate the cornea l epithe lium and water soluble to cross the corneal stroma.lJ
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 lacr imal drainage system. it may be absorbed via the nasal mucosa. If it reaches the oropharynx or gastrointestinal tract after swa llowing. th is could be another means of absorption. Hyper. emia of Ihe mucosa and lacrimal duct obstruction would tend to increase absorption and converse ly, excessive tearing would decrease absorpt ion. It is worth mentioning that since the majority of the drug is absorbed prior to reaching th e stomach, it therefore escapes any metabolic degradation by gastric enz.ymes."
In J anuary 1974, Ihe British Medical Jour· nsr' 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) Ihe muscosa to which it is accessible is readi ly 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 pre term infants less than 2 1 days postnatal life, Nachman et a l~ showed an increased skin permeability by observing degrees of skin blanching from topic ally 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 prcterm inlanls is also immaturc. It has been shown that absorption of chemicals does occur in nurseries.'
Cyclopemolale: (CyclogylJ
Cyclopentolate (B·dimethylami noethyi-( 1· hydroxycyclopentylj-phcnyl acetate hydro' chloridefs is an anticholinergic mydriatiC cy· cloplegic drug which belongs chemically to the class 01 basic esters 01 substituted phenyl acetic acids. It is a white, water-soluble
r '."5hOSC S1~~C1u,e fO"OWS~ o O-(CH!)N'ICH:); .HCt
Cy<:lopcnlololC Hydrochloride li s effect on t he eye is rapid and it has a short
duration of action.lI,l. In normal subjects, it docs not alter inlfaocular pressure significanlly.1$':6,:' However, it may produce acute angle closure glaucoma in susceptible indivi duals.
This drug has been studied extensively and had previously been devoid of toxic reactions from its ocular usage. Stollar)6 reported a study of 180 cases without any evidence of general or loca l toxici ty in human subjects and in test animals. Other researchers have shown similar conc!usions. lJ ,16
In 1951 , Priestly et al:6 found that when two drops of 0.5 percent cyclopentolate was dropped in each eye five min utes apart, there was "complete" mydriasisol average sile 7.0mm at about one·half hour in Caucasians and at 60 minutes in Negroes.
There have since been severa l reports of toxic effec ts with insti llation of these eyedrops. In 1962, Simcoell reported an eight-yes r-old black female who, following two drops of one percent tropicamide and four drops of one percent cyclopentolate, developed "marked ataxia:' dysar thria and incoherent speech along with other evidence of alt ered cerebellar function. Th ere was no hyperactivity, nor did
th e 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 solulion on a la ter occasion. He noted also that children with brain damage were even more susceptible to similar reactions. Th at same year, Beswick'! reported a case of a nine· year-old while boy, who upon receiving four drops of IwO percent cyclopental ate, began to hallucinate end actually tried to hide beneath the waiting bench in fear. His reaction lasted about three hours. Following recovery. the chi ld was unable to recall the incidenl.
In 1963, MBlk!1 reported fou r cases and claimed that side effects 10 Ihe drug did occu r, bu t infrequently. Reactions consisted of a schilOphren ia .like behavior pattern with ataxia. Three of his p~t ienls were fourteen years old and younger, and they all had received varying amounts of the one percent solution. Also in 1963, Binkhorst et 01') conducted a study using two percent cyc!open tolate 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 th e two percent so lution prodJ~ced a sta ti stically 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 01" reported a case of a seven-year-old white male who, after usc of four drops of the two percent solution, mani fe sted signs and symptoms of cerebellar dysfunction and visual hallucinations.
In 1967, Carpenter)) reported toxicity from four drops of a 0.2 percent solution in an 82· yea r-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 th e case in all previous reports of toxicity.
In 1970, Adcock" reported a four and onehal! year-o ld male Cauca sia n who received six drops of a two percent solution. The child became markedly flushed and his mucous membranes beca me dry. ThiS con tin ued over the next hour and was accompanied by periods of wretching, hallucinations, gross ataxia, incoherent babbling, con fusion, somnolence, episodes of hyperacti vity, an inability to recog· nize family members, and an acute tachycardia. Central nervous system toxicity lasted about
JOURNAL OF PEOIATIUC OPHTHALMOLOGY AND STRABISMUS "'
seven hours, but the tachyca rdia was noted for 36 hours.
Kenderdoll et al" reported two cases of grand mal seizures associated with two porcent cyclopentol ate eyedrops in 1972. One case was an 11 -month·old wh ite male who rece ived one drop in each eyo. The othe r was a 12·year-old known epileptic.
In 1973, Bauer ot al" report ed systemic toxicity in n ewborns. A pai r of prema ture black twins, afi er eight days of perinata l life, received one drop in each eye of ten percent phenylephrine and one percent cyclopentolate repeated twice at five:minute intervals. Symptoms in · eluded vomiting abdominal distention and ileus. After both had apparently recovered, one subsequently died from necrotizing entero· colitis and an intestinal perforation. Intoxication by the drug was confirmed by blood analysis of the infant.
In 1974. a six-year·old girl was repor ted to have tripped several t imes on the way home from the office where she had received one percent cyclopentolate and 0.25 percent hyo· scine eyedrops. She apparently became very aggressive and said odd thing s. She was subseQuently brought to the accident depart· ment active ly halluci nating. By th e following morning, she had recovered completely without reca l l of the incident.lt
Tropicamide: (Mydriacyl)
Tropi camide (N -e th y l - 2-phen l y -N·14 . pyridylmethyl)-hydracrylamide) is an anti · cholinergic mydriatic cycloplegic agent which has become known for its short latency period and its excellent pupillary dilatation. It is ve ry short acting and produces greater mydriasis in subjects with lightly pigmented irises:()-d
Its structure is as lol lows:
@-C.OH -@ c::J C·C·N.C c::J N
II I o c·e
Tropicamlde
Being an anticholinergic agent, as is cyclo· pentclate. the mechanism of action in Ihe eye is to block tho effec ts of parasympathetic innerva· t ion as we l l as to block choli nergic drugs acti ng on the ciliary body and the blood vessels 01 the eye.' In normal eyes. it rarely ca uses sign ificant altcralion of intraocu lar pressure. However, in
120
open angle glaucomatous eyes, it may cause the pressure to r ise. As with cyctopen tolate, it may precipi tatc acute angle closu re glaucoma in subjects wi th shallow anterior chambersand abnormally narrow angles. In animal testi ng, there havo been no detectable histologic abnorm al ities. Since th e 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 th e skin, dry mouth, increased pul se and body tempe rature. and disorientation with visual hallucina tions."!)
The only report fou nd in the literatur e of adverse effects following ocular admini stration was by Wahl et al:' In 1969, he reported an incident. porhaps best described as an acute hypersensitivity to the 0 .5 percenl solution in a ten~year-old white boy, which read as lollows:
tmmediatelv following instillation 01 one drop 010.5 percent tropicamlde in each eye, he fell Irom his chair to the floor unconscious."
There was no bowel or bladder inconlincnce, no psychotic behavior, ataxia, flushing or sta le of hyperactivity, all of which would be an indication of anticholinergic toxicity.',Il.l I.U
Simcoe J1 reponed th at he has used up to ten drops of the one percent solution over a 30-minute period without prodUCing toxic effects.
It i s generally agreed that in o rder to permit adequate examination of the fundus and a thorough examination by slit lamp, a mydriatic agent should produce at leas t 7 mm dilatation. The most suilable drug wou ld be one which opens the pupil rapidly and painlessly without untoward symptoms. If a problem should occur. as in precipi tating acu te glaucoma in sus· ceptible individuals, it should be easily counter· acted by a mild miotic.'I,>! In studying the mydriatic effect of 10 percent phenylephrine. Cambill et al'o measured the responses to a variety of agen ts by means of an infrared electronic pupi11ograph. They observed that in adults there is a latency period of app roximately 21 m inutes w ith a maximal effect at 65 to 72 minutes. It produced less dilata ti on than tropicamide. 1t has also been demonstrated tha t dilatation varies wi th eye color. The least dilatati on was observed in haze l.eyed subjects and the greatest was noted in those w ith blue irises. It was further demonstrated that there was almost identica l mydriasis produced with both 10 percent and 2.5 percent phenylephrine solutions.'
MARCH/APRIL, VOLUME t 5, NUMBER 2
CONCLUSION Many drugs used as drops are absorbed
systemically and cause changes in vital signs. We have shown Ihis 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 pre term. such an occurrence could precipitate or further a cerebral hemorrhage. It would seem imperative that blood pressures be known prior 10 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 raises both systolic and diastolic blood pressures.
Ten percent aqueous or viscous phenylephrine, one percent cyclopenlolate, one percent tropicamide and 2.5 percent phenylephrine. when used alone in our study for a tOlal 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.! !
Our "combination drop" protocol is effective in providing an 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 101al of three drops in each eye of 2.5 percent phenylephrine, one percent cyctopentolate. and one-half percent tropicamide we obtained an average dilatation of 7.7 mm. In two cases of this series, there was an elovation 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 eye drops.
In an attempt to facilitate the application of drops and to lessen the concentrate 01 cyclopentC!late, we prepared a 15ccdropper solution conta ining 2.5 percent phenylephrine, one-hall percent cyclopentoJate and one-half percent tropicamide. With one drop in each eye repeated twice at five minute intervals for a total 01 six drops we observed average dilata tion 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 hear! 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 ell.amination of the retina with the indirect
ophthalmoscope. The original protocol of nine drops, although safe by our testing, certainly may have tOll.ic effects. Therefore, the single instillation of our combination drops proved to be very effective while safe and we recommend it highly in ell.amination 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. In 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 di latations 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 ell.aminaton.
Our protocol at United Hospitals Medical Center is a safe combination 01 drugs - and provides ell.cellent dilatation averaging greater than 7 mm. No skin blanching or change in heart rate was observed.
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