Systemic cyclopentolate (Cyclogyl) toxicity in the newborn infant

PEDIATRIC PHARMACOLOGY AND T H E R A P E U T I C S WilliamL.Nyhan, Editor; Harry C. Shirkey, Consultant

Systemic cyclopentolate (Cyclogyl) toxicity in the newborn infant Two cases o[ atropine-like toxicity [ollowing the ocular administration of cyclopentolate hydrochloride (Cyclogyl) in a pair o[ pre.mature Negro twins are reported. The symptoms were confined to the gastrointestinal tract with vomiting, distension, and ileus. Both infants apparently recovered [rom the initial episode, but one o[ the twins subsequently died [rom necrot&ing enterocolitis complicated by an intestinal per[oration. In both children systemic concentrations o[ the drug supported the clinical impression o[ Cyclogyl intoxication.

Charles R. Bauer, M.D., Marie Claire Trepanier Trottier, M.D., and

Leo Stern, M.D.,*

Montreal, Quebec, Canada

S Y s T ~ M I C absorption and resultant toxicity are known for several topical anesthetic and therapeutic agents. The purpose of this paper is to report systemic toxic effects of a drug widely used topically in the neonate for ophthalmologic examination. To our knowledge, this is the first report of cyclopentolate toxicity in the newborn infant and the first report of its gastrointestinal toxicity in children. Cyclopentolate hydrochloride (Cyclogyl) is a mydriatic and cycloplegic agent. It is a synthetic antispasmodic agent which produces rapid, intense cycloplegia and mydriasis of moderate duration after topical ocular administration? Chemically, the compound is dimethylaminoethyl (l-hydroxycyclo-

From the Department o[ Newborn Medicine, The Montreal Children's Hospital, and the Department o[ Pediatrics, McGill University. Supported in part by Grant MA-3037 [rom the Medical Research Council o[ Canada. *Reprint address: The Montreal Children's Hospital, 2300 Tupper St., Montreal 108, Quebec, Canada.

pen@) phenylacetate hydrochloride, with a structural formula. H

//

C - O(CH,)2 N (CH3)~ 9 HC1

O Cyclogyl is a parasympatholytic drug. It is similar to atropine and homatropine in action, a similarity which relates to the chemical property of being a basic ester and quaternary derivative of fl-hydroxy acids? Structurally, Cyclogyl shares a dimethylated side chain (-N-(CH3)2) in common with many tranquilizers, psychoactive drugs, and some hallucinogens. 3 We have recently observed systemic atropine-like toxicity in two premature twins from the ophthalmologic use of Cyclogyl and have documented concentrations of the drug in their blood. Vol. 82, No. 3, pp. 501-505

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Fig. 1. Anteroposterior supine films of the abdomen of Case 1 illustrating marked gaseous distension with free air in the peritoneal cavity. The leftsided arrows illustrate the "double wail sign" seen with free peritoneal air outlining the outer intestinal wail. The right-sided arrows show air in the portal-venous system. There is also free air under the right diaphragmatic dome.

CASE REPORTS Case 1. Patient B. L. (Twin 1), a Negro male infant, was the first-born child of a 25-year-old, gravida 1, para 2 mother; length of gestation was 27 weeks and birth weight 930 Gin. The pregnancy was uncomplicated, and labor and delivery were not traumatic. Respiratory distress was noted immediately. The infant was transferred to the neonatal intensive care unit of The Montreal Children's Hospital at 1 ~ hours of age; he had nasal flaring, substernal and intercostal retractions, and occasional grunting. A radiograph of the chest demonstrated a fine reticulo-granular pattern which was consistent with the diagnosls of respiratory distress syndrome. Arterial blood gas determinations with the infant in room air demonstrated a PAO2 of 4g ram. Hg, a Pco= of 56 mm. Hg, and a [H+] of 59 /~mEq per liter. After breathing 40 to 60 per cent ambient oxygen for 48 hours the chest radiograph and arterial blood gases became normal. The infant received phototherapy because of immaturity and a large cephalohematoma. Peak

The Journal of Pediatrics March 1973

bilirubin concentration was 8.4 rag. per cent, of which 1.1 mg. per cent was direct acting. Phototherapy and oxygen were discontinued, and the umbilical catheter was removed on the fourth day of life. At the age of eight days, the infant's eyes were exarained, as is the routine procedure for all premature in[ants who receive oxygen therapy. He was prepared for the examination by the instillation of Neo-Synephrine 10 per cent (phenylephrine hydroehloride solution, U.S.P., Winthrop Labs., Aurora, Ontario) and Cyclogyl 1 per cent (Mydplegic, Smith, Miller & Patch [Canadal, Ltd., Toronto, Ontario) eyedrops-one drop in each eye repeated twice at 5 minute intervals for a total of six drops (one drop of 1 per cent Cyclogyl solution contains 0.5 rag. of cyclopentolate hydrochloride). Approximately four hours folIowing this procedure, the infant vomited and was noted to be distended. The following morning he vomited again and became apneic. The heart rate decreased to less than 60 beats per minute, and the infant was without spontaneous respirations for about two minutes. He responded quickly to resuscitation. A chest radiograph at this time failed to demonstrate any signs of aspiration, and abdominal radiographs were consistent with a paralytic ileus. Subserosal air was not visualized. Blood, urine, throat, and cerebrospinal fluid cultures were done. At this time the possibility of Cyclogyl toxicity was entertained, as the second twin (see Case 2) was exhibiting the same symptomatology. Cyclogyl blood concentrations were determined 24 hours after the instillation of the eye drops. The distension decreased over the next 48 hours and feeding was reinstituted. The infant vomited again and the abdomen remained distended. He was treated with intermittent gastrointestinal suction and intravenous fluids. After 48 hours of this therapy, the abdominal distension decreased, and gavage feedings were resumed on the thirteenth day of life. One week later the infant again had an apneic spell after a feeding and required resuscitation. Abdominal distension reoccurred but chest and abdominal radiographs failed to demonstrate any additional changes. Because of convulsions and apnea, he required intubation and artificial ventilation. Penicillin and gentamicin were administered after cultures were obtained. The infant died on the twenty-second day of life. An abdominal radiograph just before death showed necrotizing enterocolitis (Fig. t ) with air in the portal system and free air in the abdomen. Blood and peritoneal fluid cultures taken immediately after death showed a heavy growth of

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Klebsiella. However, both sets of antemortem cultures were negative. At postmortem examination, the jejunum was markedly congested and dilated. The mucosa was grossly hyperemic and covered in part by a yellowish white cordlike material. The ileal mucosa had patchy hyperemic areas as did the ascending colon and cecum. No perforation site could be identified. These findings are pathologically indicative of necrotizing ischemic enteropathy. Case 2. Patient B. L. (Twin 2), a Negro male infant, was the second-born twin of Case 1; birth weight was 1,020 Gin. Respiratory difficulty occurred immediately after birth with nasal flaring, substemal and intercostal retractions, and grunting. A chest radiograph taken when he was admitted to the neonatal intensive care unit of The Montreal Children's Hospital was consistent with the respiratory distress syndrome. Initial arterial blood gases in 32 per cent ambient oxygen were PAO2 of 40 mm. Ilg, Pco 2 of 46 ram. Hg, and [H § of 56 /~mEq per liter. The infant was kept in ambient oxygen up to 58 per cent and received phototherapy. The peak bilirubin was 10.8 mg. per cent, of which 1.4 mg. per cent was direct acting. He, as his brother, did well initially and by the seventh day administration of oxygen and phototherapy were discontinued, and the umbilical catheter was removed. An ophthalmologic examination was done on the eighth day of life with the same preparation of Neo-Synephrine 10 per cent and Cyclogyl 1 per cent as was given to his brother. He was noted to have abdominal distension four hours after the examination which persisted for 48 hours. He then improved. Two days after his brother died, he again developed marked abdominal distension and vomiting. Specimens for bacterial culture were obtained, and therapy with penicillin and gentamicin was initiated. He remained ill for five days. Cultures of blood, urine, cerebrospinal fluid, and throat were negative. He was ultimately discharged on the forty-fifth day of life; weight at that time was 1,850 Gm. and he was doing well. SYSTEMIC DRUG CONCENTRATIONS

Blood for systemic concentrations of Cyclogyl was examined 24 hours after the instillation of the eyedrops. Gas chromatograph analysis ~ showed a drug concentra~Courtesy of James E. Boyd, Ph.D., of Smith, Miller & Patch, Inc., New Brunswick, N. J.

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tion of 22 ~g per milliliter of plasma in Twin 1 who later died and 2 ~g per milliliter of plasma in Twin 2 who had the less severe symptomatology and survived. Since the half-life of Cyclogyl is felt to be two to four hours, it is remarkable that at 24 hours these concentrations were still very high. DISCUSSION

Prior to the introduction of Cyclogyl into ophthalmologic practice, atropine and homatropine were the drugs most commonly used for funduscopic examinations. Their toxicity was well known and frequently demonstrated. " H o t as a hare, red as a beet, dry as a bone, blind as a bat, and m a d as a wet hen" is a description of the postganglionic cholinergic blockade and direct central nervous system effect of atropine poisoning. 4 T h e actual physiologic effects of atropine intoxication initially include dryness of the skin and mouth, thirst, flushed skin, an elevated body temperature, dilated pupils, and impaired vision, followed soon by a burning sensation in the throat, difficulty swallowing, nausea, vomiting, excitement, delirium, hallucinations, staggering gait, rapid pulse and respiration, urinary retention, and disorientation? T h e final stage is a depressive one with eventual coma and death. All the secretory glands--salivary, sweat, lacrimal, mucous, gastric, and pancreatic--are inhibited. 6 An ideal cycloplegic would be one that had a rapid effect, extensive depression of accommodation, p r o m p t recovery, a dissociation of the mydriatic and cycloplegic effects, and little or no side reactions. 7 Cyclogyl, when first introduced in the early 1950's, seemed to satisfy all these criteria in a comprehensive study of over 3,000 patients in whom the drug was used. 8 Neo-Synephrine, a direct-acting sympathomimetic mydriatic agent, has been used in combination with Cyclogyl to augment pupil dilatation. 9 It is still considered a safe drug if used appropriately. Systemic absorption has been well demonstrated with its topical application, especially in the premature infant. 1~ However, the only reported toxicities

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have been blanching of the skin and transient elevations in blood pressure. 11 After Cyclogyl was considered to be safe, its use in infants and children became more widespread, and toxic reactions began to emerge. Its most common toxic side effect is its ability to evoke psychotic behavior. This has been well demonstrated in adults and children. The symptomatology is similar to that of LSD (lysergic acid diethylamide) ~2 or atropine poisoning. In essence, it produces an "acute brain syndrome" with clouding of the sensorium, hallucinatory phenomena, and disorientation. This has been shown to be a dose-related effect rather than an idiosyncratic one? 3 The most striking finding in pediatric patients remains the schizoid behavior and the cortical and cerebellar dysfunction characterized by slurred and incoherent speech, ataxia, visual and tactile hallucinations, and hyperactivity? ~, ~ Grand real seizures have been the most recent toxic effect reported in children. 1~ It is of importance to note that a large number of reported reactions have occurred in Negro patients; our two infants were Negro. The eye of the Negro individual is usually considered to be less responsive to cycloplegics and mydriaticsY There may, therefore, be a tendency to increase the dose empirically to achieve the desired effect when dealing with the eyes of Negro patients. It has also been pointed out that there is an increased incidence of toxicity in the brain damaged child, ~s a finding similar to that noted with atropine. 19 The toxicity demonstrated in our patients is that of the atropine-like effect of gut relaxation, thereby delaying gastric emptying and producing a "paralytic ileus." We cannot causally relate the terminal necrotizing enteroeolitis in Case 1 with the original incident of ileus, an episode apparently shared by the surviving twin as well. Since little is known about the localized vascular dynamic effects of these preparations, it is possible that the infant sustained a vascular compromise to his bowel which led to necrosis, perforation, sepsis, and death. We have observed several cases of otherwise un-

The Journal o[ Pediatrics March 1973

explained abdominal distension with necrotizing enterocolitis in our nursery in infants who likewise received cyclopentolate in similar dosage (6 drops--1 per cent). This was at a time before the relationship between the two had been established. It is currently our impression that this incidence has decreased since we instituted a reduced dosage of cyclopentolate (2 drops--0.5 per cent). Systemic absorption from ocular application of medication occurs in one of three ways in infants: through the nasolacrimal duct to the nasal mucosa where absorption is rapid, by direct topical absorption through an immature skin, and by transcorneal absorption. In view of our findings in these two infants, we would recommend that for routine examinations of any infant's eyes, 0.5 per cent Cyclogyl be used, using one drop in each eye with or without Neo-Synephrine, and repeating once only if satisfactory dilation as judged by the examining ophthalmologist has not been achieved in five minutes. Although direct pressure on the puncta is not believed by all to be effective in preventing systemic absorption, it is a simple procedure and may decrease the total amount absorbed by eliminating the nasal route of absorption.

REFERENCES

1. Monograph by Council on Pharmacy and Chemistry, J. A. M. A. 158: 1523, 1955. 2. Ehrenberg, M. H., Ramp, J. A., Blanchard, E. W., and Treves, G. R.: Antispasmotic activity of basic esters and quaternary derivatives of fl-hydroxy acids, J. Pharmacol. Exp. Ther. 106: 141, 1952. 3. Adcock, E. W., III: Cyclopentolate (Cyclogyl) toxicity in pediatric patients, J. PEDIATR. 79: 127, 1971. 4. Morton, H. G.: Atropine intoxication, J. PEDIATR. 14: 755, 1939. 5. Stoll, H. C.: Pharmacodynamic considerations of atropine and related compounds, Am. J. Med. Sci. 215: 577, 1948. 6. Havener, W. H.: Ocular pharmacology, St. Louis, 1966, The C. V. Mosby Company. 7. Stolzar, I. H.: A new group of cycloplegic drugs, Am. J. Ophthalmol. 36: 110, I953. 8. Gordon, D. M., and Ehrenberg, M. H.: Cyclopentolate hydrochloride: A new mydri-

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9. 10. 1i.

12. 13.

atic and cycloplegic agent, Am. J. Ophthalmol. 38: 831, 1954. Borthne, A., and Martin, D.: Mydriatics and age, Acta Ophthalmol. 49: 380, 1971. Nachman, R. L., and Esterly, N. B.: Increased skin permeability in preterm infants, J. PEDIATR.79: 628, 1971. Hughes, F. N., and Rotenberg, G. N.: Compendium of pharmaceuticals and specialities (Canada), ed. 4, Toronto, Ontario, 1968, The Canadian Pharmaceutical Association Inc. Mark, H. H.: Psychotogenic properties of cyclopentolate, J. A. M. A. 186: 430, 1963. Binkhorst, R. D., Weinstein, G. W., Baretz, C., and Clahane, A. C.: Psychotic reaction induced by cyclopentolate (Cyclogyl), Am. J. Ophthalmol. 55: 1243, 1963.

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14. Beswick, J. A.: Psychosis from cyclopentolate, Am. J. Ophthalmol. 53: 879, 1962. 15. Praeger, D. L., and Miller, S. N.: Toxic effects of cyclopentolate (Cyclogyl), Am. J. Ophthalmol. 58: 1060, 1964. 16. Kennerdell, J. S., and Wucher, F. P.: Cyclopentolate associated with two cases of grand real seizure, Arch. Ophthalmol. 87: 634, 1972. 17. Gettes, B. C.: Three new cycloplegic drugs, Arch. Ophthalmol. 51: 467, 1954. 18. Simcoe, C. E.: Cyclopentolate (Cyclogyl) toxicity, Arch. Ophthalmol. 67: 406, 1962. 19. Hoefnagel, D.: Toxic effects of atropine and homatropine eyedrops in children, N. Engl. J. Med. 264: 168, 1961.