Oxford Handbook of Paediatrics (2 edn)
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Prescribing for children
Licensing
Many medicines used in children are not licensed for such use. This does not mean that they should not be used, but that the pharmaceutical company has not sought a license from the regulatory authorities. Hence, many medicines in children are used off label, i.e. they are used at a different dose, route, age, or indication than specified within the product license. It is important that medicines are used in children in relation to the scientific evidence available. In certain circumstances this may involve off label use.
Disease states
Certain diseases, e.g. cystic fibrosis, or clinical conditions, e.g. shock, may affect drug metabolism. Both liver and renal failure delay drug elimination, and so require dosage reduction.
Breastfeeding
Most medicines taken by a breastfeeding mother are safe for her infant. Mothers should not be discouraged from breastfeeding because of uncertainty about possible toxic effects. The British National Formulary (BNF) for children gives detailed information regarding which medicines to avoid.1
Medication errors
Medication errors are a significant problem in children. In particular, tenfold errors have been associated with significant mortality and morbidity, especially in the very young. All health professionals will commit a medication error during their career! Medication errors include:
Incorrect dose: commonest error and also the type most likely to be associated with a fatality. Knowledge of the child’s actual weight and checking of dose calculation is vital, especially on the neonatal unit and with parenteral medicines.
Incorrect drug: second most common type of error and also associated with significant fatalities.
Incorrect route: this is a particular problem with IT drugs. This is a procedure for specialists and great care should be taken when drugs are to be given this way!
Other errors: include incorrect rate of administration, duplicate dosing, and administration of the drug to the wrong patient.
Reference
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 hepatotoxicity, 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 antibiotic. Reduction in the dosage prevents grey baby syndrome.
Children, particularly neonates, are more likely to have a reduced capacity to metabolize drugs than adults. Therefore, lower doses are usually required.
Altered drug metabolism
Children may have reduced activity of the major hepatic enzymes associated 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 displacement 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 problem 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 children 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 syndrome 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 serious ADRs associated with widely used medicines.
| Drug | ADR |
|---|---|
Corticosteroids | Adrenal insufficiency/sepsis |
Cytotoxics | Neutropenia |
Carbamazepine | Stevens–Johnson syndrome |
NSAIDs (including ibuprofen) | GI haemorrhage |
Opiates | Respiratory depression |
Sodium valproate | Hepatotoxicity |
| Drug | ADR |
|---|---|
Corticosteroids | Adrenal insufficiency/sepsis |
Cytotoxics | Neutropenia |
Carbamazepine | Stevens–Johnson syndrome |
NSAIDs (including ibuprofen) | GI haemorrhage |
Opiates | Respiratory depression |
Sodium valproate | Hepatotoxicity |
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 regulatory authorities. In the UK the yellow card scheme is in operation.
Pharmacokinetics
Pharmacokinetics defines the relationship between the dose of a drug and its concentration in different parts of the body (usually plasma) in relation to time. This relationship is measured and defined numerically. Knowledge of several key terms is needed to understand pharmacokinetic principles.
Absorption: if a drug is given IV, 100% of the dose enters the blood stream. If a drug is given orally, usually only a fraction is absorbed and the term bioavailability is used to describe the percentage of the drug administered that reaches the systemic circulation. Absorption is often reduced following oral administration in the neonatal period.
Volume of distribution (V): this is not a physiological volume but rather an apparent volume into which the drug would have to distribute to achieve the measured concentration. Water-soluble drugs, such as gentamicin, have a V that is similar to the extracellular fluid volume. Drugs that are highly bound to plasma proteins have a low V. Children differ from adults because of their body composition (neonates and young children have a higher proportion of body water) and lower plasma protein concentrations.
Clearance: describes the removal of a drug from the body and is defined as the volume (usually of plasma) that is completely cleared of drug in a given time. In adults, clearance is described in relation to volume/time (mL/min). In children, clearance is also described in relation to body weight (mL/min/kg). Clearance is usually reduced in the neonatal period but may actually be higher in infants and young children than in adults.
Elimination half-life: this is the time taken for the concentration of a drug (usually plasma) to fall to half the original value. It is inversely related to clearance. Therefore, 50% of the dose will be eliminated in 1 half-life; 97% of a drug will be eliminated after 5 half-lives. This is also the time required for steady state to be achieved following initial administration of the drug.
Mathematical formulae are available in standard texts that describe the interrelationship between clearance, volume of distribution, and elimination half-life.
Drug metabolism
The major pathways involved in drug metabolism are divided into phase I (oxidation, reduction, hydrolysis, and hydration) and phase II (glucuronidation, sulphation, methylation, and acetylation) reactions. As a general rule, the clearance of drugs in the neonatal period is reduced. For many drugs adult clearance values are reached by the age of 2yrs.
Phase I pathways
The major pathway is oxidation which involves the cytochrome P450 enzymes (CYP). The major CYP enzymes are CYP3A4 and CYP1A2.
CYP3A4: this is responsible for the metabolism of many drugs (e.g. midazolam, ciclosporin, fentanyl, nifedipine). CYP3A4 activity is reduced in the neonatal period and early infancy. Enzyme activity between individuals varies considerably leading to a large range of plasma concentrations after the same dose of an affected drug.
CYP1A2: accounts for 13% of total enzyme activity in the liver. Caffeine and theophylline are metabolized via the CYP1A2 pathway. Enzyme activity is reduced in the neonatal period, but increases rapidly such that by the age of 6 months activity approaches that of older children and adults.
Phase II pathways
Glucuronidation and sulphation are the two major pathways. Glucuronidation is reduced in the neonatal period and there is compensatory sulphation. The development of glucuronidation varies for different drugs. For example, children who are 2yrs old have rates of glucuronidation for morphine similar to those in adults, whilst for paracetamol adult rates of glucuronidation are not reached until puberty.
Pain management
Assessment
Always consider the possibility of a child being in pain, either as a result of their disease or the interventions that are required. Accurate assessment requires an age-appropriate validated pain assessment scale. Self-reporting is the ideal, but the child needs to be ≥3yrs old to be able to do this. Do not use pain scales validated for acute pain to assess chronic pain.
Self-report scales: usually involves the child pointing to a photograph of a child in pain (the Oucher) or a diagram of a child in pain (Bieri Faces Pain Scale or Wong–Baker Faces Pain Scale). The Oucher has been validated in children as young as 3yrs of age, whereas the Bieri Faces Pain Scale has only been validated in children aged ≥6yrs. The Wong–Baker Faces Pain Scale is more reliable in children aged 8–12yrs than in the 3–7-yr age group. The Adolescent Paediatric Pain Tool is for children between the ages of 8 and 17yrs.
Behavioural pain scales: rely on assessment of the child’s behaviour. Validated for children aged 1–5yrs. Examples include the Toddler—Preschooler Postoperative Pain Scale (TPPPS) and the CHEOPS. The FLACC has been validated for children aged 2 months–7 years.
Neonatal pain scales: examples include CRIES, NFCS, NIPS, and PIPP. These rely on behavioural observation and, in some, measurements of pulse, BP, and O2 saturation. It is important to use one that has been validated for the gestation of the infant, e.g. is it valid only in full-term neonates?
Management
It is best to consider pain as being mild, moderate, or severe.
Mild pain: paracetamol is the safest analgesic available and is the first-line drug to be used for mild pain in all ages.
Moderate pain: children who are unresponsive (or unlikely to respond) to paracetamol should receive either a NSAID, such as ibuprofen or diclofenac. Alternatively, codeine or dihydrocodeine can be administered orally.
Severe pain: morphine is the drug of choice. It can be given IV (including patient-controlled analgesia (PCA)), intranasally, or orally.
Procedural pain: for certain painful procedures, e.g. dressing change in burns patients, it may be better to use inhaled entonox. This is an effective and safe analgesic with a short duration of action, which the child can control themselves.
Sedation
There are two main areas where sedation is required—during procedures and whilst receiving paediatric intensive care.
Procedural sedation
There are many sedative agents available. All sedative agents decrease conscious level and, thereby, can have significant toxicity. The choice of sedative agent depends upon local experience and how quickly and for how long sedation is needed. If a child is likely to be difficult to sedate, then consider whether a short-acting general anaesthetic, administered by a paediatric anaesthetist, is safer and kinder to the child.
Prolonged sedation (critical care)
The purpose of sedation in the paediatric intensive care unit (PICU) is to help the child not the health professional. IV midazolam is the drug of choice on admission. Subsequently, once NG feeds are tolerated, chloral hydrate and promethazine have been shown to be more effective than midazolam. Propofol is contraindicated for use in the PICU, with the exception for procedures, in view of the risk of a fatal ADR.
Fever
Fever is a sign of an underlying illness. It is more important to treat the underlying illness than the fever itself. Fever is reduced to make the child more comfortable. The two most used antipyretics (paracetamol and ibuprofen) are also analgesics (see 
p.701).
Management
Paracetamol is the drug of choice. It is less likely to be associated with a significant ADR than ibuprofen. Ibuprofen is appropriate to use as an antipyretic agent if paracetamol has failed. Although the safest of all NSAIDs, it should not be used in children with gastroenteritis or other GI symptoms.
