What is the documentation concerning the use of tropicamide as a mydriatic agent in infants (less t

Fråga: What is the documentation concerning the use of tropicamide as a mydriatic agent in infants (less than one year old)? Is it safer to use the combination of cyclopentolate (0.5 per cent)/metaoxedrine more commonly referred to as phenylephrine (0.5 per cent) than tropicamide?

Background: For ophthalmoscopic examination in neonates, it is unclear whether it is unsuitable to use tropicamide instead of ROP-drops (cyclopentolate (0.5 per cent)/metaoxedrine (0.5 per cent)). ROP-drops are currently the first choice for examination of retinopathy in the premature. However, for neonates delivered at term, there are other indications for ophthalmoscopy, such as congenital cataract, and where the use of tropicamide would be an alternative drug.

Sammanfattning: When used in concentrations of one per cent or less, both tropicamide, cyclopentolate, and phenylephrine appear to be safe drugs. However, at these concentrations the mydriatic potency appears to be lower for tropicamide than cyclopentolate. According to several reports, tropicamide in combination with either cyclopentolate or phenylephrine, induce mydriasis of sufficient size for ophthamological examination in healthy neonates, without signs of toxicity.

Svar: It is well known that drugs administered as eye drops may cause systemic effects. The systemic level of active drug is to some extent dependent on transconjunctival absorption but the main site of drug uptake is considered to be the nasolacrimal system into which excess liquid is drained off. The total volume of the tear film has been estimated to 7-10 uL in adults (1) which is comparable to the neonate (2). The standard volume of a drop is approximately 30-40 uL. It appears that reducing drop size (and thereby reducing nasolacrimal drainage of excess eye drop liquid) rather than reducing the concentration of drug solution, is of importance when trying to minimise systemic drug exposure (see below). Due to differences in body fluid volumes, systemic concentrations of absorbed drug will be higher in neonates than adults, a fact which is of general significance for the risk of adverse effects (2, 3).

Both sympathomimetic agents, such as phenylephrine, and parasympatholytic agents, eg cyclopentolate (CP) or tropicamide (TA), are used clinically to induce mydriasis. The two classes of drugs seem to differ somewhat in their adverse effects profile.

The major concern with phenylephrine is the stimulatory effect on heart rate and blood pressure. This is particularly critical in premature neonates who are at increased risk of developing cerebral hemorrhage (4, 5). The increase in blood pressure is rapid (10 to 60 min), clearly dose-dependent, and could in some cases be as much as 50 percent of base line pressure (4, 5). Literature data indicate that transient hypertension is almost always seen in neonates when phenylephrine concentrations of 2.5 per cent or higher are used, whereas 0.5-1 percent seems more safe (5, 6). Hypertension may also be avoided by reducing drop size to 6-8 uL, even when higher concentrations of phenylephrine (2.5-10 percent) are used (1, 7).

Parasympatholytic drugs, in the present context referred to as cycloplegics, have also been associated with increased blood pressure, especially when used in combination with phenylephrine (5, 6). However, an important difference to phenylephrine is that cycloplegics in addition have been associated with serious CNS-effects, eg hyperactivity, delirium, epilepsia (2, 3) which develop in a dose-dependent manner. In this respect (and in relation to the given question above) tropicamide has been described as a safer cycloplegic drug than cyclopentolate (3), which might induce hallucinations - a hallmark of cyclopentolate toxicity. However, cyclopentolate toxicity has been described as "minimal" when used at concentrations of less than one percent (3).

In line with this, there are very few reports on adverse reactions to cyclopentolate or tropicamide in the Swedish register of adverse drug reactions (8). In children less than 2 years of age, there are no reports at all on tropicamide, and only 2 reports on cyclopentolate, which describe skin reactions and a case of vomiting. In elderly patients however, except for a limited number of skin and eye-related reports, there is one report on possibly tropicamide-related convulsions and one report about confusion, but nothing similar on cyclopentolate (8).

Thus, the overall impression is that both cyclopentolate and tropicamide are relatively safe drugs, when used in concentrations of one per cent or less. Importantly however, we have not found any data on how repeated administrations of eye drops affect systemic drug concentrations or adverse effects. There is no data suggesting that tropicamide would be more toxic than cyclopentolate. However, they might differ in therapeutic efficacy, as described below.

In a study performed in 80 healthy neonates the mydriatic effects of phenylephrine, tropicamide, and cyclopentolate were compared. Tropicamide (one per cent) was found to give the weakest mydriatic response of the three (4). The combination of tropicamide (one per cent) with either cyclopentolate (one per cent) or phenylephrine (2.5 per cent) gave a more pronounced mydriasis, but all combinations with phenylephrine also increased blood pressure. In another study, when comparing 6 ul drops with 30 ul standard drops, it was evident that the smaller volume of tropicamide (0.5 per cent solution) was not enough to induce sufficient mydriasis, in contrast to the smaller volume of cyclopentolate (one per cent solution) (7). Except for an apparent difference in pharmacological potency, the information available in pharmaceutical textbooks (9) rather indicate extensive similarities between the two cycloplegic drugs; both having a more rapid onset compared to atropine, maximal cycloplegic effect within approximately 30 min, and recovery of accommodation within 6 to 24 h. 1 Lynch MG, Brown RH, Goode SM, Schoenwald RD, Chien D-S: Reduction of phenylephrine drop size in infants achieves equal dilation with decreased systemic absorption. Arch Ophtalmol 1987; 105: 1364-1365 2 Palmer EA: How safe are ocular drugs in pediatrics? Ophtalmology 1986; 93: 1038-40 3 Gray LG: Avoiding adverse effects of cycloplegics in infants and children. J Am Optom Assoc 1979; 50: 465-70 4 Ögut MS, Bozkurt N, Özek E, Birgen H, Kazokoglu H, Ögut M: Effects and side effects of mydriatic eyedrops in neonates. Eur J Ophtalmol 1996; 6: 192-6 5 Isenberg S, Everett S: Cardiovascular effects of mydriatics in low-birth-weight infants. J Pediatr 1984; 105: 111-2 6 Khoo B-K, Koh A, Cheong P, Ho N-K: Combination cyclopentolate and phenylephrine for mydriasis in premature infants with heavliy pigmented irides. J Pediatric Ophtamol Strabismus 2000; 37: 15-20 7 Elibol O, Alcelik T, Yuksel N, Caglar Y: The influence of drop size of cyclopentolate, phenylephrine and tropicamide on pupil dilatation and systemic side effects in infants. Acta Ophthalmol Scand 1997; 75: 178-80 8 Swedis (The Swedish Drug Information System) 9 Parfitt K, editor. Martindale, The complete drug reference. 32nd ed. London: Pharmaceutical Press; 1999