Pediatric Pharmacotherapy Part 1: The History of Pediatric Drug Therapy: Learning from Errors, Not Trials

Marcel J. Casavant; Jill R. K. Griffith

Disclosures

AccessMedicine from McGraw-Hill 

In This Article

Pediatric Pharmacology Disasters

One of the earliest disasters in modern pediatric drug therapy has, unfortunately, been the most repeated. In 1937, 2 years after adults had begun benefiting from sulfa antibiotics, an elixir of sulphanilamide was developed to enable administration to children.[1] Diethylene glycol was chosen as the solvent, because it’s odorless, sweet, and syrupy. Unfortunately, diethylene glycol is also highly toxic; it causes vomiting, diarrhea, cramps, dehydration, metabolic acidosis, renal and hepatic failure, seizures, and death. The deaths of 107 Americans, many of them children, were sufficient impetus for passage, in 1938, of the federal Food, Drug, and Cosmetic Act, which we will explore in more depth later.

The elixir of sulphanilamide tragedy has been repeated several times, in various countries, as diethylene glycol was used as the solvent (or was present as a contaminant in glycerin) for pediatric acetaminophen preparations. Deaths of children in Nigeria (1990 and 2009), Bangladesh (1990 and 1992), and Haiti (1995-96) remind us that excipients are hardly inactive ingredients,[2] and that lessons we fail to learn will be repeated. Glycerin, an excipient in common use in products for adults and children, can be contaminated with diethylene glycol, which has resulted in several other tragedies, both for adults and children, in recent years.[3]

The next major disaster to teach us about drug use in children happened in 1956, when newborns receiving sulphisoxazole were found to be having more kernicterus (entry of bilirubin into the brain, causing yellow discoloration of brain tissue, seizures, and death).[4] Kernicterus is a condition only seen in young children that results from high concentrations of free bilirubin in the plasma. It occurs because infants have diminished glucuronosyl transferase activity, and therefore, less ability to glucuronidate bilirubin. Infants also have immature blood-brain barriers, which allow more of the free bilirubin to cross into and damage the brain. We now know that babies with hyperbilirubinemia can be treated with “bili lights;” bilirubin is light sensitive and enough light gets through a child’s skin to detoxify bilirubin in dermal capillaries, thus preventing kernicterus and the permanent damage it causes. Until 1956 we didn’t know sulphisoxazole given to neonates could make kernicterus worse; it displaces bilirubin from plasma proteins, thus increasing the free fraction of bilirubin in the plasma and enhancing the movement of bilirubin into the brain.

Immature glucuronosyl transferase activity is also one of the reasons the grey baby syndrome, first noted in 1959, happens after premature infants receive the antibiotic chloramphenicol; inadequate renal excretion of chloramphenicol and its metabolites is the other reason. When chloramphenicol is given without regard for infants’ diminished capacities for hepatic detoxification and renal elimination, hypothermia, vomiting, acidosis, cyanosis, and a characteristic grey discoloration occur. Fortunately, we now have safer antibiotics for most indications, but when chloramphenicol is needed, changes in the dosing regimen (lower doses given at longer intervals) and carefully monitoring drug levels can help prevent this complication.[5]

In 1982 a common excipient, benzyl alcohol, was blamed for the neonatal gasping syndrome and the deaths of 16 premature babies.[6] Present as a bacteriostatic preservative, it was given to children in a flush used to keep intravenous lines patent while the babies were in intensive care units. The neonatal gasping syndrome consists of acidosis, respiratory distress (“gasping”), circulatory failure, intracranial bleeding, seizures, and death. Besides reminding us that excipients are not inactive, the neonatal gasping syndrome exemplifies the problem of differential metabolism in babies. Although the rest of us oxidize, conjugate, and excrete benzyl alcohol as less toxic hippuric acid, neonates probably metabolize benzyl alcohol to benzoic acid, which accumulates and causes toxicity.

The aforementioned pharmacological disasters teach numerous lessons individually. Considered as a group, however, they make it clear that safe and rational prescribing of drugs to children requires controlled studies of drugs in children, a proposal that many considered anathema just one generation ago.

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