The hazards of percutaneous absorption in children are well documented.1-2 Numerous reports describe devastating side effects in infants from systemic absorption of topically applied agents.3 Physicians have historically overlooked the potential for percutaneous poisoning in designing therapy for infants. For example, a 1926 review of diaper dermatitis recommended "a rapid and permanent cure for ammoniacal dermatitis" by rinsing diapers in either dilute mercuric chloride or saturated boric acid solution.4
LESSONS FROM HISTORY
In 1886, a London physician linked an epidemic of neonatal cyanosis to exposure to aniline. Prominent dye stamps from a freshly labeled diaper on the buttocks and perineum of one of the newborns were the clue to his discovery of aniline toxicity. Despite this, diapers labeled with aniline were used for decades, resulting in at least six infant deaths.3
Acrodynia, the systemic and cutaneous manifestations of chronic mercury exposure, was first reported as pink disease in Australia in 1890. In the 1930s and 1940s, the morality rate from acrodynia was as high as 10%, with more than 500 pediatric deaths from mercury poisoning.5 Several decades passed before the dangers of mercury exposure for infants became widely recognized, as diaper rinses containing mercuric chloride and teething powders, tinctures, and ointments containing mercury were commonly linked to cases of acrodynia. Public awareness of the dangers of mercury was rekindled in January 1996 when adolescents in Arkansas found several pounds of the slippery silver liquid in an abandoned factory. They distributed this to their fascinated friends, triggering an outbreak of mercury poisoning.
Historically, phenolic compounds have been infamous as a cause of neonatal toxicity. In the late 1960s, in a small birthing hospital for unwed mothers in St. Louis, Missouri, infant bed linens and diapers were laundered in pentachlorophenol. This caused at least 20 cases of percutaneous toxicity. Infants experienced profuse sweating, tachycardia, tachypnea, hepatomegaly, and metabolic acidosis, and 2 died.6 Hexachlorophene, a phenolic compound known for its antistaphylococcal properties, is marketed in a 3% concentration (pHisoHex, Sterling Winthrop Inc.). pHisoHex, an antiseptic cleanser, was popular for bathing infants until its neurotoxic properties were recognized in the early 1970s. Percutaneous absorption resulted in an acute encephalopathy, seizures, and death.7
Boric acid has been used as an antimicrobial agent for more than 200 years, despite its wellrecognized toxicities. A 1953 review included 109 cases of fatal boric acid poisoning in children. Of these, 28 occurred following topical application, most often from diaper powder.8 Boric acid toxicity has become recognized as a cause of infantile erythroderma, diarrhea, irritability, and failure to thrive. It is still included in some products for diaper rash.
The increased susceptibility of children to toxic effects of topically applied preparations has been well established. The major barrier against percutaneous absorption is the stratum corneum. By 34 weeks of gestation, the stratum corneum is fully mature. However, the poorly developed stratum corneum and thin epidermis of preterm infants place them at high risk for percutaneous toxicity.3-9 Diseased skin at any age exhibits a similar degree of impaired barrier function and increased permeability.
Despite the structural maturity of the epidermal barrier in full-term infants and children, some risk for percutaneous toxicity remains. Several unique pediatric pharmacokinetic features help to explain this. These include an increased ratio of skin surface area to body weight; immature hepatic and renal function, which impairs drug metabolism and excretion; and decreased plasma protein binding that allows toxicity at lower drug doses.210
Prilocaine-lidocaine cream is a widely used topical anesthetic. The most commonly reported toxic effect of cutaneously absorbed prilocaine is cyanosis secondary to methemoglobinemia.11 Infants with preexisting anemia or impaired renal function or those who are concomitantly treated with sulfonamide drugs are at increased risk. More recently, localized, idiosyncratic purpuric and petechial reactions have been reported.12 Corneal ulceration has also been observed (L. Eichenfield, MD, personal communication, June 20, 2000).
Iodinated compounds such as povidoneiodine are routinely used as topical antiseptics. The influence of these agents on neonatal thyroid function has been well documented. Studies indicate that preterm and low-birth-weight infants are at greatest risk for significant iodine absorption. Signs include elevated levels of iodine in the urine, transiently increased levels of thyrotropin in the blood, transiently decreased levels of thyroxine, and hypothyroidism.1314 Abnormal thyroid function is associated with serious adverse sequelae in infants, including intraventricular hemorrhage, cognitive abnormalities, growth and motor retardation, and death.1516 Iodinated compounds should be applied to infants only briefly, followed by thorough rinsing, and never under occlusion.
Alcohols are commonly applied prior to medical procedures as topical antiseptics. They are volatile and normally evaporate prior to absorption. However, a generous application followed by occlusion can lead to significant absorption, especially through immature or diseased skin. Toxicities reported following percutaneous alcohol absorption include hemorrhagic skin necrosis, dysfunction of the central nervous system, metabolic acidosis, and hypoglycemia.17 Despite their comfortable familiarity, alcohol solutions should be used sparingly for infants.
Silver sulfadiazine is the active component of a topical antimicrobial that is commonly applied to second-degree and third-degree burns. Percutaneous toxicities associated with the sulfa component include kernicterus and agranulocytosis. Argyria is a risk when there is excessive absorption of silver.18"20 Children with burns involving a large surface area and infants with moderate to severe injury are at highest risk. They should be monitored closely.
Diphenhydramine is an antihistamine in a variety of oral and topical medications. It is a well-known cause of allergic contact dermatitis. A more serious adverse effect is central anticholinergic syndrome. This had been reported in children treated with Caladryl (Warner Lambert Consumer, Morris Plains, NJ), a lotion that contained diphenhydramine before its reformulation.21-22 Presentations included dilated pupils, ataxia, urinary retention, confusion, and bizarre behavior. A 19-month-oId infant with varicella who was treated simultaneously with diphenhydramine syrup and Caladryl lotion had anticholinergic syndrome, and the serum level of diphenhydramine was 20 times that associated with toxicity.23 In all cases, the diagnosis was obscured by the underlying febrile viral illness and neurologic signs suggestive oí encephalitis. The active ingrethent of Caladryl has since been changed to pramoxine. However, all Benadryl (Warner Lambert Consumer) preparations still contain at least 1% diphenhydramine.
Cyproheptadine is another oral antihistamine that was recently reported to have caused central anticholinergic syndrome in a 9-year-old boy receiving therapeutic doses.24 Antihistamines should be used cautiously in infants and children. Parents should be provided with anticipatory guidance regarding the "idiosyncratic" agitation that occurs in some children. Anticholinergic toxicity should be considered when a child being treated with antihistamines has acute changes in mental status.
Calcipotriol is a synthetic vitamin D3 analogue approved for the topical treatment of psoriasis in adults. It is also used for children with psoriasis or disorders of cornification.25"27 There have been reports of hypercalcemia in adults following its percutaneous absorption, including a case of hypercalcémie crisis in a 17-year-old girl.28 The potential risk to children is greater but as yet unreported. Children treated with calcipotriol applied to a large area of the body surface should be monitored with baseline and follow-up serum calcium and urinary calciumcreatinine ratios. Renal ultrasound for nephrocalcinosis may be considered during long-term treatment.
The anti-inflammatory properties of corticosteroids have established these topically applied medications as one of the mainstays in dermatologie therapy. Adverse systemic reactions include adrenal suppression, growth impairment, osteoporosis, and glaucoma. Focal side effects from topical application include telangiectasia, hypopigmentation, skin atrophy, striae, hypopigmentation, and acneiform eruptions.29 Standardized measures of potency do not uniformly reflect the risk of adverse sequelae (or the clinical efficacy) of the large number of products in this category. Only a few topical corticosteroid products are approved by the Food and Drug Administration for infants and young children. Lotrisone (Schering Plough Corporation, Kenilworth, NJ) ranks among the top 10 most prescribed drugs for children, despite reports of cutaneous atrophy, striae, and even growth suppression.30 Therefore, corticosteroid products should be chosen and monitored on a case-by-case basis.
A key factor in determining drug potency is the vehicle. More effective vehicles, such as propylene glycol and hexylene glycol, also increase bioavailability. The most well-known modification to increase potency is fluorination of the basic steroid nucleus. However, it is important to realize that some fluorinated compounds have low to moderate potency and that other molecular alterations, such as esterification and acetylation, have yielded nonfluorinated alternatives that are more potent.31 For example, the nonhalogenated double-esterified corticosteroid derivatives prednicarbate and methylprednisolone aceponate are equipotent with betamethasone valerate. However, they reportedly yield less skin atrophy and minimal systemic bioavailability due to their rapid inactivation.31
The risk of corticosteroid side effects also increases with the duration of therapy. Therefore, the treatment of chronic conditions requires individualization of application regimens. Dosing schedules designed to minimize local and systemic toxicity include every-otherday therapy, weekend-only pulse therapy, and 3-weeks-on followed by a 2-week drug holiday.29'31-32
Itraconazole is an oral antifungal agent available in solution or capsules. Neither formulation has been approved for pediatric use. A few small studies have documented short-term safety and efficacy in children.33 However, the long-term effects of itraconazole in pediatric patients are unknown.34-35 Of particular concern is hydroxypropyl-cyclodextrin, the solubilizing excipient used in the oral solution of itraconazole. When administered to rats, hydroxypropyl-cyclodextrin produced pancreatic exocrine hyperplasia and neoplasia at exposure levels similar to adult doses based on comparisons of body surface area (1.0:1.7).35 Infants and children have an increased ratio of body surface area to weight, making the potential risk of the oral solution comparatively greater. The solution also contains sorbitol, which can cause significant osmotic diarrhea in children.
Itraconazole capsules do not contain either of these ingrethents. The contents of the capsules can be easily administered by sprinkling them on food until the long-term effects of the oral solution can be defined for children.
Tacrolimus (FK506; Prograf, Fujisawa Healthcare, Inc., Deerfield, IL) is a potent immunosuppressive agent approved for the prophylaxis of organ rejection in patients who have had a liver or kidney transplant. A topical formulation was recently approved by the Food and Drug Administration for the treatment of atopic dermatitis in children 2 years and younger. Preliminary reports of safety and efficacy in small numbers of children 3 to 16 years old yielded no serious systemic adverse events.36-37 In general, systemic absorption is minimal. However, in a clinical study involving a subset of severely affected children 3 to 6 years old with application of 0.1% tacrolimus ointment over a large area of the body surface (76% to 100%), 1 of 7 had a maximum peak whole blood concentration of tacrolimus of 9.58 ng/mL at 4 days.37 Peak levels decreased as the eczema improved, indicating that absorption decreases as the skin barrier returns to normal. The therapeutic trough range established for transplant prophylaxis is 5 to 20 ng/mL. Thirty percent of transplant patients with trough levels of 5 to 14 ng/mL experience adverse reactions requiring dose reduction,38,39 including hypertension, nephrotoxicity, hyperglycemia, and neurotoxicity.3839 Lymphoproliferative disease is a rare but ominous side effect. The safety and efficacy of this drug has not been studied in infants or children younger than 2 years. Caution must be taken in the use of this otherwise promising medication for infants and young children with extensive skin disease, including close monitoring of blood levels.
Interferon-a (IFN-α-2α and IFN-α-2b) is used as alternative treatment for life-threatening hemangiomas that are resistant to treatment with steroids and Kasabach-Merritt syndrome.40-41 A small number of infants treated with interferon-a have developed spastic diplegia.42 The mechanism of this neurotoxic effect is unknown. Interestingly, a recent report documented an association between spastic cerebral palsy, particularly spastic diplegia, and elevated levels of neonatal endogenous interferons. This raises the question of whether developing neural tissue could have an age-related susceptibility to increased amounts of interferons.43
Significant progress has been made in the field of skin development and pediatric skin care. One of the most important lessons is that cutaneous application includes the risk of systemic absorption, especially when there is an impaired skin barrier or an extensive area of application on an infant or child.
Increased survival of low-birth-weight infants has resulted in a large population of hospitalized premature infants with highly susceptible immature skin and unique skin care needs. An important consideration in treating these vulnerable patients is the development of standards for optimal skin care. Some aspects to be addressed are bathing practices, cord care techniques, the use of emollients and diapering products, and transcutaneous water loss.44 Further investigations into the mechanisms of skin maturation may help us develop an optimal artificial barrier or a therapeutic approach that would accelerate barrier development in these infants.
Percutaneous absorption has been advantageous as an alternative route for drug administration. Estrogen and nicotine patches are effective in adults. Methods of transdermal delivery of theophylline, diamorphine, and supplemental oxygen have been established for premature infants, and the armament of medications delivered cutaneously will no doubt continue to grow.45
Children's threshold for toxicity from absorbed and ingested drugs is enormously different from that of adults. A limited number of pharmaceutical studies designed specifically for infants and children are now under way. However, the number of studies and their extent still fall tremendously short of the need. In the absence of financial incentives to collect these data and the low likelihood of additional legislation, pediatricians must act on every level to protect the most vulnerable segment of our population.
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