Retinopathy of prematurity (ROP) is a leading cause of childhood vision impairment and blindness. To perform retinal examinations of the pupil, dilation should be provided when sufficient.1 The drugs and their doses, which are used in practice for dilation, vary between clinics. Tropicamide (0.5% to 1.0%) is a safe pupil-dilating agent for use in primary care.2 Tropicamide 0.5% may be augmented with phenylephrine 2.5% if maximal dilation is required.2,3 Instillation of one drop of 2.5% phenylephrine followed (5 minutes later) by one drop of tropicamide 0.5% or 1.0% is likely to give a greater dilation than either drug used alone for maximizing effect on both the iris sphincter and dilator muscles.2,3
This medication is not without untoward side effects, which may not be evident at the time of the examination; feeding intolerance with delayed gastric emptying can occur 24 hours after the drops are instilled.4,5
We present a case of a newborn who had clinical deterioration, transient intractable feeding intolerance, and abdominal distension mimicking ileus after undergoing screening for ROP.
A male infant was born to a 27-year-old mother after 26 weeks of gestation, delivered by spontaneous vaginal route. At birth, he weighed 1,000 grams. The mother, who was otherwise healthy, had an uneventful pregnancy. The patient’s first- and fifth-minute APGAR scores were 6 and 8, respectively, which transferred to the neonatal intensive care unit.
After birth, nasal continuous positive airway pressure and surfactant treatment was applied because of respiratory distress syndrome. Enteral nutrition was commenced on the second day and gradually increased as early as possible in the presence of clinical stability. Full enteral nutrition (150 mL/kg/day) was achieved on day 10; oral intolerance had not been observed until ocular examination. The patient had several eye examinations after the first month. The eye drops were instilled on the day of examination by the nurse responsible for pupil dilation. Pupil dilation was performed using one drop of phenylephrine 2.5% in each eye at 0, 30, and 60 minutes. One drop of tropicamide 0.5% was alternately instilled four times at 15, 45, and 75 minutes. Deep apnea requiring intubation and mechanical ventilation was seen within 1 day. Subsequently, marked abdominal distension and feeding intolerance became apparent after the first 24 hours of eye drop use (Figure 1). Ileus developed after each screening in the second or third day. The patient was extubated 3 days after the first ROP examination. There was no deep apnea after repeated examinations. The patient never passed bloody stools and there were no radiologic or clinical symptoms that would suggest necrotizing enterocolitis (Figure 2). Acute phase reactants (C-reactive protein: 2 mg/dL) were negative and showed no evidence of sepsis. Investigations toward finding the cause of these symptoms also included urinary, blood, and cerebrospinal fluid cultures, but they were negative. All intermittently performed hematological and biochemical parameters were within normal limits. Fecal occult blood tests were also negative. Cranial ultrasound imaging was not consistent with intracranial hemorrhage or hydrocephalus.
Gross abdominal distension due to instilled eye drops.
Grossly dilated large bowel loop on upright abdominal view.
No congenital anomalies involving the neurological, cardiovascular, urological, or gastrointestinal systems were observed. Oral feeding was discontinued because of intractable feeding intolerance. Rectal biopsy was not required because symptoms resolved completely after discontinuation of the drug 10 days later. The abdominal distention was relieved 5 days later. Oral feeding was initiated 7 days later and symptoms were not seen until discharge. The feeding intolerance and abdominal distension suggesting ileus were strongly associated with the use of eye drops. The patient was discharged after 90 days of hospitalization and with a discharge weight of 1,950 grams.
ROP is mild and undergoes spontaneous regression with no visual sequelae in most affected infants.1,6 However, progression to advanced ROP does occur in a significant number of infants and can lead to severe visual impairment and even complete unilateral or bilateral blindness in some cases. In general, more than 50% of premature infants weighing less than 1,250 grams at birth show evidence of ROP, with abnormal retinal vascular development, neovascularization, and traction retinal detachment in its more severe forms in approximately 3% of children.6–8 Infants with a birth weight of 1,500 grams or less or a gestational age of 30 weeks or younger are at high risk for ROP and should have retinal screening examinations according to the policy of the American Academy of Pediatrics.6
Preterm infants are routinely screened for the presence of ROP with the use of mydriatic eye drops that contain a combination of anticholinergic and adrenergic agents.7–9 The frequency and starting doses vary between clinics. Taking high doses of eye drops should be avoided because of increasing the risk of fatal consequences in preterm infants.7,8 Our case highlights a rare adverse effect of eye drops that are used for ROP examination.
Several factors may lead to feeding intolerance beyond prematurity7–9 and these should be ruled out by the tests required. The roles of sepsis and necrotizing enterocolitis are especially important. Acute phase reactants and cultures were negative in our patient. In the absence of chronic constipation or failure to thrive until symptoms occurred, we did not consider surgical causes, especially Hirschprung disease. Also, we did not consider a neurological disorder because of the normal neurologic examination and cranial imaging.
If there is any local or systemic adverse effect after ophthalmologic examination, it should be considered that the condition may be due to use of these drugs. Current doses of mydriatics inhibit duodenal motor activity and delay gastric emptying, and these gastrointestinal effects of mydriatics may underlie the feeding difficulties seen in preterm infants on the day of screening examinations for ROP.7–9
In many studies, a relationship between instilled eye drops and feeding problems has been identified.4–9 For these reasons, vomiting due to reflux, aspiration, an increase in need for oxygen, and desaturation may be observed in infants. Stress and pain, such as encountered during an ROP examination, are known to precipitate apnea and bradycardia.7
Neonates are more susceptible than adults to the effects of systemic absorption because of their lower body mass and blood volume, and their immature metabolic, excretion, and cardiovascular systems.7,8 Although eye drop-related systemic toxicity and preventive interventions have been well documented, there is little information in the literature about treatment of systemic toxicity. Determining the lowest effective dose for proper mydriatic efficacy is significant.1 Mydriatic efficacy of different numbers of eye drops (0, 1, or 2 drops) for retinal examination of premature infants was performed in a recent study, revealing no significant difference in results.1 To minimize systemic absorption, finger pressure should be applied to the lacrimal sac for 1 to 2 minutes following administration and excess eye drop fluid should be wiped from the skin immediately after administration.7,9 This procedure was used for reduction of systemic absorption.
Two categories of dilating agent were used, often in synergistic combination within one preparation. Sympathomimetic agents such as phenylephrine cause contraction of the radially oriented dilator pupil muscle. Parasympatholytic, or cycloplegic, agents such as cyclopentolate and tropicamide inhibit the sphincter pupil muscle.10
Phenylephrine is a selective alpha-1 agonist, with β activation only in high doses. Onset of action occurs 30 to 90 minutes after instillation and effects last for 6 to 7 hours.8,10 Tropicamide is a synthetic antimuscarinic agent used topically as a mydriatic and cycloplegic. Moreover, it has a shorter duration of action than cyclopentolate (0.25 days versus 1 day) and thus a shorter period of time available for systemic actions. Tropicamide may be the preferable topical antimuscarinic drug to use in children, owing to a reduced propensity to cause systemic effects.7–11
Although the effect of tropicamide is brief, improvement in the clinical presentation lasted for 10 days in our patient. This may be due to the additive effect of this combination and the immaturity of enzymes in very low birth weight infants that affect the metabolism of these drugs. Depending on the immature nature of these enzymes, prolonged effects may be seen.
Another study showed a significant elevation in systolic blood pressure in infants given phenylephrine 2.5% with tropicamide 0.5% versus those given tropicamide only.7 During the period of oral intolerance, no related blood pressure changes were observed in our patient. There have been isolated case reports of paralytic ileus, necrotizing enterocolitis, and acute gastric dilatation with vomiting and apnea in neonates in the 24-hour period after ROP screening, using combined phenylephrine and cyclopentolate.4,5,11,12
There are recommendations about the combination of 2.5% phenylephrine and 0.5% tropicamide to achieve sufficient diagnostic mydriasis without systemic side effects in preterm infants.2,3 Tropicamide 0.5% may be augmented with phenylephrine 2.5% if maximal dilation is required.2,3 We report symptoms that occurred after the instillation of eye drops mimicking ileus and associated with the use of this combination in the literature.
We should be aware of possible systemic side effects of instilled ocular eye drops, such as the combination of phenylephrine and cyclopentolate or phenylephrine and tropicamide after examination for ROP screening. Consequently, it is more important than ever to differentiate intestinal disease from other nonsurgical conditions.