Laurence A Goldberg
Testing medicines in children raises serious scientific and ethical issues, according to Simon Keady (Lead Divisional Clinical Pharmacist, Women and Children’s Services, University College London Hospitals NHS Foundation Trust, UK). Although 20% of the population of the EU is under 18, few data are available on long-term safety or late effects in this patient group. Children are not small adults and the pharmacokinetics and pharmacodynamics of drugs vary considerably with age. It is not always possible to extrapolate data from adult studies and there is now a strong move towards testing medicines in children. This raises a number of practical issues. Many childhood diseases are rare and obtaining sufficient numbers of patients to conduct clinical trials can be difficult. Multicentre studies are the obvious answer. Children may have difficulty in tolerating excipients and care needs to be taken when developing child-friendly formulations. Benzyl alcohol can cause gasping syndrome and propylene glycol can cause circulatory collapse. Children are considered to be a vulnerable group and obtaining informed consent can be challenging, particularly if financial incentives are offered.
Routes of administration
In the neonate, elevated pH in the stomach increases the bioavailability of acid-labile drugs such as penicillin G while reducing the bioavailability of acid-stable drugs such as phenobarbital. Biliary function is reduced and gastric emptying/intestinal motility is delayed, leading to reduced absorption of lipophilic drugs and generally slower absorption from the GI tract. Mr Keady went on to discuss other routes of administration. The stratum corneum of the skin is much thinner in neonates and the surface area/body mass ratio is increased in infants and young children, leading to increased systemic absorption of topical drugs. Topical corticosteroids should be used in reduced concentrations, for example, starting with 0.25% hydrocortisone in preference to 1%.
The intramuscular route should not be used, as it is painful and erratic absorption occurs due to low muscle mass, reduced skeletal muscle blood flow and inefficient muscle contraction. Infants have a higher rate of rectal contractions and suppositories do not remain in the rectum for as long as expected, leading to reduced absorption by this route. The vital capacity of the lungs in infants and children is lower and the respiratory rate is higher than in adults, said Mr Keady. This leads to increased systemic exposure to inhaled corticosteroids, especially when administered via a nebuliser. Currently there are no spacer devices on the market suitable for children and it is necessary to fill adult devices with six to eight puffs in order to give an adequate dose to an infant.
Mr Keady went on to discuss a number of specific drugs that showed age-dependent differences in action. Children seem to be more sensitive to warfarin and the response is augmented. Ciclosporin shows greater immunosuppression dose for dose, while increased sedation is seen with midazolam. Sodium valproate produces increased hepatotoxicity in children whilst the intestinal motilin agonist activity of erythromycin is age-dependent.
Pharmacogenetic effects such as variations in acetylator status or G6PD deficiency will play a far more important role, in the future, in tailoring treatment for children. Slow acetylators may be susceptible to increased toxicity from drugs such as phenytoin, isoniazid, tetracyclines and sulphonamides and children with G6PD deficiency should avoid sulphones, quinolones and possibly certain antimalarials (quinine and chloroquine) and aspirin.
A medication error is any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the healthcare professional, patient or consumer, said Sharon Conroy (Lecturer in Paediatric Clinical Pharmacy, Derbyshire Children’s Hospital/University of Nottingham, UK).
There are several ways to measure medication errors but methodologies differ so much that it is very difficult to compare studies. Spontaneous reporting requires a staff member to fill in a report at the time of the incident. This leads to gross under-reporting. A chart review will identify prescribing errors but not administration errors. The most reliable studies are observational but these are very labour-intensive.
Limited evidence from the USA suggests medication errors are three times more common in children than in adults.(1) In a two-year prospective study on a paediatric cardiac ward and paediatric intensive care unit (PICU), 441 medication errors from 682 admissions (0.65/admission) were identified by way of an anonymous reporting scheme. Errors occurred seven times more often in the PICU and prescribing errors doubled when new doctors started.(2)
A number of factors put children at a greater risk of medication errors, Ms Conroy said. Drug doses are calculated for individual patients, there is inadequate information, there is incorrect use of formulae to calculate doses, there are often no suitable dosage forms or concentrations and there is a need for complex calculations and dilutions.
There are a number of ways to reduce the risk of medication errors in children (see Box 1).
Purchasing medicines with safety in mind has now become an important issue across Europe.
Drug names that “look alike” or “sound alike” should be avoided where possible. Clear labelling and good packaging along with concise package inserts are required. When considering formulations, one should remember that excipients may have undesirable effects in children. Phenobarbital elixir contains 38% alcohol, while the injection contains 90% propylene glycol, which is an irritant to veins and requires dilution before use.
Ms Conroy then discussed extemporaneous dispensing. This is risky as there are often no published standards available. There is a lack of stability of information and a shortage of formulation expertise with little opportunity for testing the final product.
“Specials” purchasing from reputable sources lowers the risks, as more data are available along with improved quality assurance. Certificates of analysis or conformity are provided. Alternatively, licensed imports may meet needs. For 75% of extemporaneously dispensed liquids and capsules there is a suitable licensed alternative available in another European country, North America or Australia, but not in the country in question.(3) However, systems need to be in place to deal with urgent recalls. In addition, guaranteed availability, information in the appropriate language(s) and the cost of such imports are factors for consideration.
Many children need to continue these medicines after discharge from hospital and systems must be in place to ensure continuity of supply.
Ms Conroy pointed out that medication errors happen and children are more vulnerable than other patients. “We must be aware of the potential for errors and establish systems to protect the patient. Observe! Get involved! Don’t wait to be asked!”
There is no universal definition of asthma, according to Phillip Dale (Child Health Pharmacist, Royal Cornwall Hospital, Truro, UK), but there are two accepted pathophysiological features: airway inflammation and increased airway reactivity. There is an increased risk of a child having asthma if either parent is asthmatic. The prevalence of asthma increased through the 1990s and currently, 15% of parents report wheezing in their children. Many reasons were given for this, including an increase in reporting, particularly of mild symptoms. There were 1.8 deaths per million population of children aged 0–4 years reported in 1999, a fall of 40% over the previous 20 years, while a figure of 2.4 deaths per million population of children aged 5–14 years was reported in the same year, a fall of 37% over the same period.
Sara Arenas-López (Specialist Paediatric Pharmacist, Evelina Children’s Hospital, London, UK) described the symptoms of asthma as wheeze, shortness of breath, chest tightness and cough. The hallmark of asthma is that these symptoms are variable, intermittent, worse at night and provoked by triggers such as exercise. Certain measures can be taken to cut the number of attacks in young children. There is a strong correlation between sensitisation to common airborne allergens (eg, house dust mite, dog and cat hair) and asthma; breastfeeding has a protective effect in early life and children should live in a smoke-free environment. Despite the lack of published double-blind, placebo-controlled immunotherapy trials, preliminary results from an ongoing study comparing untreated children with children undergoing pollen immunotherapy suggest a lower rate of asthma onset in the treated group.
Attention to “Airway, Breathing, Circulation” (ABC) is the first step in treating acute seizure. What follows depends on ease of venous access. Intravenous (IV) lorazepam at 100 mcg/kg is given over 30–60 seconds. This can be repeated after 10 minutes. If the child is still fitting after a further 10 minutes, IV phenytoin should be considered. Where venous access is difficult, rectal diazepam 500 mcg/kg is administered and if the child is still fitting after 10 minutes, rectal paraldehyde 0.4 ml/kg in an equal volume of olive oil can be given. Paraldehyde is mixed with olive oil, not arachis oil, in case the child has a nut allergy. Plastic syringes can be employed if the preparation is used immediately. The medicine is unlicensed, so must be obtained from a reputable source. An unlicensed form of buccal midazolam is available. As effective as rectal diazepam, it is administered into the corners of the mouth with an oral syringe.(4)
In a joint presentation, Simon Keady and Rowena McArtney (Paediatric Directorate Pharmacist, University Hospital of Wales, Cardiff, UK) offered reasons why formulation changes should not be made to the treatment of seizure-free children. There are variations in bioavailability, different pharmacokinetic profiles, and there is the potential for reduced effects and for excessive side-effects. Ideally, a single drug should be prescribed long-term wherever possible. If this is unsuccessful, monotherapy with another agent can be tried. If this is still unsuccessful, a second drug can be added.
The pharmacist has an important role to play in educating patients, their families and carers on helping to simplify treatment regimens and in helping to reduce the stigma attached to the condition.
Neonatal and Paediatric Pharmacy Group