Ranking	Diagnosis
1	Respiratory tract infections
2	Chronic diseases of tonsils and adenoids
3	Asthma
4	Abdominal and pelvic pain
5	Viral infection (unspecified site)
6	Non-suppurative otitis media
7	Inguinal hernia
8	Unspecified head injury
9	Gastroenteritis/colitis
10	Undescended testicle

Congenital anomalies

Congenital anomalies remain an important cause of infant and child mortality in England and Wales, and account for an increasing proportion of infant deaths. The National Congenital Anomaly System (NCAS), established in 1964 in the wake of the thalidomide tragedy, has monitored congenital anomalies nationally in England and Wales. Registers such as NCAS are important in planning service delivery and alerting specialists to conditions where research is required. However, it relies on voluntary notifications and collaborates with local registers to improve the quality and quantity of data (see Useful Paediatric Websites at end of chapter).

Data for 2008 are available but there is ongoing discussion about the future direction of the recording service, given the wide variability in reporting between areas with and without regional congenital anomaly registers. In 2007, a new classification of congenital anomalies was introduced to include tighter rules for deciding which congenital anomalies should be included in the Office for National Statistics report making year on year comparisons more difficult.

In 2008, there were 175 central nervous system (CNS) anomalies, for example, hydrocephalus, 282 cleft lip/palate, 932 heart and circulatory, 258 hypospadias and 225 Down’s syndrome reported to NCAS.

Neural tube defects (spina bifida) are one example of devastating congenital malformations that have been influenced by public health intervention programmes. The results of a long-term study (MRC Vitamin Study Research Group, 1991) showed that folate supplementation prevented 72% of neural tube defects when given to women at high risk of having a child with a neural tube defect. Hence, folate supplementation is now part of the routine advice given in antenatal clinics.

Cancer

Cancer is very rare in childhood; around 1700 new cases are diagnosed in children less than 15 years old in the UK each year. About one-third of all childhood cancers are leukaemias and of these, about 80% are of the acute lymphoblastic type (ALL). Although rare, childhood cancer is the most common cause of death from illness in children aged between 1 and 15 years of age.

As a consequence of the technical advances in treatment and the centralisation of services in specialist centres, a much greater number of childhood cancer sufferers are surviving to adulthood.

Asthma, eczema and hay fever

Asthma, eczema and hay fever (allergic rhinitis) are among the most common chronic diseases of childhood and most of the affected children are managed in primary care. During the 1970s and 1980s there was considerable expansion of epidemiological research into these disorders, prompted mainly by concern about the increase in hospital admissions for childhood asthma despite the availability of effective anti-asthma medication. These studies failed to identify any demographic, perinatal or environmental factor which could explain more than a small proportion of the large changes in prevalence of asthma, hay fever or eczema. Incidence rates of acute asthma in children under 5 years old were reported to be 1.5 per 1000 per week in 1991; the rates for children aged 5–14 years old were 0.9 per 1000 per week. Between 1993 and 2000 the incidence rates for both groups declined, but asthma continues to be an important childhood illness placing a burden on the health service.

Infections

Despite a dramatic decline in the incidence of childhood infectious diseases during the twentieth century, they remain an important cause of ill health in childhood. Major advances in the prevention of infections have been achieved through the national childhood vaccination programme.

The importance of maintaining high vaccine uptake has been demonstrated by the resurgence of vaccine-preventable diseases where children have not been vaccinated. Adverse publicity surrounding the MMR (measles, mumps and rubella) vaccine, involving a possible association with Crohn’s disease and autism, resulted in a loss of public confidence in the vaccine and a decrease in MMR coverage. This occurred in spite of rigorous scientific investigation and evidence refuting the claims. The annual coverage for MMR for 2-year olds declined from 92% in 1992 to 87% in 2000 and data for 2004 show that it dropped to 81.5%. Although this decline is far less than that seen for pertussis in the 1970s, if MMR coverage remains at this level or declines further, resurgences of MMR in primary schoolchildren will become more common. NHS information centre data revealed 85% of children in England had received the MMR vaccine in 2007/8. However, to achieve herd immunity, 95% of children need to be immunised; unless this figure is improved a measles epidemic still remains a possibility.

An important gastro-intestinal infection that appears to be increasing is infection with verotoxin-producing Escherichia coli (VTEC). This is important because it is the main cause of haemolytic uraemic syndrome, a severe condition which can lead to acute renal failure in children. VTEC is an example of an emerging infection. Before the 1980s it was unknown and during the 1990s reports of infection with VTEC in children in the UK tripled from 172 in 1991 to 531 in 1999. In 2009 the rates of VTEC 0157 decreased as age increased, with significantly higher rates in the 0–4 year age group (8 per 100,000) than in 5–9 year olds (4 per 100,000) and a further decrease (2 per 100,000) in the 10–19 year age group. It is a public health priority to improve VTEC 0157 surveillance and improve diagnostic testing.

Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract infection in infants and young children in the UK, in whom it causes bronchiolitis, tracheobronchitis and pneumonia. It is responsible for seasonal outbreaks of respiratory tract infection most commonly between October and April. The main burden of disease is borne by children under 2 years and there are around 7000–10000 confirmed laboratory reports of RSV in children in England and Wales each year. During the winter months, RSV is the single greatest cause of admission to hospital in children.

Mental health disorders

Mental health disorders are another emerging concern in the child health arena. In 2004, 1 in 10 children and young people aged 5–16 years old had a clinically diagnosed mental health disorder. These included 4% with an emotional disorder such as depression or anxiety, 6% with a conduct disorder, 2% with a hyperkinetic disorder and 1% with less common disorders, for example, autism, tics.

Groups at particular high risk of psychiatric disorder include children in the care system, young people who are homeless and young offenders. Longitudinal evidence has confirmed that many child psychiatric disorders persist well into adult life. Biological, psychological and social factors all seem likely to contribute to the risk of psychiatric disorders, and may act in combination.

Drugs, smoking and alcohol

The harm that drugs, smoking and drinking can do to the health of children and young people is recognised and a number of targets have been set in an attempt to reduce prevalence. Recent figures on smoking, alcohol and drug use among young people have been provided by the NHS Information Centre in their 2008 report.

In 2008, 6% of schoolchildren smoked regularly (at least once a week). Girls are more likely to smoke than boys and the prevalence increases with age. Around 14% of 15-year olds smoke regularly compared to 0.5% of 11-year olds. However, the prevalence of smoking amongst children has halved since its peak in the mid-1990s (13% in 1996), suggesting a decline in prevalence to below government targets. In 2007, the minimum age for buying tobacco was increased from 16 years old to 18 years old.

More than half of pupils (52%) aged 11–15 years have drunk alcohol in their lifetime. In 2008, a national survey identified that the mean amount of alcohol consumed by pupils who had drunk in the last week was 14.6 units. Boys drink more than girls and older pupils drink more than younger pupils. In one large survey, 17% of pupils aged 11–15 years old admitted to being drunk in the last 4 weeks.

The prevalence of drug use has declined since 2001. In 2008, 22% of pupils said that they had ever used drugs with 33% reporting that they had ever been offered drugs. Pupils were most likely to have taken cannabis (9%). Five percent of pupils had sniffed glue or other volatile substances in the last year and 2.9% had sniffed poppers. Overall, 3.6% of pupils had taken class A drugs in the last year.

Nutrition and exercise

Health during childhood can impact upon well-being in later life. Good nutrition and physical exercise are vital both for growth and development and for preventing health complications in later life. In addition, dietary patterns in childhood and adolescence have an influence on dietary preferences and eating patterns in adulthood.

In 2000, an international definition of overweight and obesity in childhood and adolescence was proposed to help calculate internationally comparable prevalence rates of overweight and obesity in children and adolescents. The definition interprets overweight and obesity in terms of reference points for body mass index (BMI, in kg/m²) by age and sex, and is linked to the widely used adult overweight cut-off point of 25 and adult obesity cut-off point of 30.

In 2004, it was estimated that 14% of boys and 17% of girls aged 2–15 years of age were obese. Probable reasons for a rise in overweight and obesity in children are changes in diets and an inactive lifestyle. There is evidence that obesity at an early age tends to continue to adulthood.

Being overweight is linked to the development of type 2 diabetes, high blood pressure, heart disease, stroke, certain cancers and other types of illnesses. Therefore, healthy eating is not only important in relation to weight but also contributes to reducing the risk of heart disease, stroke and some cancers in later life. It is recommended that a well-balanced diet providing all the nutrients required should include at least five portions of fruit and vegetables a day. It is now practice in many areas for infant children (aged 4–7 years) each day to be provided with a piece of free fruit during school break time.

The normal child

Growth and development are important indicators of a child’s general well-being and paediatric practitioners should be aware of the normal development milestones in childhood. In the UK, development surveillance and screening of babies and children is well established through child health clinics.

Weight is one of the most widely used and obvious indicators of growth, and progress is assessed by recording weights on a percentile chart (Fig. 10.1). A weight curve for a child which deviates from the usual pattern requires further investigation. Separate recording charts are used for boys and girls and since percentile charts are usually based on observations of the white British population, adjustments may be necessary for some ethnic groups. The World Health Organization (WHO) has challenged the widely used growth charts, based on growth rates of infants fed on formula milk. In 2006, it published new growth standards based on a study of more than 8000 breast-fed babies from six countries around the world. The optimum size is now that of a breast-fed baby. Recently, new growth charts have been introduced for children from birth to 4 years of age. These combine the UK and WHO data. Copies can be accessed at http://www.rcpch.ac.uk/Research/UK-WHO-Growth-Charts.

Fig. 10.1 Example of a centile chart (Child Growth Foundation).

Height (or length in children less than 2 years of age) is another important tool in developmental assessment. In a similar way to weight, height or length should follow a percentile line. If this is not the case or if growth stops completely, then further investigation is required. The normal rate of growth is taken to be 5 cm or more per year and any alteration in this growth velocity should be investigated.

For infants up to 2 years of age, head circumference is also a useful parameter to monitor. In addition to the above, assessments of hearing, vision, motor development and speech are undertaken at the child health clinics. A summary of age-related development is shown in Fig. 10.2.

Fig. 10.2 A summary of the various stages of development.

Child health clinics play a vital role in the national childhood immunisation programme, which commences at 2 months of age. Immunisation is a major success story for preventive medicine, preventing diseases that have the potential to cause serious damage to a child’s health, or even death. An example of the impact that immunisation can have on the profile of infectious diseases is demonstrated by the meningitis C immunisation campaign, which began in November 1999. The UK was the first country to introduce the meningitis C conjugate (MenC) vaccine and uptake levels have been close to 90%. The programme was targeted at under-20 year olds and has been a huge success, with a 90% reduction in cases in that age group. Authorities were hoping to mirror the success of the meningitis C campaign with the introduction of the seven valent pneumococcal vaccine into the routine UK childhood immunisation schedule in April 2006. Post-licensing surveillance has shown a large reduction in both invasive and non-invasive disease incidence due to vaccine serotypes in vaccinated individuals. However, during the same period, the UK has seen an increase in invasive disease due to the non-vaccine serotypes, caused for a large part by the six serotypes not covered by the seven valent vaccine, but present in a new 13 valent vaccine. In April 2010, the 13 valent pneumoccocal vaccine replaced the seven valent vaccine in the standard immunisation schedule. Human papilloma virus vaccine has also recently been introduced to the immunisation programme in the UK for females aged 12–13 years of age, to reduce the risk of cervical cancer.

Advice on the current immunisation schedule can be found in the current edition of the British National Formulary for Children.

Drug disposition

Pharmacokinetic factors

An understanding of the variability in drug disposition is essential if children are to receive rational and appropriate drug therapy (Anderson and Holford, 2008, 2009). For convenience, the factors that affect drug disposition will be dealt with separately. However, when treating a patient all the factors have a dynamic relationship and none should be considered in isolation.

Absorption

As a percentage of total body weight, the total body water and extracellular fluid volume decrease with age (Table 10.2). Thus, for water-soluble drugs such as aminoglycosides, larger doses on a milligram per kilogram of body weight basis are required in the neonate than in the older child to achieve similar plasma concentrations.

Table 10.2 Extracellular fluid volume and total body water as a percentage of body weight at different life stages

Age	Total body water (%)	Extracellular fluid (%)
Preterm neonate	85	50
Term neonate	75	45
3 months	75	30
1 year	60	25
Adult	60	20

Protein binding

Despite normal blood pH, free fatty acid and bilirubin levels in infants, binding to plasma proteins is reduced as a result of low concentrations of both globulins and albumin. It has been suggested that binding values comparable with those seen in adults are reached within the third year of life for acidic drugs, whereas for basic drugs adult values are not reached until between 7 and 12 years of life. The clinical significance of this reduction in infants and older children is minimal. The influence of disease states, such as renal impairment, on plasma protein binding is more important.

Drug metabolism

At birth the majority of the enzyme systems responsible for drug metabolism are either absent or present in considerably reduced amounts compared with adult values, and evidence indicates that the various systems do not mature at the same time. This reduced capacity for metabolic degradation at birth is followed by a dramatic increase in the metabolic rate in the older infant and young child. In the 1–9 year age group in particular, metabolic clearance of drugs is shown to be greater than in adults, as exemplified by theophylline, phenytoin and carbamazepine. Thus, to achieve plasma concentrations similar to those observed in adults, children in this age group may require a higher dosage than adults on a milligram per kilogram basis (Table 10.3).

Table 10.3 Theophylline dosage in children older than 1 year

Age	Dosage (mg/kg/day)
1–9 years	24
9–12 years	20
12–16 years	18
Adult	13

Metabolic pathways that play only a minor role in adults may play a more significant role in children and compensate for any deficiencies in the normal adult metabolic pathway. For example, glucuronidation accounts for up to 70% of the metabolic pathway of paracetamol in adulthood; however, in the early newborn period glucuronidation is deficient, accounting for less than 20% of paracetamol metabolism. This is compensated for by a more pronounced sulphate conjugation and this leads to an apparently normal half-life in newborns. Paracetamol appears to be less toxic in children than in adults and this may be in part explained by the compensatory routes of metabolism.

Renal excretion

The anatomical and functional immaturity of the kidneys at birth limits renal excretory capacity. Below 3–6 months of age the glomerular filtration rate is lower than that of adults, but may be partially compensated for by a relatively greater reduction in tubular reabsorption. Tubular function matures later than the filtration process. Generally, the complete maturation of glomerular and tubular function is reached only towards 6–8 months of age. After 8 months the renal excretion of drugs is comparable with that observed in older children and adults. Changes in renal clearance of gentamicin provide a good example of the maturation of renal function (Table 10.4).

Table 10.4 Renal clearance of gentamicin

	Plasma half-life
Small premature infants weighing less than 1.5 kg	11.5 h
Small premature infants weighing 1.5–2 kg	8 h
Term infants and large premature infants less than 1 week of age	5.5 h
Infants 1 week to 6 months	3–3.5 h
Infants more than 6 months to adulthood	2–3 h

Other factors

In addition to age-related changes in drug disposition, nutritional status and disease states can influence drug handling. High plasma clearance of antibiotics such as penicillins and aminoglycosides has been demonstrated in children with cystic fibrosis; increased elimination of furosemide has been reported in children with nephrotic syndrome, while prolonged elimination of furosemide has been reported in infants with congestive cardiac failure. Altered protein binding has been demonstrated in hepatic disease, nephrotic syndrome, malnutrition and cardiac failure.

Drug therapy in children

Dosage

Doses of medicines in children should be obtained from a paediatric dosage handbook and should not be extrapolated from the adult dose. There are a number of such texts available internationally. The information within them may be based on evidence from clinical studies in children or reflect the clinical experience of the contributors. In the UK, the BNF-C (see Further reading section) is a national formulary which includes prescribing guidelines and drug monographs. It contains information on licensed, unlicensed and off-label use of medicines. When consulting any dosage reference resource, care should be taken to identify the dosage convention being used. Most formularies use a single dose convention and indicate the number of times the dose should be repeated in a 24-h period. Other formularies indicate the total daily dose and the number of doses this is divided into. Some formularies combine both conventions. Confusing the total daily dose with the single dose to be repeated may have catastrophic consequences and the single dose convention has become the preferred convention.

While age, weight and height are the easiest parameters to measure, the changing requirement for drug dosage during childhood corresponds most closely with changes in body surface area (BSA). Nomograms which allow the surface area to be easily derived are available. There are practical problems in using the surface area method for prescribing; accurate height and weight may be difficult to obtain in a sick child, and manufacturers rarely provide dosage information on a surface area basis. The surface area formula for children has been used to produce the percentage method, giving the percentage of adult dose required at various ages and weights, although use should be reserved for exceptional circumstances (Table 10.5).

Table 10.5 Percentage of adult dose required at various ages and body weights

In selecting a method of dosage calculation, the therapeutic index of the drug should be considered. For agents with a narrow therapeutic index, such as cytotoxic agents, where recommendations are quoted per square metre, dosing must be based on the calculated surface area. However, there may be exceptions, for example, in children less than 1 year of age who have a proportionally larger surface area than other age groups. In children less than 1 year, dosages of chemotherapeutic agents are often based on weight rather than surface area to prevent overestimation of the dose in this age group.

For drugs with a wide therapeutic index, such as penicillin, single doses may be quoted for a wide age range. Between these two extremes, doses are quoted in milligrams per kilogram and this is the most widely used method of calculation. Whichever method is used, the resulting dosage should be rounded sensibly to facilitate dose measurement and administration and subsequently modified according to response or adverse effects.

It is important to note that none of the available methods of dosage calculation account for the change in dosage interval that may be required because of age-related changes in drug clearance. Where possible, the use of therapeutic drug monitoring to confirm the appropriateness of a dose is recommended.

Choice of preparation

The choice of preparation and its formulation will be influenced by the intended route of administration, the age of the child, availability of preparations, other concomitant therapy and, possibly, underlying disease states. The problems of administering medicines to children were reviewed by the European Medicines Evaluation Agency (EMEA, 2005).

Buccal route

Drugs may be absorbed rapidly from the buccal cavity (the cheek pouch) or they may dissolve when administered and be swallowed and absorbed from the stomach. ‘Melt^®’ technology, for example, desmopressin, piroxicam, ondansetron, in which the drug and flavourings are freeze-dried into a rapidly dissolving pellet, can be very useful. The ‘melt’ dissolves instantly into a very small volume which is difficult for the child to reject. Gels, sprays and liquids can also be administered into the buccal cavity, using drugs such as midazolam to treat seizures.

Oral route

The oral route is usually the most convenient but in an uncooperative child it can be the least reliable. Safe and effective drug therapy requires accurate administration, yet the 5-mL spoon is a difficult means of administering liquid medicines. Use of an oral syringe can provide controlled administration, ensure accurate measurement of the calculated dose and avoids the need for dilution of preparations with syrup. Use of oral syringes (which will not fit an intravenous Luer connector) are mandatory in UK practice. Concentrated formulations may be administered as oral drops in a very small volume. Although convenient, there could be significant dosage errors if drops are not delivered accurately.

In general, liquid preparations are more suitable for children under 7 years of age; there is a wide variability in the age at which children can swallow tablets and capsules but some quite young children can cope with solid dose formulations, especially mini-tablets. Some commercially available products contain excipients such as alcohol, propylene glycol and dyes that may cause adverse effects or be inappropriate for use in children with particular disease states. The osmolality and tonicity of preparations may be important; necrotizing enterocolitis (a disorder seen in the neonatal period) has been associated with many different factors including high-osmolality infant feeding formulae and pharmaceutical preparations, although a causal relationship has not been established. Oral liquids with high-osmolality or extremes of pH may irritate the stomach and should be diluted for administration. Sugar-free preparations may be necessary in the diabetic child or be desirable in other children for the prevention of dental caries. It is, however, important to be aware of the potential problems associated with substitutes for sucrose. The artificial sweetening agent aspartame, used in some preparations, should be used with caution in children with phenylketonuria because of its phenylalanine content. Other substitutes such as sorbitol and glycerol may not contribute to dental caries but produce diarrhoea if large doses are given. In these instances, a specially formulated preparation containing a higher amount of the active drug in small volume may be preferable.

Injection solutions can sometimes be administered orally, although their concentration and pH must be considered together with the presence of unsuitable excipients. Powders or small capsules may be prepared and used as an alternative. However, lactose is a common diluent in powders and caution must be exercised in children with lactose intolerance as a result of an inborn error of metabolism, or temporarily following gastro-intestinal diseases or gut surgery.

Parents are often discouraged from adding the dose of medicine to an infant’s feed. Quite apart from potential interactions which may arise with milk feeds, if the entire feed is not taken a proportion of the dose will be lost. It is also important to advise parents when it is not appropriate to crush solid dosage forms (e.g. sustained-release preparations). However, it should be recognised that addition of a medicine to a food or liquid may be the only way of rendering an unpalatable medicine acceptable. Whenever possible, evidence that this is pharmaceutically acceptable should be sought.

Manufacturers are increasingly recognising the difficulties associated with administration of medicines to children and are responding with novel formulations.

Mini tablets of just a few millimetres diameter may be useful to ease administration and allow flexibility of dosage. They may be presented in capsules or counted from bulk and can be individually coated for positioned or sustained release. Increased surface area may present larger quantities of excipients to the child and requires careful control.

If an age-appropriate formulation is not available, for example, for a medicine used off-label, a liquid oral preparation may be prepared extemporaneously, often by crushing the ‘adult’ tablets and suspending the powder in commercial or locally produced suspending agents. Alternatively the ‘adult’ dosage form may be manipulated, for example, by splitting tablets. Due consideration must be given to safety, accuracy and stability, when modifying dosage forms.

Nasogastric and gastrostomy administration

Medicines may be administered into the stomach via a nasogastric tube in the unconscious child or when swallowing is difficult. A gastrostomy tube may be placed into the stomach transcutaneously if the problem is long term, for example, in some children with cerebral palsy. Enteral nutrition may also be administered through such tubes. Drugs such as phenytoin may adsorb to the plastic of the tubes and interact with enteral feeds, requiring special administration techniques to ensure bioavailability. Suitability of drugs for nasogastric or gastrostomy tube administration should always be checked.

Intranasal route

Several drugs, such as desmopressin, diamorphine, fentanyl and midazolam, have been shown to be absorbed from the nasal mucosa. This route may avoid the need for injections but administration may be difficult in the uncooperative child and drugs administered may irritate the mucosa or be painful.

Rectal route

Although the rectal route can be useful, it is limited by the range of products available and the dosage inflexibility associated with rectal preparations. Some oral liquid preparations such as chloral hydrate and carbamazepine can be administered rectally. The route is useful in the unconscious child in the operating theatre or intensive care unit and it is not uncommon to administer perioperative analgesics such as diclofenac and paracetamol and the antiemetic ondansetron using suppository formulations. Parents and teachers may express concerns about using this route, fearing accusations of child abuse, but it is an important route of administration for diazepam or paraldehyde in the fitting child. Increasingly, buccal administration of midazolam may be preferred.

When oral and rectal routes are inappropriate, the parenteral route may be necessary.

Parenteral route

The problems associated with the administration of intramuscular injections in infants and children have been described earlier in this chapter. The route has a limited role in paediatric drug therapy and should not be used routinely. The intravenous route of administration is more widely used, but it is still associated with a number of potential problems that are outlined below.

Intravenous access

The practical difficulties of accessing small veins in the paediatric patient do not require explanation. However, these difficulties can often explain the sites of access that are chosen. Scalp veins, commonly used in newborn infants, are often very prominent in this age group, allowing easy access. It is also more difficult for the infant to dislodge a cannula from this site than from a site on the arm or foot. Likewise the umbilical artery offers a useful route for monitoring the patient but can also be used for drug administration in some circumstances. Vasoconstrictive drugs, such as adrenaline (epinephrine), dopamine and isoprenaline, should not be given by this route.

Fluid overload

In infants and children, the direct administration of intravenous fluids from the main infusion container is associated with the risk of inadvertent fluid overload. This problem can be avoided by the use of a paediatric administration set and/or a volumetric infusion device to control the flow rate. A paediatric administration set incorporates a graduated volumetric chamber with a maximum capacity of 150 mL. Although this system is intended primarily as a safety device, the volume within the burette chamber can be readily adjusted, allowing its use for intermittent drug administration and avoiding the need for the ‘piggyback system’ commonly used in adult intravenous administration.

Dilution of parenteral preparations for infusion may also cause inadvertent fluid overload in children. In fluid-restricted or very young infants, it is possible that the volume of diluted drug can exceed the daily fluid requirement. In order to appreciate this problem, the paediatric practitioner should become familiar with the fluid volumes that children can tolerate. As a guide these volumes can be calculated using the following formula: 100 mL/kg for the first 10 kg, plus 50 mL/kg for the next 10 kg, plus 20 mL/kg thereafter. Worked examples are given in Table 10.6. It is important to remember that these volumes do not account for losses such as those caused by dehydration, diarrhoea or artificial ventilation. While the use of more concentrated infusion solutions may overcome the problem of fluid overload, stability data on concentrated solutions are often lacking. It may, therefore, be necessary to manipulate other therapy to accommodate the treatment or even to consider alternative treatment options. Fluid overload may also result from excessive volumes of flushing solutions and is described later. Guidance on selecting appropriate intravenous fluids for administration to children to avoid fluid induced hyponatraemia are available (National Patient Safety Agency, 2007).

Table 10.6 Calculation of standard daily fluid requirements in paediatric patients

15 kg patient	35 kg patient
100 mL/kg × 10 kg = 1000 mL	100 mL/kg × 10 kg = 1000 mL
Plus 50 mL/kg × 5 kg = 250 mL	Plus 50 mL/kg × 10 kg = 500 mL
Total = 1250 mL/day	Plus 20 mL/kg × 15 kg = 300 mL
	Total = 1800 mL/day

Lack of suitable paediatric formulations

A large number of parenteral products are only available in adult dose sizes. The concentrations of these products can make it difficult to measure the small doses required in paediatrics. Dilution to achieve measurable concentrations, miscalculations and misinterpretation of decimal points may lead to errors. ‘Ten times’ errors are common particularly when drawing the dose from a single ampoule or vial that contains sufficient for an adult patient.

Displacement volume

Reconstitution of powder injections in accordance with manufacturers’ directions usually makes no allowance for the displacement volume of the powder itself. Hence, the final volume may be greater than expected and the concentration will, therefore, be less than expected. This can result in the paediatric patient receiving an underdose, which becomes even more significant in younger patients receiving smaller doses or more concentrated preparations. Paediatric units usually make available modified reconstitution directions which take account of displacement volumes.

Rates of infusion

The slow infusion rates often necessary in paediatrics may influence drug therapy. The greater the distance between the administration port and the distal end of the delivery system, and the slower the flow rate, the longer the time required for the drug to be delivered to the patient. In very young infants and children, it may take several hours for the drug to reach the patient, depending on the point of injection. This is an important consideration if dosage adjustments are being made in response to plasma level monitoring. Bolus injections should always be given as close to the patient as possible.

Dead space

Following administration via an injection port, a residual amount of drug solution can remain trapped at the port. If dose volumes are small the trapped fluid may represent a considerable proportion of the intended dose. Similarly, the volume of solution required to prime the intravenous lines or the in-line filters (i.e. the dead space) can be a significant proportion of the intended dose. This problem can be minimised by ensuring that drugs are flushed at an appropriate rate into the main infusion line after administration via an injection port or through a filter, and by priming the lines initially with a compatible solution. The small volumes required to prime filters and tubing specifically designed for infants and children can be used to minimise the dead space. Modern filter materials can produce less adsorption of drugs so that more of the drug is delivered to the patient.

It is important to remember that flushing volumes can add a significant amount to the daily fluid and sodium intake, and it may be important to record the volume of flushing solutions used in patients susceptible to fluid overload.

Excipients

Analogous to oral preparations, excipients may be present in parenteral formulations and can be associated with adverse effects. Benzyl alcohol, polysorbates and propylene glycol are commonly used agents which may induce a range of adverse effects in children including metabolic acidosis, altered plasma osmolality, central nervous system depression, respiratory depression, cardiac arrhythmias and seizures. Knowledge of the products that contain these ingredients may influence drug selection.

Many hospitals have established centralised intravenous additive services (CIVAS) that prepare single intravenous doses under aseptic conditions, thus avoiding the need for preparation at ward level. Such services have not only significantly decreased the risks associated with intravenous therapy, particularly in the paediatric population, but can also produce considerable cost savings.

Pulmonary route

The use of aerosol inhalers for the prevention and treatment of asthma presents particular problems for children because of the coordination required. The availability of breath-activated devices and spacer devices and large-volume holding chambers has greatly improved the situation. Guidance has been published on the use of inhaler devices in children less than 5 years of age (National Institute for Health and Clinical Excellence, 2000) and older children (National Institute for Health and Clinical Excellence, 2002) and updated in 2008 (British Thoracic Society and Scottish Intercollegiate Guidelines Network, 2008). Recent experience has shown that different types of large-volume holding chambers alter drug delivery and absorption and should not be considered as interchangeable.

It must be remembered that drugs can be absorbed into the systemic circulation after pulmonary administration or may be absorbed by the enteral route when excess drug is swallowed. High-dose corticosteroid inhalation may suppress the adrenal cortical axis and growth by this mechanism.

Dose regimen selection

A summary of the factors to be considered when selecting a drug dosage regimen or route of administration for a paediatric patient is shown in Table 10.7.

Table 10.7 Factors to be considered when selecting a drug dosage regimen or route of administration for a paediatric patient

Factor	Comment
1. Age/weight/surface area	Is the weight appropriate for the stated age? If it is not, confirm the difference. Can the discrepancy be explained by the patient’s underlying disease, for example, patients with neurological disorders such as cerebral palsy may be significantly underweight for their age? Is there a need to calculate dosage based on surface area, for example, cytotoxic therapy? Remember heights and weights may change significantly in children in a very short space of time. It is essential to recheck the surface area at each treatment cycle using recent heights and weights
2. Assess the appropriate dose	The age/weight of the child may have a significant influence on the pharmacokinetic profile of the drug and the manner in which it is handled. In addition, the underlying disease state may influence the dosage or dosage interval
3. Assess the most appropriate interval	In addition to the influence of disease states and organ maturity on dosage interval, the significance of the child’s waking day is often overlooked. A child’s waking day is generally much shorter than that of an adult and may be as little as 12 h. Instructions given to parents particularly should take account of this, for example, the instruction ‘three times a day’ will bear no resemblance to ‘every 8 hours’ in a child’s normal waking day. If a preparation must be administered at regular intervals, then the need to wake the child should be discussed with the parents or preferably an alternative formulation, such as a sustained-release preparation, should be considered
4. Assess the route of administration in the light of the disease state and the preparations and formulations available	Some preparations may require manipulation to ensure their suitability for administration by a specific route. Even preparations which appear to be available in a particular form may contain undesirable excipients that require alternatives to be found, for example, patients with the inherited metabolic disorder phenylketonuria should avoid oral preparations containing the artificial sweetener aspartame because of its phenylalanine content
5. Consider the expected response and monitoring parameters	Is the normal pharmacokinetic profile altered in children? Are there any age-specific or long-term adverse effects, such as on growth, that should be monitored?
6. Interactions	Drug interactions remain as important in reviewing paediatric prescriptions as they are in adult practice. However, drug–food interactions may be more significant; particularly drug–milk interactions in babies having 5–6 milk feeds per day
7. Legal considerations	Is the drug licensed? If an unlicensed drug is to be used, the pharmacist should have sufficient information to support its use

Counselling, adherence and concordance

Parents or carers are often responsible for the administration of medicines to their children and, therefore, the concordance and adherence of both parties must be considered. Literature about non-adherence and concordance in children is limited, but the problem is considered to be widespread and similar to that reported in adults.

Non-adherence may be caused by several factors such as patient resistance to taking the medicine, complicated dosage regimens, misunderstanding of instructions and apparent ineffectiveness or side effects of treatment. In older children and adolescents who may be responsible for their own medication, different factors may be responsible for non-adherence; for example, they may be unwilling to use their medication because of peer pressure.

Several general principles should be considered in an attempt to improve adherence. Adherence is usually better when fewer medicines are prescribed. Attention should be given to the formulation, taste, appearance and ease of administration of treatment. The regimen should be simple and tailored to the child’s waking day. If possible the child should be involved in choosing a suitable preparation when choice is available.

Many health professionals often counsel the parents/carer only, rather than involving the child in the counselling process. Where possible, treatment goals should be set in collaboration with the child. Studies have shown that parents consider the 8–10 year age group the most appropriate at which to start including the child in the counselling process. As well as verbal instruction, parents often want written information. However, current patient information leaflets (PILs) must reflect the Summary of Product Characteristics (SmPC) and so are often inappropriate. If a drug is used in an ‘off-label’ manner, statements such as ‘not recommended for use in children’ may cause confusion and distress. Care needs to be taken, therefore, to ensure that the information provided, whether written or spoken, is appropriate for both the parent and the child.

Information provided with medicines is often complex and may not always be relevant to children. The Royal College of Paediatrics and Child Health in conjunction with other bodies have launched a range of information leaflets on medicines for parents and carers. The leaflets cover off-label use of specific drugs and aim to provide appropriate and accurate and easily understandable information on dosage and side effects to those administering medicines to children. The leaflets can be downloaded from the website: www.medicinesforchildren.org.uk

Medicines in schools

Children who are acutely ill will be treated with medicines at home or in hospital, although during their recovery phase it may be possible to return to school. Children with chronic illness such as asthma or epilepsy, and children recovering from acute illnesses, may require medicines to be administered whilst at school. In addition, there are some medical emergencies which may occur at school or on school trips that require prompt drug administration before the arrival of the emergency services. These emergencies include anaphylaxis (associated with food allergy or insect stings), severe asthma attacks and seizures.

Policies and guidance

There is considerable controversy over the administration of medicines in schools. There is no legal or contractual duty on school staff to administer medicine or supervise a pupil taking it. This is a voluntary role. Some support staff may have specific duties to provide medical assistance as part of their contract. Policies and procedures are required to ensure that prescribed medicines are labelled, stored and administered safely and appropriately, and that teachers and care assistants are adequately trained and understand their responsibilities.

Advice has been provided for schools and their employers on how to manage medicines in schools (Department for Education and Skills, 2005). The roles and responsibilities of employers, parents and carers, governing bodies, head teachers, teachers and other staff and of local health services are all explained. The advice considers staffing issues such as employment of staff, insurance and training. Other issues covered include drawing up a health care plan for a pupil, confidentiality, record keeping, the storage, access and disposal of medicines, home-to-school transport, and on-site and off-site activities. It also provides general information on four common conditions that may require management at school: asthma, diabetes, epilepsy and anaphylaxis.

Responsibility for common medicines

Responsible pupils should be allowed to administer their own medication. Asthmatics should carry their ‘reliever’ inhaler (e.g. salbutamol or terbutaline), a spare should be available in school, and easy access before and during sports assured. There should be no need to have ‘preventer’ inhalers at school since two or three times daily administration schedules are appropriate and can avoid school hours. Medicines with a two or three times daily administration schedule should be supplied wherever possible so that dosing during school hours is avoided. Sustained-release preparations or drugs with intrinsically long half-lives may be more expensive but avoid the difficulties of administration at school. Sustained-release methylphenidate and atomoxetine, both used in the management of attention deficit hyperactivity disorder or ADHD, are examples. When administration at school is unavoidable, the school time doses can be provided in a separate, labelled container.

Special schools

Some children with severe, chronic illness will go to special rather than mainstream schools where their condition can receive attention from teachers and carers who have undergone appropriate training. Some special schools will be residential. Pupils may also attend another institution for respite care. Particular attention to communication of changes to drug treatment between parents, primary care doctors, hospital doctors and school staff is required if medication errors are to be avoided.

Monitoring parameters

Paediatric vital signs (Table 10.8) and haematological and biochemical parameters (Table 10.9) change throughout childhood and differ from those in adults. The figures presented in the tables are given as examples and may vary from hospital to hospital.

Table 10.8 Paediatric vital signs

Table 10.9 Biochemical and haematology reference ranges

Assessment of renal function

There are a number of methods of measuring renal function in children. These include the use of ⁵¹Cr-EDTA, ^99mTc-DTPA and using serum and urine creatinine concentrations over a timed period. However, despite some limitations, serum creatinine and estimated creatinine clearance are the most frequently used and most practical methods for day-to-day assessment of renal function.

In adults, several formulae and nomograms are available for calculating and estimating renal function. However, these cannot be extrapolated to the paediatric population; the Cockcroft and Gault equation and the estimated GFR (eGFR) equation are validated only for patients aged 18 years and over.

A number of validated models are available for use in children. These equations use combinations of serum creatinine, height, weight, BSA, age and sex to provide a simple estimate of creatinine clearance. A number of these equations have been further modified to better predict creatinine clearance; however, the advantage of simplicity is thereby lost. Several examples with their validated age ranges are shown below:

• Traub and Johnson (age 1–18 years)

• Counahan-Barratt (age 2 months to 14 years)

• Schwartz

where k varies dependent on the age of the patient:

low birth weight infants = 30

normal infants 0–18 months = 40

girls 2–16 years = 49

boys 2–13 years = 49

boys 13–16 years = 60

Whichever equation is chosen, it should be borne in mind that there are limitations to their use; for example, they should not be used in rapidly changing renal function, anorexic or obese patients, and they should not be taken as an accurate measure but as a guide to glomerular filtration rate.

Adverse drug reactions

The incidence of ADRs in children outside the neonatal period is thought to be less than at all other ages; however, the nature and severity of the ADRs that children experience may differ from those experienced by adults.

Studies have shown an incidence of ADRs in paediatric patients of between 0.2% and 22% of patients. The wide range reflects the limited number of formal prospective and retrospective studies examining the incidence and characteristics of ADRs in the paediatric age group and the variations in study setting, patient group and definition of ADR used. Data can also be skewed by vaccination campaigns since adverse effects are common and reporting encouraged. One consistent finding is that the greater the number of medications the child is exposed to, the greater the risk of ADRs.

ADRs in infants and older children typically occur at lower doses than in adults, and symptoms may be atypical. Examples include:

• enamel hypoplasia and permanent discolouration of the teeth with tetracyclines

• growth suppression with long-term corticosteroids in prepubertal children

• paradoxical hyperactivity in children treated with phenobarbital

• hepatotoxicity associated with the use of sodium valproate. There are three major risk factors:

– age under 3 years

– child receiving other anticonvulsants

– developmental delay

• increased risk of Reye’s syndrome with the use of salicylates in children with mild viral infection. Reye’s syndrome is a life-threatening illness associated with drowsiness, coma, hypoglycaemia, seizures and liver failure. The mechanism of this toxicity remains unknown but aspirin should generally be avoided in children under 16 years of age.

Many ADRs occur less frequently in the paediatric population, for example, gastro-intestinal bleeds with NSAIDs, hepatotoxicity with flucloxacillin and severe skin reactions with trimethoprim/sulfamethoxazole.

The reporting of ADRs is particularly important because the current system of drug development and authorisation not only deprives children of useful drugs because of the lack of clinical trials in children but may also exclude them from epidemiological studies of ADRs to prescribed drugs. The Commission on Human Medicines strongly encourages the reporting of all suspected ADRs in children, including those relating to unlicensed or off-label use of medicines, even if the intensive monitoring symbol (an inverted black triangle) has been removed. This reporting scheme has been extended in recent years to allow pharmacists, nurses and patients/carers to report suspected ADRs.

Medication errors

In contrast to ADRs, medication errors occur as a result of human mistakes or system flaws. Medication errors are now recognised as an important cause of adverse drug events in paediatric practice and should always be considered as a possible causative factor in any unexplained situation. They can produce a variety of problems ranging from minor discomfort to death. In the USA, it is estimated that 100–150 deaths occur annually in children in hospitals due to medication errors. The actual reported incidence of errors varies considerably between studies, ranging from 0.15% to 17% of admissions. However, different reporting systems and criteria for errors make direct comparisons between studies difficult.

The incidence of medication errors and the risk of serious errors occurring in children are significantly greater than in adults. The causes are many and include:

• Heterogeneous nature of the paediatric population and the corresponding lack of standard dosage.

• Calculation errors by the prescriber, pharmacist, nurse or caregiver.

• Lack of available dosage forms and concentrations appropriate for administration to children, necessitating additional calculations and manipulations of commercially available products or preparation of extemporaneous formulations from raw materials.

• Lack of familiarity with paediatric dosing guidelines.

• Confusion between adult and paediatric preparations.

• Limited published information.

• Need for precise dose measurement and appropriate drug delivery systems; absence leads to administration errors and use of inappropriate measuring devices.

• Ten-fold dosing errors are particularly important and potentially catastrophic; but reports still appear regularly in the published literature.

The reporting and prevention of medication errors is important. The causes of medication errors are usually multifactorial and it is essential that when investigating medication errors, particular focus should be placed on system changes.

Licensing medicines for children

Medicines licensing process

All medicines marketed in the UK must have been granted a product licence (PL) under the terms of the Medicines Act 1968, or a marketing authorisation (MA) following more recent European legislation on the authorisation of medicines. The aim of licensing is to ensure that medicines have been assessed for safety, quality and efficacy. In the UK, evidence submitted by a pharmaceutical company is assessed by the Medicines and Healthcare products Regulatory Agency (MHRA) with independent advice from the Commission on Human Medicines (CHM) and its paediatric medicines expert group.

The licensed indications for a drug are published in the SmPC. Many medicines granted a product license or MA for adult use have not been scrutinised by the licensing authorities for use in children. This is reflected by contraindications or cautionary wording in the SmPC. There has been a lack of commercial incentive to develop medicines for the relatively small paediatric market and perceived difficulties in carrying out clinical trials in this group. It is not illegal to use medicines for indications or ages not specified in the data sheet but to ensure safe and effective treatment, health professionals should have adequate supporting information about the intended use before proceeding. Failure to ensure that the use of a medicine is reasonable could result in a suit for negligence if the patient comes to harm.

Unlicensed and ‘off-label’ medicines

It has been reported that up to 35% of drugs used in a children’s hospital and 10% of drugs used in general practice may be used outside the terms of the approved, licensed indications (McIntyre et al., 2000, Turner et al., 1998). The term ‘off-label’ is often used to describe this. Because many of these medicines will have been produced in ‘adult’ dose forms, such as tablets, it is often necessary to prepare extemporaneously a suitable liquid preparation for the child. This may be made from the licensed dose form, for example, by crushing tablets and adding suitable excipients, or from chemical ingredients. An appropriate formula with a validated expiry period and ingredients to approved standards should be used. Care must be taken to ensure accurate preparation, particularly when using formulae or ingredients which are unfamiliar.

On some occasions the drug to be used has no product license or MA, perhaps because it is only just undergoing clinical trials in adults, has been imported from another country, has been prepared under a ‘specials’ manufacturing licence or is being used for a rare condition for which it has not previously been employed. As with ‘off-label’ use, there must always be information to support the quality, efficacy and safety of the medicine as well as information on the intended use. There is always a risk in using such a medicine, which must be balanced against the seriousness of the child’s illness and discussed with the parents if practicable.

Many authorities require that the patient should always be informed if the medicine prescribed is unlicensed or ‘off-label’ and even that written informed consent be obtained before treatment begins. In many situations, in paediatrics, this would be impractical but if parents are not informed the PIL included with many medicines may cause confusion since it may state that it is ‘not for use in children’. Patient or parent information specific to the situation should be prepared and provided.

Recent legislation on medicines for children

The worldwide legislation on medicines for children is changing. This is in recognition of the limited research and small number of licensed medicines brought about by a lack of incentive for commercial development. Both Europe and the USA have orphan drugs regulations designed to offer incentives for the development of medicines for rare diseases. Although not exclusively for paediatric conditions, the regulations have assisted the development of important drugs such as antiretrovirals (HIV/AIDS), alendronate (osteogenesis imperfecta), α-galactosidase (Fabry’s disease), sodium phenylbutyrate (hyperammonaemia) and ibuprofen injection (closure of patent ductus arteriosus).

The USA has had regulations designed to promote the development of paediatric preparations for more than 10 years (Best Pharmaceuticals for Children Act 2002 and Pediatric Research Equity Act 2003). However, these regulations have resulted in few significant developments in medicines for children in other countries. In the European Union, the ‘European Parliament and Council Regulation (EC) on medicinal products for paediatric use’ became law in January 2007. Thereafter, pharmaceutical companies wishing to market medicines for adults must agree to a Paediatric Investigation Plan with the EMEA. In return for such development, the company will receive an additional 6 months market exclusivity for its product. There are also expected to be incentives for developing paediatric formulations and indications for off-patent medicines.

Several European governments have funded paediatric clinical trials networks to stimulate research and help undertake studies resulting from the paediatric medicines regulations. In the UK, the Medicines for Children Research Network (MCRN) is part of the UK National Institute for Health Research and has six local research networks in England with equivalent provision in the other UK countries. Research and development of paediatric formulations is part of the MCRN programme.

The WHO has a ‘Make medicines child size’ programme to stimulate the development of age-appropriate formulations of medicines for children, particularly for those which appear in the List of Essential Medicines for Children. In June 2010, the first ever WHO model formulary for children was released to provide information on how to use over 240 essential medicines for treating illness and disease in children from 0 to 12 years of age. A number of individual countries have developed their own formularies over the years, but until now there was no single comprehensive guide for all countries (available at: http://www.who.int/childmedicines/en/).

Service frameworks

National service frameworks (NSFs) are long-term strategies for improving specific areas of care. Two paediatric service frameworks have been published; one for paediatric intensive care (Department of Health, 2002) and another for children, young people and maternity services (Department of Health, 2004) and continue to influence practice.

The service framework for paediatric intensive care defines the nature of paediatric intensive care, the elements of a high-quality paediatric intensive care service and a policy framework for the future organisation of services. Standards for district general hospitals, lead centres, major acute general hospitals and specialist hospitals are set out and cover medical and nurse staffing, facilities, and clinical effectiveness and management. Other aspects considered include retrieval services, education and training needs, and the implications for audit and research.

The framework for children, young people and maternity services sets standards for children’s health and social services, and the interface of those services with education. It establishes clear standards for promoting the health and well-being of children and young people and for providing high-quality services which meet their needs.

The recommendations that relate to the use of medicines for children and young people include:

• All children and young people should receive medicines that are safe and effective, in formulations that can be easily administered and are appropriate to their age, having minimum impact on their education and lifestyle.

• Medicines should be prescribed, dispensed and administered by professionals who are well trained, informed and competent to work with children to improve health outcomes and minimise harm and any side effects of medicines.

• Children and young people and their parents or carers should be well informed and supported to make choices about their medicines and competent in the administration of medicines.

Markers of good practice are defined as:

• The use of medicines in children is based on the best available evidence of clinical use and cost-effectiveness and safety, ideally derived from clinical trials but also including, where appropriate, medicines that are not licensed for their age group or for their particular health problem (‘off-label’) or those that do not have a licence at all (‘unlicensed’) in order to achieve the best possible health outcomes and minimise harm and side effects.

• In all settings and whatever the circumstances, children and young people have equitable access to clinically safe and cost-effective medicines in age-appropriate formulations.

• Appropriate information and decision support are available for professionals who prescribe, dispense and administer medicines for children and young people.

• Children, young people and their parents/carers receive consistent, up-to-date, comprehensive, timely information on the safe and effective use of medicines.

• In all settings, professionals enable parents, young people and, where appropriate, children to be active partners in the decisions about the medicines prescribed for them.

• Primary and secondary care providers should ensure that the use of medicines in children is incorporated in their clinical governance and audit arrangements.

• The contribution of pharmacists to the effective and safe use of medicines in children is maximised.

Case studies

Case 10.1

Name: PT
Age: 7 years old
Sex: Male
Weight: 16 kg
Presenting condition:	Presented in the emergency department with a 2-day history of worsening groin and hip pain. Could not bear weight. Patient was febrile with a temperature of 39.2°C, vomiting and dehydrated. There was no history of injury.
Previous medical history:	Nil of note
Allergies:	No known drug allergies
Drug history:	Nil of note
Differential diagnosis:	Septic arthritis, osteomyelitis
Tests:	Urea and electrolytes
	Full blood count
	CRP, ESR
	Blood culture and sensitivities
	X-ray (hips and abdomen)
	Bone scan
Results:	Bone scan revealed right pubic osteomyelitis
	CRP = 56 mg/L (normal range 0–10 mg/L)
	ESR = 34 mm/h (normal range 1–10 mm/h)
	Blood culture revealed Staphylococcus aureus sensitive to flucloxacillin
Prescribed:	Flucloxacillin i.v. 800 mg four times a day for 2 weeks. To be followed by oral flucloxacillin 800 mg four times a day for 4 weeks
Progress:	Temperature settled and ESR/CRP decreased following initiation of antibiotic therapy

On the third day of treatment the patient developed a raised red rash which was suspected of being an allergic reaction to flucloxacillin. Treatment was changed to i.v. clindamycin 160 mg three times a day (10 mg/kg/dose) for 2 weeks followed by oral clindamycin 160 mg three times a day for a further 4 weeks.

Question

Comment on the drug therapy and any monitoring required.

Answer

There are a number of points to consider in this patient.

• Body weight appears low for age; therefore, need to check if the weight is correct (expected weight for a 7-year old to be approx. 23 kg). If incorrect, doses of medication will need to be recalculated.

• There is a need to consider compliance with oral flucloxacillin therapy due to poor palatability of the suspension formulation (if the child would not take capsules) and the frequent dosing regimen.

• Whilst the risk of flucloxacillin-induced hepatotoxicity is low in children, there is a need to consider measuring baseline and repeat liver function tests because of the prolonged course (more than 2 weeks) of flucloxacillin therapy.

• Clindamycin has good oral bioavailability, so i.v. therapy may be unnecessary.

• Consideration should be given to how to administer clindamycin. Clindamycin palmitate suspension, which was palatable, is no longer available as a licensed preparation in the UK. Whilst extemporaneous formulations are available that use clindamycin hydrochloride capsules, the palatability of the resultant suspension is a major concern, particularly given the prolonged course of therapy. A 75 mg/5 mL suspension, licensed in Belgium, can be imported. From a safety and efficacy perspective it is preferable to use such a product, which has been through a regulatory process similar to that of the UK, than to compound an extemporaneous preparation, which has not undergone appropriate pharmaceutical/pharmacokinetic evaluation.

• Consideration could be given to decreasing the dose of clindamycin to 150 mg three times a day to accommodate capsules, although the child may have difficulty taking these.

• The most serious adverse effect of clindamycin is antibiotic-associated colitis. Therefore, it is important to monitor for diarrhoea. If this arises treatment should be discontinued.

Case 10.2

Name: CS
Age: 18 months old
Sex: Female
Weight: 10 kg
Presenting condition:	Severe right-sided abdominal pain
	Vomiting and loss of appetite
	Increased temperature 38.2°C
Previous medical history:	Nil of note
Allergies:	No known allergies
Drug history:	Nil of note
Tests:	Ultrasound
Provisional diagnosis:	Appendicitis
CS went to theatre where an appendicectomy was performed. The appendix was noted to be perforated.
Prescribed:	Morphine 50 mg in 50 mL to run at 1–4 mL/h (10–40 μcg/kg/h)
	Paracetamol 200 mg four times a day as required orally or per rectum
	Diclofenac 12.5 mg twice a day as required per rectum.
	or
	Ibuprofen 100 mg four times a day as required orally when tolerating milk
	Five days of i.v. antibiotic therapy with:
	Gentamicin 70 mg daily
	Ampicillin 250 mg four times a day
	Metronidazole 75 mg three times a day