Paediatrics: Adverse drug reactions

Adverse drug reactions

One in 10 children in hospital and one in 100 attending outpatients will experience an adverse drug reaction (ADR). 71 in 8 will be severe. ADRs are responsible for almost 2% of children admitted to hospital. ADRs in children can be as varied as in adults. Children, because of growth and development, also suffer specific ADRs. Differences in drug metabolism make certain ADRs a greater problem in children, e.g. valproate hepato-toxicity, or less of a problem, e.g. paracetamol hepatotoxicity following an overdose. The mechanisms of ADRs specifically affecting children are illustrated with examples below.

Mechanisms of ADRs

Impaired drug metabolism

Chloramphenicol, when first used in neonates, led to the development of the grey baby syndrome (vomiting, cyanosis, cardiovascular collapse, and in some cases death). The newborn infant metabolizes chloramphenicol more slowly than adults and so only requires a lower dose of the antibi-otic. Reduction in the dosage prevents grey baby syndrome.

Children, particularly neonates, are more likely to have a reduced capac-ity to metabolize drugs than adults. Therefore, lower doses are usually required.

Altered drug metabolism

Children may have reduced activity of the major hepatic enzymes associ-ated with drug metabolism. To compensate for this, they may use other enzyme pathways. This is thought to be one of the factors contributing to the increased risk of hepatotoxicity in children under the age of 3 years who receive sodium valproate. This risk is raised by the concurrent use of other anticonvulsants which may cause enzyme induction of certain metabolic pathways.

Sodium valproate should not be used as a first-line anticonvulsant in children under the age of 3yrs.

Protein-displacing effect on bilirubin

The use of the sulphonamide sulphisoxazole in ill neonates in the 1950s was associated with the development of fatal kernicterus due to drug dis-placement of protein bound bilirubin into the blood because of its higher binding affinity to albumin. Ceftriaxone also is highly protein bound and will displace bilirubin in sick neonates.

The protein-displacing effect of medicines should be considered in sick preterm neonates.

Percutaneous absorption 

Percutaneous toxicity can be a significant prob-lem in the neonatal period due to their higher surface area to weight

ratio than that of both children and adults. An example of this is the use of antiseptic agents such as hexachlorophene that have been associated with neurotoxicity.

Drug interactions 

Ceftriaxone and calcium containing solutions when used together in neonates may result in the precipitation of ceftriaxone— calcium salt in the lungs. This drug interaction can result in fatalities and therefore ceftriaxone should be avoided in neonates.

Ceftriaxone should be avoided in neonates.

Unknown

There are several examples of major ADRs that occur in children for which we do not understand the mechanism. Salicylate given during the presence of a viral illness increases the risk of the development of Reye’s syndrome in children of all ages. Since the use of salicylates has been avoided in chil-dren the incidence of Reye’s syndrome has dramatically reduced. Propofol has minimal toxicity when used to induce general anaesthesia. Used as a sedative in critically ill children, however, it has been associated with the death of over 10 children in the UK alone. The propofol infusion syn-drome is thought to be related to the total dose of propofol infused, i.e. high dose or prolonged duration is more likely to cause problems.

Propofol should not be used as a sedative in critically ill children

Suspect ADRs 

One should always consider the possibility of an ADR being responsible for a child’s symptoms. Table 29.1 lists some of the seri-ous ADRs associated with widely used medicines.

Preventing ADRs 

Recognizing which patients are at greater risk of ADRs can help reduce the overall incidence. Health professionals should follow guidelines.

Reporting ADRs 

Suspected ADRs should be reported to the regula-tory authorities. In the UK the yellow card scheme is in operation.