In the large number of reports concerning adverse reactions to topical ophthalmic drugs, it is evident that infants and children are particularly prone to toxic reactions.^1–10 Many topical ophthalmic drugs frequently used in children are not approved by the Food and Drug Administration (FDA) for the pediatric age group. However, they are commonly prescribed by ophthalmologists for infants and children unless serious side effects specific to the pediatric population have been reported. Since 1999, the FDA has had the authority to request pediatric studies for marketed drugs that are often administered to young patients, and “me-too” drugs must be studied first in adults to establish safety and efficacy profiles.^11,12 The numerous isolated case reports and pharmacologic studies of the toxic effects of topical ophthalmic drugs in the pediatric age group are summarized for the practicing ophthalmologist in this updated chapter.

Infants and children have increased potential for ocular and systemic drug-induced adverse reactions for several reasons: (1) they may receive an excessive dose owing to difficulty in instilling drops or ointment, particularly if they are uncooperative; (2) administration of a drug may be continued by a parent or nurse who does not recognize early signs of drug toxicity; (3) differences exist between children and adults in their physiologic response to the same drug^13,14; (4) drug absorption through the conjunctival epithelium and skin may be more rapid in infants^15,16; (5) metabolic enzyme systems are immature, especially in neonates, and may prolong the half-life of drugs¹⁷; and (6) the dose relative to blood volume, body weight, and surface area is greater for infants and children (blood in adults dilutes absorbed drug 20 times more than in neonates)^5,18,20

This factor of the relationship of the dose to blood volume, body weight, and surface area is particularly important in causing toxicity. If drops only are considered, an approximation can be made of the total dose delivered to the eyes following a routine instillation. The dose per drop of certain topical ocular drugs used in the pediatric age group for examination and therapeutic purposes is listed in Table 1, along with the usual systemic pediatric therapeutic dose and the lethal dose, if known.

Table 1. Administered Dosage of Commonly Used Topical Ophthalmic Drugs

Relative overdosage of all drugs listed in Table 1 can occur in children, particularly if repeated doses are given. Limited quantitative data on the systemic absorption of drugs after conjunctival instillation indicate that 30% to 80% of a retained topically applied dose enters the general circulation.²⁰ If systemic absorption averages 50% of the instilled medication, the systemic dose can be dangerously large. For example, one drop of 10% phenylephrine (100 mg/mL) instilled into each eye delivers about 7 mg of the drug (see Table 1). Assuming 50% absorption, a child weighing 20 kg receives almost twice the usual parenteral subcutaneous or intramuscular therapeutic dose (2 mg) or nine times the usual parenteral intravenous therapeutic dose (0.4 mg). Similar comparisons can be made for other drugs in Table 1. Topical corticosteroids are frequently instilled into the eye every 2 hours for treatment of uveitis or vernal catarrh in a child. If prednisolone acetate 1% is used, a total of 16 mg of the drug (one drop in each eye every 2 hours for 16 hours) is instilled each day. Assuming that 50% of the administered drug (8 mg) is absorbed, this can be twice the daily pediatric physiologic replacement dose of prednisolone given orally (4–10 mg). Plasma timolol levels have been measured in infants and children receiving topical timolol for glaucoma. Levels ranged from a low of 3.5 ng/mL in a 5-year-old child to a high of 34 ng/mL in a 3-week-old infant, which is far in excess of the usual therapeutic dose of an equivalent amount of propranolol.¹⁹

Measures to reduce excessive absorption and toxicity of topical eye medication in pediatric patients have been based on techniques for resisting drainage into the nasolacrimal system or on the use of vehicles and delivery systems that increase topical bioavailability and absorption by the cornea while decreasing total drug concentration in the eye. These measures include the following:

1. Use of proper technique of drug instillation, that is, correct immobilization of the child and the eyelids to avoid instilling more than the prescribed dose (note that instilling multiple doses at intervals of 30 seconds or less will increase absorption and possibly deliver a larger systemic dose).^18,20 Care should be taken in children with Down syndrome to avoid hyperflexion and hyperextension of the neck as there is an instability between the first and second cervical vertebrae in this group of patients.²¹
   
2. Digital pressure on the periphery of the nasolacrimal system at the medial canthus for 3 to 5 minutes (a recommended maneuver that may be difficult in pediatric patients) to obstruct drainage to the vascular nasopharyngeal mucosa and thus reduce (67% in one study²²) potentially rapid systemic absorption.^22–25
   
3. Gentle and quiet eyelid closure for 3 minutes after drug instillation (65% reduction of absorption in the same study as in no. 2²²).
   
4. Quick blotting away of any excess to reduce the volume of drug administered and encourage the eyelids to stay closed for a short time.⁵
   
5. Placement of an absorbent pledget at the punctum prior to drug instillation to restrict absorption by the conjunctiva and cornea.
   
6. Cutaneous drug delivery to eliminate difficulty with instillation and reflex washout. Eye drops can be instilled on the inner canthus with eyes closed followed by immediate opening of the eyes. This technique can deliver ocular cycloplegics with the same ocular effect and safety as the usual open-eye method. This may be helpful in uncooperative children.^26,28 An alternative delivery system incorporates the drug in a lipid-based vehicle that is streaked on the lateral lower eyelid below the eyelashes. The ointment is automatically transferred over the skin to the inferior tear film.^29,30
   
7. Occlusion of the lacrimal puncta by collagen punctual plugs, silicone punctual plugs, cautery, suture, or laser to block drainage of eye drops through the nasolacrimal system. This also keeps the medication in contact with the cornea for a longer duration and improves the therapeutic index of administered medication.^31,32
   
8. Decreasing dimensions of the eye-dropper tip since the volume delivered by commercial ophthalmic droppers (25.1 to 56.4 μL) is large in relation to tear volume and not as effective therapeutically as drug equivalents given in smaller volumes.^33–39 The ideal volume for a drop is 10 to15 μL, based on the amount of fluid the eye can hold.⁴⁰ The volumes given in several “home-made” tips for achieving a drop size range from 8 to15 μL, but current commercial production methods limit drop size to 20 μL and above.⁴¹
   
9. Application of a spray to open or closed eyelids. This is as effective as eye drops, is easier to administer, produces less discomfort, and may be more acceptable to children.^42–45
   
10. Use of a single eye drop combination of two drugs to reduce the number of drug instillations and the amount of drug delivered to the eye.⁴⁶
    
11. Use of a preceding local anesthetic such as proparacaine to enhance the effect of drugs by increasing transcorneal absorption and decreasing the dilution effect of tearing caused by the stinging sensation of diagnostic or therapeutic drops.^40,46–48
    
12. Increasing the viscosity of the eye drop by dissolving the drug in an oil or emulsion base, which boosts retention in the tear film.^49,50
    
13. Employing drug suspensions instead of drug solutions. Suspended drug particles are retained in the conjunctival sac longer than solutions. Note that the bottle must be adequately shaken to suspend the particles uniformly.^51,52
    
14. Substituting ointments for drops. Ointments can double eye contact time in blinking eyes, quadruple it in patched eyes, and remain in the conjunctival sac for nearly 3 hours after instillation, producing a controlled, prolonged response.⁴⁰ Also, ointments decrease absorption through the conjunctiva and decrease passage into the nasolacrimal duct.^53–56 However, parents often find ointments difficult to instill.
    
15. Use of gel-based systems that release small amounts of drug continuously have proven themselves commercially. A gel-forming system is currently available for timolol (Timoptic-XE). Gel-foam discs are applicators placed in the inferior fornix and releasing drugs slowly over time.^57,58 A semisolid gel base, marketed as Pilocarpine HCl 4%, acts as a prolonged drug release form.
    
16. Use of controlled delivery systems including hydrophilic soft contact lenses (nondisposable and disposable),⁵⁹ collagen corneal shields (usefulness has been demonstrated in pediatric patients after cataract surgery and in treating corneal ulcers),^60,61 collagen discs,⁵² and collagen pieces (Collasomes) suspended in a viscous vehicle.⁶³
    
17. Treating with site-specific or soft drugs that are activated enzymatically on the eye but rapidly become inactive metabolically when absorbed into the systemic circulation. The result is improved bioavailability and reduction of the potential for ocular and systemic side effects.⁶⁴
    
18. Addition of vasoconstrictive agents (i.e., phenylephrine) to minimize systemic absorption.^50,65
    
19. Creating prodrugs with high lipophilicity allowing rapid corneal penetration, desired effectiveness at a lower dose, and a reduction in systemic side effects. An example is dipivefrin (see later), a prodrug of epinephrine.
    
20. Use of cyclodextrins to form aqueous eye drop solutions with lipophilic drugs such as corticosteroids, carbonic anhydrase inhibitors, and pilocarpine. The resulting drug has increased water solubility, enhanced absorption into the inner eye, and decreased topical irritation.⁶⁶
    

Until medications and delivery systems are available commercially in pediatric doses, the potential remains for administration and absorption of medications in high doses through the ocular route in infants and children. It is thus important to be able to recognize the complex of signs and symptoms associated with toxic reactions to a specific drug, so that the drug may be discontinued and appropriate treatment begun before serious and even fatal consequences ensue.

EPINEPHRINE AND DIPIVEFRIN

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.^76–81

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).

HYDROXYAMPHETAMINE

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

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,^93–97 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.^99–102 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%.^96,104–106 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.^68,107–109 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

ATROPINE

Since the introduction of atropine in 1833, many cases of systemic toxicity have been reported after conjunctival instillation of the drug.^113–127 These cases include six deaths in children, all of whom were younger than 3 years of age.^124–128 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.^130–132 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

Table 2. Signs and Symptoms of SystemicAtropine Toxicity

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.

Table 3. Choice of Cycloplegic Agent for Infants and Children

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

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

SCOPOLAMINE

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

CYCLOPENTOLATE

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^151–160 and the elderly.^161–163 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.^164–166 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

Toxic reactions to cyclopentolate are dose dependent and are more likely to occur with the 2% solution than with repeated doses of 1% solution. Toxic reactions in children and adolescents are much less common with the 1% compared with the 2% solution.¹⁵³ Systemic adverse reactions are rarely encountered with the use of the 0.5% concentration in children. Cyclopentolate 0.5% solution has been used for both mydriasis and cycloplegia in infants and children. For newborns, a safer drug is cyclopentolate 0.2% concentration in combination with 1% phenylephrine (Cyclomydril). A 1% solution of cyclopentolate may be used for refraction in older infants and children if the irides are highly pigmented. The 1% solution is close to atropine in cycloplegic effectiveness (in white children, only .34 D less hypermetropia was found with cyclopentolate-induced cycloplegia than with atropine-induced cycloplegia).¹⁶⁹ There are few, if any, indications for use of the 2% solution in the pediatric age group. Cycloplegia protocol recommendations are summarized in Table 3.

The onset of cyclopentolate toxicity occurs within 20 to 30 minutes of drug instillation, and although usually transient (subsiding in 4 to 6 hours), the symptoms can last 12 to 24 hours. The treatment of systemic cyclopentolate poisoning is the same as for atropine^137,138 Kothery and coworkers found that cyclopentolate inhibits cholinesterase in vitro.¹⁷⁰ Accordingly, the authors advise using succinylcholine in weak doses for patients undergoing general anesthesia who have been treated with cyclopentolate within the past several weeks, or avoiding the use of succinylcholine completely.

A local or generalized allergic-type response to cyclopentolate consisting of an urticarial rash has been described in children.^171–173 No treatment is necessary except antihistamines. Severe anaphylactic reactions are rare and are treated with epinephrine, steroids, and antihistamines according to standard anaphylactic treatment protocols.

TROPICAMIDE

Tropicamide (Mydriacyl) is a rapid-acting mydriatic with mild and transient cycloplegic action. Tropicamide 0.5% or 1% eye drops combined with phenylephrine 2.5% eye drops, given either separately 5 minutes apart or combined in one drop, produces wide papillary dilation for indirect ophthalmoscopy in infants and children. Down syndrome mydriatic response is three times greater in comparison with healthy patients.¹⁷⁴ Milder found 1% tropicamide a relatively inadequate cycloplegic drug compared with 1% cyclopentolate.¹⁷⁵ One study found tropicamide equal to cyclopentolate in measuring the refractive error of low to moderate hyperopia in school-aged children¹⁷⁶

Although two studies report no adverse reactions with the use of 1% tropicamide,^177,178 serious CNS disturbances have been observed on rare occasions.⁸⁵ The low affinity for muscarinic receptors in plasma after conjunctival instillation explains the low incidence of serious systemic side effects of tropicamide drops.¹⁸⁰

There are many protocols for cycloplegic refraction that are individualistic and heterogeneous. Based on the authors' review of the literature and clinical experience, Table 3 has been formulated to guide clinicians in the proper selection of cycloplegic agents in the different age groups. When cyclopentolate is used, tropicamide 0.5% can be added in infants up to 3 months of age and 1% thereafter, to enhance the cycloplegic effect. Phenylephrine drops can enhance mydriasis for ophthalmoscopy. The use of a topical anesthetic drop prior to administration of cyclopentolate (and of other drops) can result in a more comfortable and atraumatic cycloplegia in children.¹⁸¹

PILOCARPINE

Pilocarpine has limited therapeutic use in infants and children, but occasionally it is employed in the treatment of congential or juvenile glaucoma. Pilogel (Pilopine HS Gel) may be better tolerated by children, as the increase in myopia produced occurs primarily during sleep. Pilocarpine is a direct-acting miotic with effect on the muscarinic (parasympathomimetic) receptors in the eye. The drug is rapidly absorbed into the systemic circulation after ocular instillation.¹⁸² Systemic toxicity after repeated instillation of pilocarpine, evidenced by salivation, lacrimation, rhinorrhea, sweating, nausea, vomiting, diarrhea, muscle tremor, muscle weakness, ataxia, and confusion, is uncommon.^183,184 Since pilocarpine also may produce bronchospasm, a typical asthmatic attack may be precipitated in susceptible patients. Toxicity may be treated with systemic administration of parenteral atropine, which antagonizes the muscarinic effects.¹⁸²

Newborns of mothers taking topical pilocarpine may have hyperthermia, hyperemia, diaphoresis, restlessness, and seizures.¹⁸⁵ Because this symptom complex may be mistaken for neonatal meningitis and cause needless therapy, it is important that the ophthalmologist inform the pediatrician and obstetrician that the mother is using pilocarpine eye drops. Pilocarpine infrequently produces iris cysts in children¹⁸⁶ and has no consistent cataractogenic effect in children. There have been reports received by the National Registry of Drug Induced Ocular Side Effects of peripheral, white, subepithelial corneal deposits and iritis with pilocarpine use. Other local ocular reactions include burning and smarting, conjunctival and ciliary congestion, ocular pain, eyelid twitching, accommodative myopia, lacrimal canalicular obstruction, and allergic blepharoconjunctivitis.¹⁸⁷

CARBECHOL

Carbechol is similar in action to pilocarpine but has a longer duration of action and more frequent systemic toxicity. Like pilocarpine, it should be used with caution in children with bronchial asthma. Systemic toxic reactions are treated in the same manner as for pilocarpine.¹⁸²

PHYSOSTIGMINE

Physostigmine (Eserine) is an indirect-acting miotic. The drug inhibits the enzyme cholinesterase and thus enhances the effects of acetylcholine. A short-lived, reversible depression of blood cholinesterase has been observed in children following the topical use of physostigmine.¹⁸³ Physostigmine is rapidly absorbed from the nasal mucosa after conjunctival instillation and may result in systemic toxicity similar to that of acetylcholine. An effective antagonist to physostigmine toxicity is atropine sulfate given parenterally. Physostigmine salicylate by injection is the standard antidote for anticholinergic drug toxicity.^137,138

ECHOTHIPHATE AND ISOFLUROPHATE

Echothiophate iodide (phospholine iodide) and isoflurophate (Floropryl, DFP) are indirect-acting miotics that cause a prolonged and irreversible inactivation of cholinesterase. They commonly are referred to by the misnomer “strong miotics.” These anticholinesterase inhibitors are not really strong but have a long duration of action, and their action makes the pupillary sphincter highly sensitive to a lower concentration of cholinergic drugs. These miotics are used in children mainly to identify or treat the accommodative component of esotropia. Occasionally they are used to treat developmental glaucoma and parasitic infestations of the eyelids. Isoflurophate is no longer available commercially, and echothiophate 0.125% is in short supply and presently only available on a limited basis from Merck Pharmaceuticals.

Echothiophate iodide aqueous solution can be readily absorbed into the general circulation, lowering the blood cholinesterase level and producing systemic toxicity. No consistent relationship exists, however, between symptoms of toxicity and blood cholinesterase levels. Immediate systemic reactions from echothiophate iodide are rare¹⁸⁸ Clinical evidence of generalized toxicity may not appear for weeks to months after beginning therapy, and because systemic toxicity may mimic other illnesses, the relationship between anticholinesterase therapy and toxic symptoms may go unrecognized.¹⁸⁸ Children generally tolerate the anticholinesterase agents better than adults do, and they suffer fewer ocular and systemic toxic effects¹⁸⁹

The ocular toxic effects of the anticholinesterase agents in children have been reviewed by several authors,^1,3 and include the following:

  Ciliary spasm (headache, pain in eye and brow, transient myopia)
  Miosis (rarely irreversible)
  Hyperemia of conjunctiva and iris
  Iritis (mild, infrequent)
  Pupillary block and angle-closure glaucoma (rare)
  Iris cysts
  Cataracts (rare)
  ? Retinal tear, detachment
  Allergic blepharoconjunctivitis

Ciliary spasm, hyperemia, and iritis are of little consequence in children and disappear after 5 to 10 days of continuous treatment. Chronic irreversible miosis has been reported in a 15-month-old girl who received echothiophate daily for 9 months. Two years later, her pupils were still 2 mm in normal light.¹⁹⁰ Young infants may be more susceptible to this effect because of an immature iris dilator muscle. Angle-closure glaucoma is a rare occurrence.¹⁹¹ The association of retinal detachment and anticholinesterase agents in adults is controversial; no instances of retinal detachment have been reported in children receiving ocular anticholinesterases.¹⁹²

Intraepithelial cysts of the iris have been associated with the use of most miotics, but they are seen most often in conjunction with the prolonged and intense miosis produced by echothiophate iodide and isoflurophate.^185,193,194 These large brown cysts appear either along or behind the pupillary margin of the iris and are secondary to an accumulation of fluid between the epithelial layers of the iris. The incidence of miotic cysts may be reduced by the use of lower dosage strengths of the miotic or by less frequent instillation. Occasionally the miotic must be discontinued. In some cases, the cysts may persist for up to 10 weeks after the miotic is stopped.¹⁹³ Phenylephrine in combination with echothiophate iodide or isoflurophate reduces pupillary cyst formation and does not impair the effect of the miotic.¹⁹⁴ Iris cysts may attain such size in children that in combination with a miosis they totally occlude the pupil. In one instance, a mistaken diagnosis of malignant melanoma led to enucleation of a child's eye.¹⁹⁵ In this case, several iris cysts nearly occluded the pupil and, since they did not transilluminate well because of iris pigment, they were mistaken for a melanoma. Histologic study showed the “tumor” to consist of intraepithelial cystic spaces extending beyond the pupillary margin.

Lenticular opacities occur rarely in children receiving anticholinesterase miotics. These begin as anterior subcapsular opacities, and later posterior subcapsular opacities and nuclear sclerosis can develop. The opacities require 10 to 18 months to appear and are related to total dosage.¹⁹⁶ Older children are more commonly affected. Although the cataracts may seem reversible and resolve on cessation of the miotic,¹⁹⁷ they often redevelop.¹⁹⁶

Systemic anticholinesterase poisoning is unusual in children, and the toxic effects that do occur are milder and of shorter duration than those experienced by adults¹⁹⁸ Children at highest risk are those with asthma, Down syndrome, myasthenia gravis, epilepsy, and gastrointestinal disturbance.⁸ Children with Down syndrome can develop excitement, crying, restlessness, tremors, and uncontrollable behavior. The signs and symptoms of systemic anticholinesterase toxicity are summarized in Table 4. An additional toxic effect has been noted but has not received widespread attention. A “miotic URI” consisting of persistent mild rhinorrhea, lacrimation, and upper respiratory congestion can occur and frequently may be missed. A number of children using strong miotics have undergone repeated laboratory tests, radiography, and drug therapy for a “chronic resistant cold or allergy” because this association between localized parasympathetic stimulation of the glands of the upper respiratory tract and anticholinesterase agents was overlooked.¹⁸⁹

Table 4. Signs and Symptoms of Anticholinesterase Toxicity

The systemic absorption of anticholinesterase agents may be enhanced in patients with fistulizing devices (e.g., Jones tube) inserted after lacrimal surgery for dacryostenosis.²⁰⁰ The development of adverse systemic effects can also be accelerated in patients receiving anticholinesterases who are exposed to organophosphate pesticides because these pesticides are also cholinesterase inhibitors.^196,201

Although systemic toxicity secondary to topical anticholinesterase use is uncommon in children, the ophthalmologist should be familiar with treatment of this complication. The fatal dose of echothiophate iodide and isoflurophate is 10 mg given topically¹³³ Havener states that a child could easily die of the systemic toxic effects associated with ingestion of a 5-ml bottle of anticholinesterase eye drops.²⁰² The classic antidote for anticholinesterase poisoning has been atropine, which can be given intravenously or intramuscularly at an initial dosage of 0.05 mg/kg up to 2 to 5 mg. The intravenous dose can be repeated every 5 minutes, and the intramuscular dose every 15 minutes, until the signs and symptoms of parasympathomimetic overdosage disappear. Additional doses should be given to maintain atropinization for 24 to 48.²⁰⁵ The cholinesterase activator pralidoxime (Protopam, PAM) has been found to be an effective antidote used in conjunction with atropine for anticholinesterase toxicity.^203–205 Pralidoxine is ineffective topically due to poor corneal penetration but is effective after subconjunctival injection (0.1 – 0.2 ml 5% aqueous solution) for reversal of ocular side effects.²⁰² The systemic effects of the anticholinesterase drugs may be counteracted by giving pralidoxime as a 5% solution slowly intravenously over about 30 minutes every 8 to 12 hours in a dosage of 25 to 50 mg/kg up to a maximum of 1 g in older children.²⁰⁵

Patients with depressed levels of blood cholinesterase due to anticholinesterase therapy may suffer prolonged respiratory paralysis, and even death, if the depolarizing muscle relaxant succinylcholine is used to aid endotracheal intubation during the initiation of general anesthesia.¹⁹⁸ If the anesthesiologist is informed of the potential problem, he may substitute a nondepolarizing agent that does not require cholinesterase for its breakdown. Preferably, anticholinesterase agents should not be used for at least 6 weeks prior to an elective surgical procedure requiring general anesthesia. Whenever possible, a blood cholinesterase level determination should be obtained when any topical anticholinesterase therapy has been used, to be sure that the level is in the safe range.

Topical ocular corticosteroids are frequently used routinely after strabismus surgery. One survey found that more than 90% of strabismus surgeons gave corticosteroid drops to young patients after strabismus surgery.²¹⁸ This common practice is disturbing in the light of recent studies in children that show a marked dose-dependent ocular hypertensive response to 0.1% dexamethasone after strabismus surgery in all childhood age groups.^219–222 This response is more severe and more rapid than that reported in adults, with as many as 56% of studied children showing a high response in most cases within 8 days of instituting treatment.²²² This hypertensive effect was also seen in a young rabbit model.²²³ Because it is difficult to monitor intraocular pressure in young children, the routine use of topical dexamethasone or prednisolone in children after strabismus surgery should be avoided if possible. Acceptable alternatives shown to have comparable anti-inflammatory action with much less hypertensive effect are fluorometholone 0.1% (FML),^219,220 rimexolone 1% (Vexol),^224,225 diclofenac 1% (Voltaren),^226–228 and loteprednol etabonate (Alrex 0.2%, Lotemax 0.5%).^229–233 These anti-inflammatory agents have not been thoroughly studied in the pediatric age group, but they appear to be safe to use in infants and children for postoperative inflammation and the long-term treatment of ocular inflammatory diseases such as uveitis and giant papillary conjunctivitis (vernal keratoconjunctivitis).

Since 1960, when Black and associates first reported the induction of posterior subcapsular cataracts (PSCs) by systemic corticosteroids in patients with rheumatoid arthritis,²³⁴ considerable evidence has accumulated linking PSCs with long-term systemic corticosteroid therapy in adults.²⁰⁶ PSCs are seen following as little as 4 months of topical steroid use.²⁰⁶ Topical ophthalmic corticosteroids have been incriminated similarly in adults.²⁰⁶ Only a few reports have dealt with this problem in children. One study found PSCs in 8 of 15 children receiving systemic corticosteroids for more than 2 years,²³⁵ and another study added eight more cases of systemic corticosteroid-induced cataracts.²³⁶ In a report by Burde and Becker, two older adolescents with redness due to contact lens wear developed PSCs and severe glaucoma following the use of topical prednisolone daily for 2 years in one case and topical dexamethasone or prednisolone twice daily for 4 years in the other.⁴ The paucity of reports of PSCs in infants and children attributable to long-term topical corticosteroid use may in part be due to difficulty in examining this age group with the slit lamp to discover subtle or minimal lens changes. The proven induction of lens opacities in adults receiving systemic and ocular corticosteroids for periods of months and the occurrence of PSCs in children on chronic systemic corticosteroid therapy make it obligatory to perform slit-lamp examinations periodically in each child who is receiving long-term systemic or ocular corticosteroid therapy. No correlation has been found between PSCs and total corticosteroid dose, weekly dose, duration of dose, or age of patient. The most important etiologic factor seems to be individual susceptibility to the side effects of corticosteroids.²³⁷

Systemic absorption of topically applied ophthalmic corticosteroid preparations has not been quantified, but significant absorption is implied by several research and case studies. Volunteers receiving 0.01% dexamethasone topically to the eye showed a reduction in urinary excretion of 17-hydroxycorticosteroids and a reduction in endogenous cortisol production.^238,239 Adrenal atrophy, chronic pyelonephritis, weight change, and fetal malformations have been described in rabbits receiving corticosteroid eye drops.^240,241 Nursall described a patient who demonstrated allergic symptomatology and a reproducible decrease in circulating eosinophils each time she was given corticosteroid eye drops²⁴²

Two cases of induced Cushing's syndrome (one fatal) in children receiving dexamethasone eye drops have been reported.^243,244 Both patients received eight drops per day of 0.1% dexamethasone, equivalent to 0.4 mg. When this quantity is compared with the daily oral physiologic replacement dose of dexamethasone for these two children, aged 8 months and 2 and a half years (approximately 0.4 mg/day and 0.6 mg/day, respectively), the potential for partial adrenal suppression is evident, especially with long-term use of corticosteroids. The older child, in a case reported by Romano and associates, received, in addition to dexamethasone eye drops, periocular injections of triamcinolone, 0.5 ml (20 mg), on several occasions during therapy.²⁴⁴ This child died after 4 months of corticosteroid therapy for a corneal homograft rejection. Postmortem examination confirmed the diagnosis of Cushing's syndrome with adrenal suppression and atrophy. Two infants with periocular hemangiomas treated with a 1-ml intralesional injection of a 50:50 mixture of triamcinolone acetonide (Kenolog-40, 40 mg/mL) and betamethasone phosphate/acetate (Celestone Soluspan, 6 mg/mL) promptly developed adrenal suppression, as evidenced by depression of their serum cortisol and adrenocorticotropic hormone levels. The hormone levels and the growth and weight rates in one of the infants remained depressed for 5 months post injection.²⁴⁵

Topical corticosteroids tend to decrease resistance to bacterial, viral (especially herpes simplex), and fungal infections. Other adverse local reactions include mydriasis, epithelial punctuate keratitis, delayed corneal and scleral healing, corneal and scleralmalacia, tear-film instability, uveitis, crystalline keratopathy, orbital fat atrophy, limitation of ocular movement, and occasional allergic reactions.³⁴

SULFONAMIDES

Serious allergic reactions leading to death from Stevens-Johnson syndrome or aplastic anemia have occurred in children receiving systemic sulfonamides.^246,247 Three cases of Stevens-Johnson syndrome, one in an 8-year-old boy, have occurred following ocular sulfonamide use.^248–250 For this reason, topical sulfonamide eye drops should be used prudently and only after a careful medical history regarding exposure to sulfonamides and specifically any record of reactions to these drugs. Sulfonamide ointments used to treat marginal blepharitis have led to local photosensitization that caused circumscribed sunburn of the lid margin. Erroneous diagnoses of allergy to the drug have been made.²⁵¹ True allergic dermatoconjunctivitis occurs occasionally.

CHLORAMPHENICOL

Topical ocular chloramphenicol is widely used throughout the world in the treatment of superficial ocular infections because of its broad spectrum of activity, infrequent local irritative and hypersensitive reactions, and low cost. Its use in the United States has declined markedly since the report published by Fraunfelder et al in 1982 of two fatal cases of aplastic anemia attributable to chloramphenicol eyedrops.²⁵² By 1993, the National Registry of Drug-Induced Ocular Side Effects listed 23 patients with blood dyscrasias, including seven published cases possibly due to topical ocular chloramphenicol.²⁵³ The current Physicians Desk Reference emphasizes that ocular chloramphenicol be used for eye infections only if no alternative exists.²⁵⁴

The association of aplastic anemia and systemic administration of chloramphenicol in adults is well established²⁵⁵ The cause-and-effect relationship between topical ocular chloramphenicol and aplastic anemia is not clearly proven by current reports, and the data has been reviewed by several authors.^256–259 The risk of aplastic anemia with ocular chloramphenicol may be the same as the risk of aplastic anemia after oral administration of chloramphenicol: approximately 1 in 30,000 to 1 in 50,000 courses of therapy.²⁵⁶

Chloramphenicol has two effects on bone marrow. First, there is a dose-related hematopoetic toxicity with systemic and rarely topical use. The toxic effect on bone marrow usually is reversible with cessation of the drug. Secondly, there are the rare cases of idiosyncratic aplastic anemia, usually with prolonged (months to years) or frequent intermittent (over months to years) use of ocular chloramphenicol. This effect is not dose related and appears to occur only in genetically predisposed individuals. Although serum levels do not reach detectable levels after short-term ocular treatment with chloramphenicol in children,²⁶² some systemic absorption may occur and precipitate an idiosyncratic aplastic anemia.^231,262

The potential danger of chloramphenicaol merits judicious use of this drug in children. It should be avoided in any young patient with a genetic predisposition to hematologic disorders (a careful personal and family history of blood dyscrasia is important), those requiring long-term treatment, and patients for whom there are suitable alternatives. Appropriate substitute drugs for superficial ocular infections include polymyxin in combination with bacitracin (Polysporin) or trimethoprim (Polytrim), or one of the fluoroquinilone antibiotics alone. In one European study, Ciprofloxacin in a 0.3% solution was found to be safe and as effective as 0.5% chloramphenicol solution in the treatment of conjunctivitis and blepharitis.²⁶³

AMINOGLYCOSIDES

The aminoglycosides can produce allergic contact and toxic conjunctivitis in all age groups with neomycin the major sensitizer. Cross-allergenicity does occur.²⁶⁴ Allergic contact dermatoconjunctivitis is a cell-mediated reaction (type IV hypersensitivity) caused by sensitization through previous exposure to the drug. The cutaneous changes are those of acute eczema with significant itching. The conjunctiva typically has a papillary reaction initially more apparent in the inferior conjunctiva with a mucoid discharge. A report of five newborns with orbital irritant contact dermatitis caused by gentamicin ointment used in newborn preventive therapy may have been due to the preservative in gentamicin, paraben.²⁶⁵

Gentamicin and tobramycin have broad gram-negative coverage, but corneal epithelial toxicity and inhibition of wound healing are common with continued use. Tobramycin has been found to be equally effective (90%) as ciprofloxacin in treating childhood bacterial conjunctivitis.²⁶⁶ Resistance to gentamicin and tobramycin is increasing annually. Erythromycin has been an effective treatment for gram-positive organisms and ophthalmia neonatorium prophylaxis. No current available treatment, however, offers complete protection against neonatal chlamydial infection²⁶⁷ One study found povidine-iodine 2.5% solution an effective antibacterial agent on the conjunctiva of newborns that caused less toxicity than silver nitrate. Erythromycin was found ineffective in this same study.²⁶⁸

Absorption of aminoglycosides after ocular use appears to be insufficient to cause toxic systemic effects.²⁶⁹

FLUOROQUINILONES

Since their introduction in 1990, the ocular fluoroquinilone antibiotics have demonstrated a broad spectrum of activity with low toxicity. They have found wide acceptance for the treatment of superficial ocular infections in infants and children. These drugs inhibit DNA synthesis by binding to two specific enzymes: DNAsyrase and topoisomerase IV, both of which are required for DNA replication. Third-generation fluoroquinilone antibiotics—ofloxacin, ciprofloxacin, levofloxacin, and norfloxacin—have proved effective against gram-negative organisms, but gram-positive coverage has been variable and resistance to some organisms is emerging. Fourth-generation fluoroquinilones currently in development—gatifloxacin and moxifloxacin—may be more effective against Staphylococcus aureus and other organisms currently resistant to the third-generation drugs.

The safety profile of this class of antibiotics is excellent. White crystalline precipitates are seen in the cornea epithelium with intense treatment for corneal ulcers. These precipitates cause no harm. A single case of idiosyncratic acute psychosis after the use of ciprofloxacin for a severe conjunctivitis in a 27-year-old woman has been reported.²⁷⁰

ANTI-VIRAL AGENTS

Idoxuridine (Herplex), an antiviral drug used for treatment of herpetic eye infections, frequently causes contact dermatoconjunctivitis and chronic follicular conjunctivitis.²⁷¹ Use of idoxuridine has been replaced by newer, more effective agents, but contact dermatitis has also been reported in patients using trifluridine (Viroptic).²⁷¹ Punctal stenosis and occlusion, conjunctival scarring, and delayed wound healing can occur from both agents. Systemic reactions are unlikely, as there were no untoward effects from the ingestion of an entire 7.5-cc bottle.⁷¹

DECONGESTANTS

These drugs have a good safety record but can be irritating, causing stinging, burning, and tearing. They can initiate rebound conjunctival hyperemia, follicular or papillary conjunctivitis, and allergic dermatoconjunctivitis.^272,273 Systemic side effects are infrequent because of the low concentrations required for ocular decongestion. These drugs, however, are adrenergic agonists, and caution is advised concerning use in infants and children, as they can cause a marked decrease in body temperature.⁹ Systemic absorption of imidazole decongestants, such as naphazoline, through accidental or intentional poisoning, can cause CNS and respiratory depression, bradycardia, and hypotension.²⁷⁴

PROPRIETARY ANTIHISTAMINES

Limited data is available for children, but the effectiveness and adverse reaction profile for this group of allergy medications is similar to that seen in adults. Levocabastine (Livostin) has been found equal or superior to cromoglycate in treating seasonal allergic conjunctivitis^275,276 and vernal keratoconjunctivitis.^277,278 It is well tolerated with minimal nasal and ocular adverse irritant reactions. Emadastine (Emadine), another H₁-antagonist, has been studied in pediatric patients and was superior to levocabastine in relieving the itching of seasonal allergic conjunctivitis.^279,280

MAST CELL STABILIZERS AND MAST CELL STABILIZER/ANTIHISTAMINE COMBINATIONS

Cromoglycate (Cromolyn) was the first mast-cell stabilizing drug and is useful in treating vernal and atopic keratoconjunctivitis when used alone or in combination with other drugs. It causes transient stinging, burning, hyperemia, and watering on ocular instillation.²⁸¹ Contact dermatitis is a well-known side effect.²⁸² Absorption into the eye and systemic circulation is poor.²⁸³ Lodoxamide (Alomide) is a mast-cell stabilizer that has been well studied in children. It is a safe and effective treatment for allergic conjunctivitis^276,284 and vernal keratoconjunctivitis.^283,285,286 Its clinical effectiveness is superior to that of levocabastine and cromoglycolate.

All of the mast-cell stabilizer/antihistamine drugs are useful in treating seasonal allergic conjunctivitis and vernal keratoconjunctivitis. Adverse effects are few, with 15% of patients reporting headache and rhinitis, and less than 5% burning and stinging. Azelastine (Optivar) eye drops are effective and well tolerated for the treatment of seasonal allergic conjunctivitis in young children.^287,288 Nedocromil (Alocril) was studied in children with vernal keratoconjunctivitis and demonstrated excellent efficacy exceeding that of cromoglycate.²⁸⁵ Olopatadine (Patanol) is the most effective conjunctival mast-cell inhibitor for topical use in the conjunctiva and offers the advantage of immediate effect and relative comfort upon instillation.

Non-steroidal anti-inflammatory drugs should be used with caution in the pediatric age group. Closely monitor patients and limit use to short-term treatment. In general, these drugs should be avoided in treating ocular allergy because there are other, safer drugs such as the proprietary antihistamines and mast-cell stabilizers. If an anti-inflammatory effect is desired, a better alternative is a site-active steroid.

CORTICOSTEROIDS

Because of the side effects of potent steroids, they should be used only if an allergic condition is refractive to other treatment. If steroids are required, therapy should be initiated with milder or site-active steroids that have a good safety profile, such as fluoromethalone, rimexalone, or loteprednol. When the initial insult is past, a mast-cell stabilizer or mast-cell stabilizer/antihistamine combination may be substituted.

There is very little pediatric data on steroidal treatment of allergic eye disease. Several studies on lotepradnol (Alrex 0.2%, Lotemax, 0.5%) have found that it produces a rapid clinical response with a low incidence of side effects (including a low and transient elevation of intraocular pressure in some patients) in giant papillary conjunctivitis,^231–233 and seasonal allergic conjunctivitis.^292–294 Lotepradnol is a the only true soft steroid in the ophthalmic world. The drug is metabolized soon after making its way into the eye and has less likelihood of causing cataracts and glaucoma. The 0.2% solution is the weaker formulation of the two available and hence is the one approved for ocular allergies.

CYCLOPSORINE A

Cyclosporine A is a potent immunosuppressive agent used to treat severe, resistant ligneous conjunctivitis and atopic and vernal keratoconjunctivitis in children^295–301 It is useful as a steroid-sparing drug and is relatively safe, although not always well tolerated due to side effects, including stinging, lid rash, and superficial punctate keratitis. A commercial topical cyclosporine A (Restasis) has just received FDA approval. No measurable drug blood levels or renal toxicity have been found in long-term treatment of adult patients with ocular cyclosporine A.²⁹⁷

MITOMYCIN-C

Mitomycin-C can be considered for patients with severe vernal keratoconjunctivitis refractive to conventional treatment. Akpek and associates³⁰² studied 26 patients, including older children, with severe vernal keratoconjunctivitis. Used in low-dose, short-term therapy, mitomycin-C was effective with no adverse effects of treatment. Long-term studies are lacking.

BETA-ADRENERGIC ANTAGONISTS

Timolol maleate was introduced to clinical usage in 1978 as the first beta-blocker for the treatment of glaucoma. A wide range of adverse reactions led to the development of second-generation beta-blockers that had similar adverse effects, but in varying frequency and severity. In general, these anti-hypertensive drugs have been well tolerated by older children, but the reduced blood volume and immature metabolic systems in young children and infants pose a significant risk of adverse systemic side effects.

Timolol

Timolol maleate (Timoptic), timolol maleate gel (Timoptic-XE), and timolol hemihydrate (Betimol) are non-cardioselective (beta 1 and beta 2) beta-blockers that have been a useful adjunct to the treatment of severe pediatric glaucomas. Timolol is rapidly absorbed after ocular application in adults³⁰³ and potentially can reach blood levels high enough to produce toxic effects known to follow the systemic administration of beta-adrenergic blocking agents.

Blood levels ranging from 3.5 ng/mL (5-year-old child) to 34 ng/mL (3-week-old infant) have been measured in a group of small children 2 to 6 hours after instillation of timolol eyedrops.¹⁹ This exceeds the equivalent beta-blocker levels achieved with oral or parenteral treatment of systemic pediatric cardiovascular disorders.³⁰⁴ In addition, the beta-blockers have a longer half-life in children—two to six times that in adults.³⁰⁵ The literature suggests that neonates and infants are most at risk for systemic bronchopulmonary toxic effects. Apnea has been possibly associated with timolol in infants in several reports.^19,306–308 Bronchospasm with precipitation of asthmatic attacks in predisposed children is well known.^307–309 Other adverse effects in childhood glaucoma patients include arrthymias and bradycardia, depression and other mood alterations, and light-headedness.^310–312 The clinician is urged to be aware of potential drug interactions of ophthalmic beta-adrenergic antangonists with systemic medications.³¹³

Local adverse side effects of the beta-blockers include stinging, burning, dryness, nasolacrimal duct obstruction, conjunctival hyperemia, superficial punctuate keratitis, corneal anesthesia (adults only), allergic blepharoconjunctivitis, and anterior uveitis (rare).^305,314

In general, timolol seems to be well tolerated in older children, but caution is advised particularly in infants. Other antiglaucoma drugs are recommended in infants and those children with a history of asthma, allergic rhinitis, lung disease (including cystic fibrosis), cardiac disease, and labile diabetes mellitus. A complete medical consultation including electrocardiography should precede initiation of treatment. In healthy children, the lowest concentration and dosage possible of timolol should be used. The gel-forming sustained-release form of the drug (Timoptic-XE) used once a day is preferred. Passo and associates have recommended that all pediatric patients be observed for 2 hours in the office after the initial drops are instilled before the eye drop is prescribed for home use.¹⁹ The anesthesiologist should be alerted if general anesthesia is required for a child taking timolol eye drops because the risk of cardiovascular failure and sustained hypotension is increased.

Beta-adrenergic blockers are generally safe during pregnancy and without neonatal side effects.^315,316 It has been recommended, however, that timolol be avoided during the first trimester and be discontinued a few days before delivery to reduce possible complications from beta-blockade in the neonate.¹⁸⁵ Since breast milk timolol levels (5.6 ng/ml) have been measured to be six times higher than plasma levels (0.93 ng/mL) in nursing mothers on timolol treatment, infants born to nursing mothers using timolol should be observed for signs of beta-blockade.³¹⁷

Levobunolol

Levobunolol (Betagan) is another non-cardioselective (beta 1 and beta 2) beta-adrenergic antagonist that has demonstrated fewer cardiovascular effects than timolol in adults.³¹⁸ Therefore, it may be a better choice than timolol for children. Levobunolol has been safely used in pediatric patients after pupilloplasty with neodymium:YAG laser.³¹⁹ Caution is advised, because the larger drop size (50 μL) of levobunolol compared with that of timolol (35 μL) means that more drug is delivered with each instillation.³²⁰ Once-daily use is suggested in children.

Metipranolol

No side effects have been reported for children, but the observed serious side effects in adults, including reported loss of pressure control (tachyphylaxis) make metipranolol (Optipranolol) an unsuitable choice for treating pediatric glaucomas.⁸ Like timolol, metipranolol has been used to treat progressive myopia in children with unproven and controversial results.^321,322

Carteolol

Carteolol (Ocupress) is a non-cardioselective (beta 1 and beta 2) beta-adrenergic antagonist with intrinsic sympathomimetic activity (ISA). Ocular instillation produces less discomfort than with the other beta-blockers.⁸ Side effects are similar to those of timolol, but fewer systemic adverse side effects have generally been encountered.³²³

Betoxolol

Betoxolol (Betoptic) is a cardioselective beta 1 adrenoreceptor antagonist with weak beta-2 blocking capability. Because of this, betoxolol has fewer bronchopulmonary and cardiac effects and might be a better alternative for treating pediatric glaucomas.³²⁴ However, there is no data to substantiate this. Significant stinging upon ocular instillation in 30% to 40% of patients has been observed.

As with all members of this class of drugs, contact dermatitis can occur with some cross-sensitivity and reactivity among the drugs.³²⁵

CARBONIC ANHYDRASE INHIBITORS

Dorzolamide (Trusopt) is useful in pediatric glaucoma, although its long-term safety is not established. One study of six children with glaucoma who were previously treated with oral acetazolamide were treated effectively with dorzolamide with no adverse reactions.³²⁶

Local side effects include stinging, burning, blurred vision, superficial punctuate keratopathy, headache, and bitter taste.³²⁷ Corneal edema has been reported in patients with borderline endothelial function.³²⁸ Systemic side effects are minimal compared with oral use of the carbonic anhydrase inhibitors.

Brinzolamide (Azopt) and the combination drug of dorzolamide and timolol (Cosopt) have similar adverse side effects as dorzolamide.³²⁹

ALPHA-2 SELECTIVE ANTAGONISTS

Apraclonidine

After a few doses of apraclonidine (1 % Iopidine solution) used to suppress acute intraocular pressure spikes after laser treatments, side effects including hypotension, bradycardia, arrhythmia, and somnolence have been observed and reported to the National Registry of Drug Induced Ocular Side Effects, but have not been proven.¹⁰ Chronic use of 0.5% Iopidine solution seems to have minimal effects on respiratory and cardiovascular systems, and these effects are rarely a cause for discontinuing the drug in adults.³⁰ With prolonged use of apraclonidine, there is a high incidence of allergic reactions of either a direct toxic or hypersensitivity nature (20%–50%).³³¹ The high incidence of local side effects and the frequently observed tachyphylaxis seen in one half of patients after 3 months use make this drug undesirable in the chronic treatment of pediatric glaucoma.

Brimonidine

After its introduction in 1996, brimonidine 0.2% solution (Alphagan) was found to be effective as monotherapy and as adjunctive treatment in adult open-angle glaucoma. Recently the preservative benzalkonium chloride was replaced by Purite (Alphagan P). This led to an increase in pH, which improved absorption, allowing use of a lower concentration of brimonidine (0.15% versus 0.2%) and improving its safety profile.^32,333

Brimonidine differs from clonidine by a chemical alteration that decreases its ability to cross the blood-brain barrier. In young children, however, the immaturity of this barrier may allow more access to the CNS. There have been numerous case reports of single pill ingestion of clonidine causing bradycardia, hypotension, apnea, and coma in young children.³³⁴ Reports of bradycardia, hypotension, hypothermia, lethargy, and apnea in infants after brimonidine eye drop instillation^335,336 and CNS depression in children³³⁷ make this drug unsuitable for treating pediatric glaucoma.

PROSTAGLANDIN ANALOGS

The prostaglandin analogs are the newest group of antiglaucoma medications, and use to-date has been thoroughly reviewed.^338,339 Latanoprost (Xalatan), unoprostone (Rescula), bimatoprost (Lumigan), and travopost (Travatan) show an excellent safety profile. Pressure-lowering efficacy in adult open-angle glaucoma has been superior to that of the beta-blockers. However, only 20% of pediatric patients show a significant reduction in intraocular pressure in studies on children.

Local side effects have been notable but have not led to cessation of treatment in most cases. Conjunctival hyperemia is usually tolerable, although a study of patients with Sturge-Weber syndrome and glaucoma found a 23% incidence of significant conjunctival hyperemia, causing one patient to stop therapy.³⁴⁰ A permanent darkening of iris color, especially in patients with nonhomogeneous eye color, has been observed in 5% to 20% of patients after several months of therapy. There is a report in the literature of this increase in iris pigment in a 1-year-old patient after 5 months of treatment³⁴¹ This color change does not seem to have any adverse ocular consequences. Other local side effects include a reversible increase in eyelid skin pigment,³⁴² hypertrichosis, superficial punctuate keratopathy, corneal erosions, pseudodendrites, initiation or reactivation of herpes simplex keratitis,³⁴³ and contact dermatitis.³⁴⁴ All of the manufacturer's product information for the prostaglandin analogs suggest that they be used with caution in patients with active uveitis, in aphakic patients, in pseudophakic patients with a torn posterior capsule, and in patients with known risk factors for macular edema. Cystoid macular edema has been reported during treatment in these susceptible patients.

Studies on latanoprost indicate some systemic absorption after topical instillation, but the drug does not cross the blood-brain barrier,³⁴⁵ and its metabolites are rapidly eliminated, with a systemic half-life of 17 minutes.³⁴⁶ This suggests a margin of safety in children. No serious systemic side effects were reported with latanoprost therapy of pediatric glaucoma in three studies.^340,347,348 There is one report in the literature of a child with aniridia and glaucoma who developed heavy sweat secretion 1 to 2 hours after instillation of latanoprost.³⁴⁹ Systemic side effects in adults have infrequently included fatigue, dizziness, asthma, angina, nausea and vomiting, nasal congestion, and headache.³³⁹

The major local side effect of topical ocular anesthesia is corneal epithelial toxicity, which is most pronounced with cocaine. Significant epithelial desquamation is unusual in children and more characteristic of elderly patients. Local allergic reactions are rare and are mainly observed with the ester group of anesthetics used for eye drops. Since there is no cross-sensitivity between classes of local anesthetics, another anesthetic can be substituted.³⁵⁴ Unfortunately, no topical anesthetic with an amide linkage ( i.e., benoxinate) is available in the United State except in combination with fluorescein sodium for applanation tonometry.

Systemic hypersensitivity reactions after ocular anesthetic use are extremely rare and no life-threatening episodes have been reported in the literature.⁸⁵ Clinicians should be alerted , however, to an increased susceptibility in infants and children with drug allergies or asthma.⁸⁵ Signs of a systemic reaction include angioneurotic edema, urticaria, bronchospasm, hypotension, and joint pain.⁸⁵

COCAINE

Cocaine has the greatest potential for systemic toxicity in children. The 4% solution is used rarely for topical anesthesia, but in most cases, other safer, synthetic local anesthetics are preferable. The 10% and higher solutions should be avoided completely. Systemic toxicity can develop from as little as 20 mg (10 drops of 4% solution).³⁵⁴ It is recommended that a dosage of 3mg/kg body weight not be exceeded. Potential systemic toxic side effects include hypertension, tachycardia, arrhythmia, headache, excitement, dilated pupils, nausea and vomiting, abdominal pain, delirium, and seizures.⁸⁵ Propranolol can reverse the cardiovascular toxicity.³⁵⁵

PROPARACAINE HYDROCHLORIDE

Proparacaine 0.5% solution is a widely used topical anesthetic agent with few side effects, possibly because of its poor penetration of the conjunctiva and cornea.³⁵⁶ However, there is one report of seizures following the use of proparacaine eye drops.³⁵² Proparacaine is popular for pediatric use because it has minimum sting after ocular administration. As a result, it can be used prior to the instillation of other more uncomfortable eye drops (eg., cycloplegics) to aid in an atraumatic examination.¹⁸¹

TETRACAINE

Tetracaine 0.5% solution is available in sterile minums for use in the operating room. It produces a degree of anesthesia similar to proparacaine and has a similar speed of onset and duration of effect.⁸⁵ It penetrates the conjunctiva and cornea better than proparacaine,³⁵⁶ and overdosage with toxicity can result if more than 1.5 mg/kg of body weight is administered.³⁵⁷ Because of stinging and burning upon ocular instillation, tetracaine is less desirable than proparacaine as a topical anesthetic for alert children. Local allergic reactions and corneal epithelial toxicity are similar to those for proparacaine.

Of the various preservatives, BAC has been implicated most often in local toxic and hypersensitivity reactions. Many eye drops contain BAC, and some of the toxic and allergic reactions attributable to the main therapeutic agent are probably secondary to the BAC preservative. Cytotoxicity has been demonstrated for BAC in cell culture as well as in animal and human studies. Chronic use of BAC-preserved eye drops can cause an unstable tear film and reduced tear secretion,^359–361 conjunctival metaplasia and inflammation,^359,360 corneal epithelial and endothelial toxicity,³⁶² inhibition of corneal healing,³⁶² trabecular inflammation,³⁶⁰ and allergic reactions.^362,363

The use of thimerasol as a preservative in medicated eye drops and contact lens solutions has been largely discontinued owing to the high rate of allergic hypersensitivity reactions. Blepharoconjunctivitis with corneal infiltrates occurred in up to 25% of contact lens wearers using a thimerasol-preserved contact lens storage and rinsing solution.

For pediatric use, preservative-free eye drops are preferred because they create less burning upon instillation, have reduced foreign body sensation and dry eye sensation, and produce less tearing than preserved eye drops.³⁶⁴ Unfortunately, except for non-preserved artificial tears, preservative-free eye drops are unavailable and impractical because of the need for antimicrobial protection in multi-dose topical solutions.

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