Epinephrine has been employed topically during various surgical procedures for its vasoconstrictive and mydriatic effects. It must be used with extreme caution on the eye undergoing surgery because rapid absorption of epinephrine from the hyperemic and surgically traumatized conjunctival sac is well established.^67,68 In addition, general anesthetic agents such as halothane and cyclopropane sensitize the myocardium to the cardiotoxic effects of systemically absorbed epinephrine.⁶⁸ Tachycardia and arrhythmias in children following topical use of epinephrine during general anesthesia have been noted by anesthesiologists, many of whom prohibit its use.⁶⁹ If epinephrine must be used with halothane anesthesia, a concentration of 1:100,000 to 1:200,000 is recommended in children. Concentrations greater than 1:200,000 apparently do not give any additional vasoconstriction.⁶⁹ A recent study on adults undergoing cataract surgery found a concentration of 1:400,000 safe and effective for mydriasis.⁷⁰

Dipivalyl epinephrine (dipivefrin [Propine]) is a prodrug of epinephrine that penetrates the cornea about 17 times better than epinephrine.⁷¹ It is converted to epinephrine in the eye and has the same effect as epinephrine, but with fewer local and systemic side effects. Epinephrine and dipivefrin have a systemic absorption of 55% to 65% of the ocularly applied dose in rabbits.⁷²

This potential for high systemic absorption can lead to sympathomimetic effects such as excessive sweating, pallor, faintness, occipital headaches, hypertension, palpitations, tachycardia, and cardiac arrhythmias, particularly in patients with preexisting cardiac disease,^67,73,74 and premature infants and neonates.⁸ The administration of epinephrine by subcutaneous injection in patients taking propranolol can lead to a marked hypertensive episode followed shortly by bradycardia progressing to cardiac arrest or hypertensive stroke.⁷⁵ Epinephrine should therefore be used with great caution in a patient taking propranolol. Local side effects of epinephrine and dipivefrin include irritation, foreign body sensation, brow ache, blurred vision, adrenochrome deposits in the conjunctiva and cornea, corneal edema, allergic blepharoconjunctivitis, reactive hyperemia, giant follicles of the tarsal and bulbar conjunctiva, shrinkage of the conjunctiva with symblepharon, and nasolacrimal duct obstruction.^{76,77,78,79,80,81}

The association of epinephrine and dipivefrin with cystoid macular edema in adults has not been reported in children, although safety of these drugs in children has not been fully tested.⁸

The use of epinephrine and dipivefrin has largely been replaced by the newer adrenergic agonists apraclonidine and brominidine for the treatment of glaucoma in adults. These selective adrenergic agonists have significant side effects in infants and children (see section on alpha-2 selective antagonists).

Similar in chemical structure to epinephrine, hydroxyamphetamine (Paredrine) produces mydriasis with little, if any, effect on accommodation.⁸² It is a weaker mydriatic than phenylephrine in infants and children,⁶ but equivalent to 2.5% phenylephrine in young adults. Paredrine is not currently available.⁸³ Hydroxyamphetamine 1% has been combined with tropicamide 0.25% commercially (Paremyd), producing a more pronounced mydriatic effect than either hydroxyamphetamine 1% or tropicamide 0.5% alone.⁸⁴ Topical instillation of hydroxyamphetamine can produce increased blood pressure, and significant cardiac events have been reported after systemic administration, although a causal relationship is unproven.⁸⁵

Phenylephrine is a powerful local and systemic vasoconstrictor and mydriatic that has been widely used in the pediatric age group since its introduction by Heath in 1936.⁸⁶ Initially it was believed to have a wide margin of safety with topical use,⁸⁷ and it rapidly became a standard drug in all age groups for mydriasis prior to examination of the fundus.

Before 1972, the reports of systemic reactions to phenylephrine were few. Schepens, in 1951, noted that the drug used topically in eyes undergoing retinal detachment surgery “may cause unpleasant systemic reactions such as nervousness, pounding of the heart, violent headaches, nausea, and vomiting.”⁸⁸ Over the years, with widespread use, numerous case reports and research studies demonstrated that topical phenylephrine in 10% concentration had a potent and dangerous systemic hypertensive and cardiotoxic effect in patients in high-risk categories, such as the young and the elderly. A 3-month-old infant who received three drops of 10% phenylephrine in one eye at the conclusion of cataract surgery had a prompt increase in blood pressure to 230 mm Hg that returned to a normal level gradually over the next 2 hours.⁸⁹ The same report described two elderly patients who had similar sharp and sudden increases in systolic blood pressure following the ocular application of 10% phenylephrine either preoperatively or immediately postoperatively. Other workers described an adult whose blood pressure rose to 270/170 mm Hg after administration of three drops of phenylephrine in one eye.⁹⁰ Vaughan reported that an 8-year-old boy, while undergoing strabismus surgery, received four to five drops of 10% phenylephrine to control conjunctival bleeding.⁶⁸ Almost immediately, the patient’s blood pressure rose from 100/60 to 190/120 mm Hg, and he developed ventricular arrhythmias. He reverted to normotension and normal sinus rhythm after lidocaine was given intravenously. Because phenylephrine is solely an alpha-adrenergic receptor stimulator, it has no direct cardiotoxic effect; however, its hypertensive action can initiate reflex vagal stimulation, which can then induce serious ventricular arrhythmias.

A definitive study of the dangers of the use of 10% phenylephrine in infants was done by Borromeo-McGrail and associates.⁹¹ They compared the hypertensive effect of 10% and 2.5% phenylephrine in healthy low-birth-weight neonates. Systolic and diastolic blood increases of 20% to 40%, lasting up to 1 hour, were found consistently in the group of infants who received one drop of 10% phenylephrine; 2.5% phenylephrine did not cause blood pressure elevation in any of the infants tested. The authors concluded that the hypertensive effect of the 10% concentration could be especially dangerous in the infant with intracranial bleeding or with a left-to-right shunt, or even in the normal low-birth-weight infant, because of an increased potential for intracranial hemorrhage. Caution is advised in infants with cardiac anomalies as well. In a premature infant with a ventricular septal defect, 10% phenylephrine caused acute hypertension and pulmonary edema.⁹² It has been shown that 10% phenylephrrine in both aqueous and viscous forms causes blanching of the skin of the eyelids, increased systolic and diastolic blood pressure, and inadequate papillary dilatation in neonates.⁹³

In summary, although no case of death or permanent morbidity has been reported in children from 10% phenylephrine, the drug has significant and dangerous cardiovascular effects in newborns and infants. Because of these effects, and because phenylephrine produces inadequate mydriasis in newborns, 10% phenylephrine should not be used in infants and should be employed in the older pediatric age group cautiously and only when strong active dilatation of the pupil is required. The 2.5% solution of phenylephrine has been widely used in pediatrics because it has been believed to produce fewer cardiovascular toxic effects from systemic absorption than the10% solution. However, although some past studies have shown no significant effect of 2.5% phenylephrine on systemic blood pressure in neonates,^{93,94,95,96,97} the current data in the National Registry of Drug-Induced Side Effects indicates that 2.5%, like 10%, phenylephrine can have serious cardiovascular effects in infants, the aged, insulin-dependent diabetics, and patients with high blood pressure or cardiovascular disease.⁹⁸ The low-birth-weight (<1600 g) infant is particularly at risk for elevated systolic blood pressure, and mean systolic blood pressure elevations of 20% to more than 50% have been reported.^{99,100,101,102} Because of these findings, it is recommended that 2.5% phenylephrine not be used for routine mydriasis during the first 6 weeks of life in premature infants or in any infant with cardiovascular disease.¹⁰³ Cycloplegics alone (either cyclopentolate 0.5% for infants younger than 8 months of age, and 1% thereafter, or tropicamide 1%) or phenylephrine 1% in combination with cyclopentolate 0.2% (Cyclomydril) or phenylephrine 1% in combination with tropicamide 0.5%.^{96,104,105,106} Phenylephrine frequently has been substituted for epinephrine at surgery to control bleeding because it produces fewer cardiac effects.⁸⁷ Systemic absorption, however, is enhanced in the eye undergoing surgery, and in large doses phenylephrine, like epinephrine, can cause serious cardiac arrhythmias and pulmonary edema in patients receiving general anesthesia.^{68,107,108,109} In addition, atropinization enhances the pressor effects of phenylephrine, which may lead to hypertension, tachycardia, and cardiac arrhythmias.⁹⁸ For these reasons, 10% phenylephrine should never be used topically on the eye having surgery. If phenylephrine is used, a concentration of 1:50,000 produces satisfactory vasoconstriction.⁷⁰ Phenylephrine should be avoided preoperatively and intraoperatively in patients taking tricyclic or monoamine oxidase inhibitor antidepressants, β-adrenergic blockers, reserpine, or guanethidine because potentiation of the pressor effects of phenylephrine may result.^98,110 The proprietary collyria used to produce vasoconstriction in minor eye irritations contain 0.12% to 0.2% phenylephrine, and they have not been implicated in the production of systemic hypertension in any age group.

Local reactions to topical ocular phenylephrine include transient pain, headache and brow ache, blurred vision, release of pigment into the aqueous with transient elevation of intraocular pressure, lacrimation, reactive hyperemia, transient keratitis, rebound miosis, and severe allergic dermatoconjunctivitis.^10,111

Dapiprazole (Rev-Eyes) is an alpha-1-adrenergic inhibitor that reverses mydriasis produced by phenylephrine, and to a lesser extent, tropicamide. Safety of this drug in children has not been established. The high incidence of conjunctival hyperemia (greater than 80% of patients), burning and stinging (about 50% of patients), and a weak effect on reversal of accommodation paralysis in the pediatric age group make this drug of little practical clinical usefulness in young patients.¹¹²

Since the introduction of atropine in 1833, many cases of systemic toxicity have been reported after conjunctival instillation of the drug.^{113,114,115,116,117,118,119,120,121,122,123,124,125,126,127} These cases include six deaths in children, all of whom were younger than 3 years of age.^{124,125,126,127,128} Two mechanisms appear operative in cases of atropine poisoning. First, in some children a definite idiosyncratic response occurs, consisting of acute systemic toxicity and even death after the instillation of only one or two drops in each eye (a total dose of 1 to 2 mg of a 1% solution).^126,127 Increased susceptibility to atropine has been reported for infants,^6,13 blond children, children with spastic paralysis or brain damage,^6,121 children with akinetic seizures,¹²⁹ and children with Down syndrome.^130,131,132 The eyes of patients with Down syndrome, compared with normal controls, dilate more rapidly and mydriasis lasts longer after instillation of atropine eye drops.¹³⁰ Harris and Goodman demonstrated a twofold increased sensitivity to the vagolytic action of atropine in Down syndrome patients.¹³² Atropine should be administered with great caution to these sensitive persons. The second mechanism of atropine toxicity is overdosage following multiple instillations of the drug, often when early toxic symptoms are not recognized. Relative overdosage of atropine can occur easily via the conjunctival route in the pediatric age group. Frequently in the past, atropine eye drops were instilled in young strabismic children as part of a 3-day routine for cycloplegic retinoscopy (one drop in each eye three times a day for 3 days prior to the next office visit), during which time a total of at least 9 mg of 1% atropine was administered. Although not all of the drug is retained and absorbed, this amount is close to the average fatal dose of 10 mg for infants and 10 to 20 mg for children.^126,133 Death has been reported from a dose as low as 1.6 mg in a 2-year-old boy.¹²⁷ Atropine appears rapidly in the blood after ocular instillation (as rapidly as intramuscular atropine),¹³⁴ and because children have a low atropine clearance compared with adults, repeated instillation may lead to accumulation of the drug and may increase the potential for overdosage and toxicity.^123,135 Because of toxicity concerns, it may be prudent to consider abandoning the traditional 3-day atropine regimen for cycloplegic refraction in young pediatric patients. Refractive values in children 90 minutes after two drops of 0.5% atropine (in children less than 2 and a half years of age) or 1.0% atropine (in children older than 2 and a half years) have shown to be equal to the usual 3-day administration in 80% to 90% of cases.¹³⁶

Systemic atropine toxicity results from peripheral blockade of postganglionic parasympathetic fibers and from subsequent depression of certain cortical and medullary centers. The signs and symptoms of systemic atropine poisoning given in Table 2 may appear within a few minutes to a few hours after instillation. Peripheral signs and symptoms generally occur at lower doses and usually are of little consequence. Central nervous system (CNS) toxicity, however, is most serious and can result in stupor or coma lasting up to 5 days or even in death. In general, the clinical picture of systemic atropine toxicity is the same in older children and adults. Infants and young children have fewer symptoms of CNS excitation and are more likely to show CNS depression with drowsiness and coma.^118,121 Hyperpyrexia may reach alarming levels in infants (109°F [41.1°C] or greater), and abdominal distention usually is pronounced.⁸ It is not surprising that the combination of high fever, rash, tachycardia, and delirium in patients with systemic atropine toxicity has been confused in the past with the symptoms of scarlet fever.¹¹⁸ Atropine readily crosses the placenta and is excreted in breast milk in small amounts; therefore, neonates and breast-feeding infants of mothers treated with ocular atropine are at risk.⁸

Physostigmine salicylate (Antilirium) is an effective antidote for systemic atropine toxicity.^137,138 Physostigmine reverses atropinization by inhibiting cholinesterase so that acetylcholine accumulates at the neuroreceptor site. After subcutaneous, intramuscular, or intravenous administration, physostigmine salicylate readily enters the CNS and within minutes reverses all central and peripheral anticholinergic effects. Limited trials have indicated that it is safe for use in children.¹³⁸ The recommended dose for children as young as 1 year of age is 0.5 mg given slowly intravenously over 2 to 3 minutes or 1 mg/M² given subcutaneously or intramuscularly, repeated every 5 minutes if toxic effects persist until a maximum dose of 2 mg is reached^137,138 In adolescents and adults, the dose is 1 to 2 mg given slowly intravenously over 2 to 3 minutes or 1 to 2 mg given subcutaneously or intramuscularly, with a second dose of 1 to 2 mg in 10 to 20 minutes if toxic effects persist. One to 4 mg may then be given every 30 to 60 minutes until symptoms subside. An alternative dosage schedule for physostigmine salicylate is 0.02 to 0.03 mg/kg up to 2 mg intravenously, intramuscularly, or subcutaneously. The dose may be repeated in 15 minutes, then every 2 hours as needed. Other supportive measures for treating atropine toxicity include hospitalization in a dark, quiet room, high fluid intake, measures to control fever, artificial respiration and catheterization as needed, and sedation with short-acting barbiturates, chloral hydrate, or morphine (in small doses).

Despite the risk of intoxication in infants and children when atropine is instilled in the eye, atropine is widely used for cycloplegic refractions and in the treatment of amblyopia. A recent randomized National Eye Institute–sponsored trial of atropine 1%, one drop daily, versus patching for the treatment of moderate amblyopia in children, found that atropine was as effective as patching in visual results for the 3- to 7-old age group and had a clear advantage in parent and patient compliance. Adverse effects of atropine in the study were local and minimal.¹³⁹ Used cautiously in patients at risk and employing measures to control overdosage, atropine can be used safely and effectively. Refer to Table 3 for the authors’ protocol for atropine and other cycloplegic agent usage in cycloplegic refractions.

Local adverse reactions from atropine and other cycloplegic mydriatics (e.g., scopolamine, homatropine, cyclopentolate, tropicamide) include increased intraocular pressure (rare in pediatric patients), transient stinging, allergic reactions of the eyelid and conjunctiva, follicular conjunctivitis, hyperemia, edema, photophobia, and eczematous dermatitis. Some cycloplegic mydriatic products contain sulfites that may cause allergic reactions (e.g., hives, itching, wheezing, anaphylaxis) in susceptible persons, especially those known to have allergic disorders such as asthma and atopic dermatitis.

Homatropine is a weaker cycloplegic agent than atropine and is less reliable than similar drugs for cycloplegic refractions in children. Systemic toxic reactions following ocular instillation are similar to those for atropine (see Table 2). Walsh and Hoyt¹²⁸ stated that untoward reactions are milder with homatropine than with atropine, but Hoefnagel did not find this so in his study.¹²⁰ He reported five cases of anticholinergic toxicity in children following the instillation of 2% homatropine drops. CNS signs and symptoms, including ataxia and visual hallucinations, were striking in each of these cases, and although one patient recovered in 6 hours, another had persistent visual hallucinations for 5 days. Three more recent cases of anticholinergic delirium have been reported due to topical ocular homatropine solution.^141,142 One fatality has been reported due to homatropine hypersensitivity in a 7-month old infant with atypical Down syndrome.¹²⁸ Febrile reactions have been observed in severely retarded children in whom homatropine has been used.¹²⁸ There appears to be a relation between these reactions and high environmental temperatures and humidity.¹⁴² Like atropine, homatropine should be used with great caution in children with Down syndrome or brain damage. Physostigmine reverses the systemic anticholinergic effects of homatropine.^137,138

Systemic anticholinergic toxicity after ocular use of scopolamine (Hyoscine) in children has been reported infrequently, and no death attributable to ocular scopolamine has been reported. German authors have described toxic reactions associated with the use of scopolamine ointment^143,144 and with 1% drops.¹⁴⁵ Another report found acute systemic toxicity in three African children and four African adults following the administration of 1% scopolamine eye drops in each eye.¹⁴⁶ Confusion, disorientation, hallucination, spasticity of extremities, vomiting, and urinary incontinence lasted for several hours and then spontaneously resolved. Acute toxic psychosis with recovery within 24 hours has been described in children after the ocular use of 0.2% scopolamine.^147,148 The rapid absorption of ocularly applied scopolamine may explain its occasional systemic anticholinergic side effects.¹⁴⁹ Adverse reactions with the use of commercially available 0.25% solution in the United States have been rare. Scopolamine is an effective cycloplegic substitute for children with known hypersensitivity to atropine (although some cross-reactivity occurs). The cycloplegic strengths of 1% atropine sulfate and 0.25% scopolamine are similar, although the duration of scopolamine cycloplegia is much shorter.¹⁵⁰ Physostigmine promptly reverses the central and peripheral toxicity of scopolamine.^137,138

Introduced in the early 1950s, cyclopentolate hydrochloride (Cyclogyl) has been used to treat both cycloplegia and mydriasis primarily in children older than 1 year of age. Systemic toxicity induced by the ocular administration of cyclopentolate is similar to that produced by atropine, except that cerebellar dysfunction and visual and tactile hallucinations are more constant and striking features of cyclopentolate toxicity. This is not surprising, becausecyclopentolate is structurally similar to atropine but contains a dimethylated side group (–N–[CH₃]₂) also found in some tranquilizers and hallucinogenic drugs. Seizures and acute psychosis induced by cyclopentolate are especially prominent in children^{151,152,153,154,155,156,157,158,159,160} and the elderly.^161,162,163 The psychosis is characterized by disorientation, dysarthria, ataxia, hallucinations, and retrograde amnesia. This seems to indicate that CNS immaturity or aging is necessary for its potent psychotomimetic action to become manifest.¹⁵⁵ Additionally, ocularly instilled cyclopentolate is rapidly absorbed in adults and children.^164,165,166 The peripheral signs and symptoms of cyclopentolate toxicity are variable and frequently are absent. Gastrointestinal toxicity consisting of ileus or gastroenteritis has been observed with cyclopentolate concentrations of 0.5% or greater in preterm infants, due to reduced gastric acid secretion and volume.^156,157 Gastrointestinal effects can be minimized by delaying feeding until after the application of eye drops and ocular examination have been performed.¹⁶⁸