Premedication in children: does taste matter?

Sedative premedication is commonly prescribed for anxious, non-compliant children, those who have been distressed previously, and those with learning disabilities or behavioural issues. In addition, the type of procedure and its likely duration may influence the choice of sedative. The aims of premedication in children include: allaying their anxiety; allowing easy separation from their parent or carer; facilitation of a smooth anaesthetic induction; and a reduction in postoperative psychological problems. The ideal sedative premedication should be safe and easy to administer, have a predictable onset time, a high success rate and minimal side-effects. Administration of an oral formulation is usually preferred because it is most likely to be tolerated, yet there is currently no ideal sedative premedicant available. Most drugs are developed and marketed for adults, but their pharmacokinetic and pharmacodynamic information are not directly translatable to the paediatric population. Children form a heterogeneous group that requires special attention when developing a new drug 1. In developing such formulations the intended recipients include children of different ages and at different developmental stages, as well as those with special needs and neurodevelopmental disorders. Factors to consider in the development of an oral paediatric drug formulation include smaller and variable dose requirements depending on the patient's age and size, a formulation that allows accurate dosing, is palatable and acceptable to young children, easy to swallow and relatively cheap to manufacture. Midazolam is the most commonly prescribed pre-operative sedative in paediatric anaesthesia practice 2, 3. It is usually prescribed in an oral dose of 0.5 mg.kg−1 and has been shown to be an effective anxiolytic 4, whereby patients usually appear relaxed and quiet, allowing easy separation from parents. This should allow smooth induction of anaesthesia and alleviate stress for children and parents as well as the anaesthesia team. However, less than 20% of children appear adequately sedated at this dose 5 and although increasing the dose to 0.75 mg.kg−1 or even 1 mg.kg−1 provides sedation in more children 6, this is at the expense of increased side-effects, including loss of balance and head control, blurred vision, dysphoric reactions 7 and delayed emergence from anaesthesia. Although the anterograde amnesic property of midazolam is promoted as an important advantage compared with other sedatives, there is concern regarding its association with implicit memory in children 8. Implicit memory is defined as the preservation of unpleasant emotions or anxiety associated with an event, although this cannot be recalled consciously. The association between midazolam and implicit memory is thought to be a cause of distress at subsequent medical encounters in children who have previously been treated with midazolam 8 and could lead to paradoxical anxiety which in turn results in an increase in the incidence of emergence agitation during recovery from anaesthesia 9. In the UK, midazolam hydrochloride syrup is administered in a concentration of 2 mg.ml−1, yet an oral formulation for children is not widely available in Australia or Asia and so the intravenous (i.v.) formulation is used via the oral, buccal, intranasal or even rectal route. Although this formulation is widely used, it has its problems, including a bitter taste with oral administration and a stinging or burning sensation on exposure to the nasal mucosa if given intranasally. In this issue of Anaesthesia, Salman et al. 10 report on their development of a novel, chocolate-flavoured oral preparation of midazolam. They included 150 patients aged between 3 and 16 years who had been prescribed oral midazolam in a dose of 0.5 mg.kg−1. The children were randomly allocated to receive either the standard i.v. preparation administered orally or the new chocolate-flavoured tablet. The study authors found significantly improved tolerability with the chocolate-flavoured preparation. Although the novel formulation was subject to a higher estimated first-pass metabolism and lower relative bioavailability, the time to effect was similar in both groups and the authors concluded that the chocolate-flavoured midazolam provided improved tolerability while remaining efficacious. The authors should be congratulated on completing a study that fills a gap in clinical need, and a properly formulated and palatable version of midazolam would be welcomed by many anaesthetists. However, it is important to determine whether the new chocolate-flavoured formula would be accepted by children with neurodevelopmental disorders as it is not uncommon for these children to refuse any type of drug administration, especially medication in tablet form. It is interesting that the authors chose a chocolate flavour and tablet form rather than other flavours in a liquid form. In one study, 270 primary school aged children (aged 3–11 years) and 162 secondary school children (aged 13–14 years) answered a questionnaire 11. Each group of children was asked to choose their favourite flavour for a medicine and although other flavours emerged when given a broad list of options from which to choose, including chocolate, cola and bubble gum, strawberry was the most popular flavour. Midazolam, whether formulated in a chocolate-flavoured tablet or an i.v. preparation, is not the ideal premedicant and alternatives are in common use (Table 1). Ketamine is a N-methyl-d-aspartate (NMDA) receptor antagonist usually given in an oral dose of 5 mg.kg−1. It results in sedation and analgesia, but no anxiolysis or amnesia. It causes excessive salivation, nystagmus, nausea and vomiting, and may also result in an increased incidence of emergence agitation. Other popular sedative premedications worldwide include α2-adrenergic agonists such as clonidine and dexmedetomidine 12. Clonidine is administered in an oral dose of 4 μg.kg−1 and produces satisfactory sedation and anxiolysis. However, it is slow in onset and has a relatively long duration of action and is therefore not ideal for children undergoing short procedures. Dexmedetomidine is colourless, odourless, does not result in respiratory depression and, when administered intranasally, produces more successful sedation compared with midazolam 13. However, both these drugs may cause unwanted hypotension and bradycardia. There have been no studies examining whether dexmedetomidine affects implicit memory, but we do know that explicit memory is impaired at low-dose midazolam sedation yet preserved at low-dose dexmedetomidine sedation. These findings may be explained by the fact that the sedation state produced by dexmedetomidine is different from that of midazolam. Dexmedetomidine produces sedation by decreasing noradrenaline release at the locus coeruleus 14; the sedation state is similar to that of natural non-REM sleep 15 with neither paradoxical reactions nor euphoria occurring. It is proposed that α2-adrenergic receptor agonism reduces attention to external stimuli via noradrenergic suppression and causes ‘disconnection’ to the external environment 16. Suppression of connectedness is similar to a state of natural sleep, whereby an individual would not be bothered by, for example, a doorbell or telephone ringing. This is in contrast to GABA-ergic agents such as midazolam which suppress consciousness by reducing corticothalamic integration and sedated subjects act as if they have an altered mental state and are not able to follow commands. With our increased understanding of the mechanisms of action of various agents, we can use combinations of drugs to target different neurotransmitters. Most anaesthetic drugs work on the GABA receptor to produce a general anaesthetic state. Alpha-2 adrenergic receptor agonists, given as a premedicant, would be a logical addition to GABA-ergic drugs because they act on a different neurotransmitter and promote disconnection in addition to suppressed consciousness. This has been proposed as the mechanism for a reduction in the incidence of emergence agitation and delirium in children during recovery from general anaesthesia 17. Meta-analyses have revealed dexmedetomidine to be associated with a reduction in emergence delirium in children 18, as well as providing other benefits, such as reduced analgesic requirements and a decrease in postoperative nausea and vomiting. Another important factor when choosing a medication in children is their potential effect on the developing brain, and this issue has been of great interest to paediatric anaesthetists recently 19. The neurotoxic effects of GABA-ergic agonists and NMDA receptor anatagonists have been established in animal studies 20, whereas dexmedetomidine has been shown to be neuroprotective in rodent models 21 and primates 22. It has even been shown to attenuate the neurotoxic effects of other anaesthetic agents. Although neuroprotection is difficult to evaluate in human subjects, the ongoing international multi-centre clinical trial comparing long-term outcomes after dexmedetomidine/remifentanil/low-dose sevoflurane combination and standard dose sevoflurane anaesthesia (https://clinicaltrials.gov/ct2/show/NCT03089905) may provide us with information on whether dexmedetomidine can offer additional benefits to our paediatric patients requiring sedation and anaesthesia. In conclusion, most oral or intranasal sedatives for children are administered as i.v. formulations, and the development of new palatable preparations to cater for the specific requirements of children is needed. Whatever flavours are chosen they should be sugar free and dye free in order to benefit diabetic patients or those who are sensitive or allergic. In addition, careful consideration should be given to the effects on pH in order to maintain the medicine's stability. Oral midazolam has several limitations, but it is one of the most commonly prescribed sedatives in children and the introduction of a novel chocolate-flavoured preparation which is more palatable than existing formulations is to be welcomed. Further development of different flavoured liquid preparations, not just of sedatives but antibiotics and analgesics, for example, are urgently needed. CB is an editor of Anaesthesia. No other competing interests declared.