Challenges prescribing antiarrhythmic medications for infants and children

This article aims to discuss the issues relating to prescribing antiarrhythmic medications for infants and children. Antiarrhythmic medications are commonly prescribed for infants (0-1 years of age) and children (1–16 years of age) experiencing benign tachyarrhythmias, such as supraventricular tachycardia (SVT), in addition to those at risk of developing life-threatening tachyarrhythmias caused by inherited cardiovascular conditions, such as long QT syndrome (LQTS) or catecholaminergic polymorphic ventricular tachycardia (CPVT) (Hernández-Madrid et al, 2014). Antiarrhythmic medications reduce the likelihood of arrhythmia occurring, limit symptomology during arrhythmia and reduce the risk of sudden death (van der Werf et al, 2011; Abu-Zeitone et al, 2014). In infancy and childhood, antiarrhythmic medications are the most favoured treatment choice as invasive procedures performed routinely on adults carry a higher risk because of the smaller size of the child and are often delayed until adolescence (Ramesh Iyer, 2008).

Commonly occurring arrhythmias during infancy and childhood

Arrhythmias occurring during infancy and childhood are less common than those occurring in the adult population, with SVT (an umbrella term for arrhythmias originating within or incorporating atrial tissue) being the most prevalent (Sekar, 2008; Brugada et al, 2013). Primary arrhythmias occurring in infants and children with a structurally normal heart predominate and occur as a result of congenital, acquired and inherited underlying causes. Arrhythmias associated with structural congenital heart disease and disease of the heart muscle also occur (Brugada et al, 2013). The incidence of SVT in childhood is estimated to be between 13–16 /100 000 in children less than 19 years old (Brugada et al, 2013; Turner and Wren, 2013). Life-threatening ventricular tachyarrhythmias occur at a much lower frequency (Clausen et al, 2012). Table 1 details the most commonly occurring tachyarrhythmias treated during infancy and childhood.

Supraventricular tachycardia

The most commonly occurring tachyarrhythmia during infancy and childhood requiring pharmacological treatment is SVT (Salerno and Seslar, 2009; Spearman and Williams, 2014). There are several underlying mechanisms causing SVT in infancy and childhood, with accessory pathway meditated atrioventricular tachycardia (AVRT) and atrioventricular nodal tachycardia (AVNRT) being the most common (Till, 2012). Atrial flutter, atrial tachycardia (AT), and persistent junctional reciprocating tachycardia (PJRT) occur less commonly (Brugada et al, 2013).

In older children, SVT occurs at slower heart rates, typically exceeding 180 beats per minute (bpm) and is usually detected more easily as children can articulate symptoms. These symptoms include lethargy, poor feeding, vomiting, breathlessness and cool peripheries, with heart rates typically exceeding 220 bpm (Salerno and Seslar, 2009). If left undetected and untreated, SVT can result in severe ventricular systolic dysfunction and carries a risk of cardiovascular collapse and death. However, some types of SVT, including atrial tachycardia (AT) and PJRT can be difficult to detect as they present at slower heart rates, resulting in congestive heart failure (Vaksmann et al, 2006; Till, 2012).

Supraventricular tachycardia management

Irrespective of the underlying mechanism, prompt treatment including arrhythmia termination, arrhythmia suppression and/or heart rate control is required. Atrial flutter and infants presenting in extremis are treated with direct current cardioversion. In all remaining types of SVT, management relies on the use of vagal manoeuvres, which slows the heart rate and terminates SVT, or antiarrhythmic medications to suppress or gain SVT control (Kothari and Skinner, 2006). Intravenous adenosine is used to terminate SVT if vagal manoeuvres are ineffective.

Once the child is old enough to manage symptoms independently by employing vagal manoeuvres medications may be stopped, however, some use a combination of pharmacological therapy plus vagal manoeuvres. Definitive treatment involves referral for invasive treatment, a radiofrequency ablation (RFA). Safety of RFA is much improved in older children; therefore, younger children are managed with antiarrhythmic medications, or a combination of medication, plus the use of vagal manoeuvres until they are nearer adult size (Spearman and Williams, 2014). During infancy and early childhood, RFA carries an increased risk of damaging the heart's intrinsic electrical conduction system and small blood vessels; therefore, the use of pharmacological therapy outweighs the risk of the procedure (Salerno and Seslar, 2009).

Pharmacological treatment of supraventricular tachycardia management

The most commonly prescribed antiarrhythmic medications used to treat childhood SVTs are betablockers; however, neonates and infants suffering SVT refractory to beta-blockers may require dual or even multiple pharmacological therapies, including a combination of flecainide, amiodarone and digoxin. Amiodarone and digoxin are highly effective in controlling arrhythmia but are less desirable because of their long-term side-effect profiles or risk of toxicity (Ramesh Iyer, 2008; Lawrenson et al, 2011). Flecainide, a sodium channel blocker, is highly effective in controlling childhood SVT but also carries a risk of toxicity and should be managed within strict therapeutic parameters (Jang et al, 2013). Close electrocardiogram (ECG) monitoring during initiation of these medications often requires hospital admission, in addition to therapeutic blood monitoring, which can be challenging in infants and children (Vageur et al, 2020, British National Formulary for Children [BNFc], 2022).

Ventricular arrhythmias

Ventricular arrhythmias during infancy and childhood are less common but can be unpredictable and may cause cardiovascular collapse with sudden loss of consciousness. More stable forms of ventricular tachycardia (VT), such as fascicular VT may present similarly to SVT and are amenable to RFA longer term. Inherited conditions such LQTS and CPVT, which often present in childhood and adolescence, predispose to the development of bidirectional VT or torsade de point and if sustained may degenerate into ventricular fibrillation (VF) posing a risk of sudden death (Schwart et al, 2012; Napolitano et al, 2016)

Pharmacological treatment of ventricular arrhythmias

Pharmacological management of ventricular arrhythmias is crucial to reduce the risk of sudden death, and in some cases, treatment with daily medication will be lifelong. Consideration of arrhythmia using indwelling cardioverter defibrillator (ICD) insertion for those at risk of sudden death or poorly controlled ventricular arrhythmias is reserved for the most high-risk cases, because of the high risk of complications associated with ICD insertion in babies and smaller children (Priori et al, 2015; Olde Nordkamp et al, 2016). Therefore, antiarrhythmic pharmacological therapy forms the mainstay of ventricular arrhythmia management. Again, beta-blockers are often first-line pharmacological treatment; however, sodium channel blockers are used for arrhythmias that are more difficult to control, where risk of sudden death is increased, and in certain disease groups, such as CPVT and LQTS type 3 (van der Werf et al, 2011; Ackerman et al, 2017).

The development of arrhythmias during infancy and childhood also causes a considerable amount of parental and child anxiety; therefore, treatment with antiarrhythmic medication is not only beneficial in reducing symptoms and risk, but also in alleviating anxiety. However, access to these often lifesaving medications can be challenging with difficulties obtaining local prescriptions adding to the level of parental anxiety.

Prescribing antiarrhythmic medication for children

Once the clinical decision has been taken to treat a childhood arrhythmia with pharmacological therapy, there are several challenges to overcome to ensure the safe prescribing and supply of antiarrhythmic medications. These challenges are not uncommon when prescribing medications for children with acute and chronic conditions. A lack of drug testing in children results in the use of unlicensed and off-label medications being prescribed, in addition to the prescribing of medications classed as specialist medications, which can result in local refusal to continue prescribing medication (Barry and Smith, 2015). Prescribing antiarrhythmic medication that can be easily administered, and particularly specially prepared medications comes at an increased cost. Some antiarrhythmic medications (digoxin and flecainide) require therapeutic drug monitoring to reduce the potential for adverse reactions; therefore, additional consideration is required when prescribing these medications (Keith, 2015).

Licensing considerations

It is estimated that at least half of all medications prescribed for children in hospital are either unlicensed or used off-label (Conroy et al, 2000). Many medications used to treat children are unlicensed as a result of a lack of drug testing in children; therefore, are prescribed outside the product licence (Bourgeois et al, 2012). Licensed medications are those that have gone through rigorous drug testing for the treatment of a specific illness or condition. Licensing of medication requires identification of the age group the drug is intended for, the route of administration and dosing. Off-label prescribing occurs when a medicine with a product licence is being used to treat an illness not covered by its indicated license or is given to a patient group not originally licenced for, such as children.

There are few clinical trials involving children and antiarrhythmic medications and so the number of antiarrhythmic medications licensed for use in children is minimal (Ramesh Iyer, 2008). As a result, antiarrhythmic medications licensed for use in adults are prescribed in tertiary care paediatric cardiology centres outside their licensing terms in an unlicensed or off-label manner (Barry and Smith, 2015) (Table2 ).

This poses a problem, not only in ensuring the medication given to children is safe, but also with local prescribing by the child's GP who may not possess specialist knowledge of the medication and may therefore refuse to prescribe (Barry and Smith, 2015). Lack of product licencing for antiarrhythmic medications used for children is often cited by GPs as a reason they will not take on prescribing responsibility, even when the initial prescription is issued by a specialist in a tertiary centre and tertiary responsibility for monitoring and dose increasing is maintained. This results in difficulties for parents and patients obtaining repeat prescriptions, making ease of access to medication a problem.

Specially prepared medications

To ensure ease of administration, medications should be produced in a way that infants and children can swallow (Keith, 2015). Tablets taken by adults are not an option for an infant or younger child.

Some antiarrhythmic medications are routinely produced in liquid form (atenolol, propranolol, digoxin); however, some require special preparation and are manufactured outside the supply and distribution listed in the BNFc (2022). Flecainide and amiodarone are specially prepared so they are easily administered to babies and small children. Specially prepared medications or ‘specials’ are medications produced in liquid form by crushing the drug-containing tablet and adding it to a stabilised liquid solution. This method of drug preparation falls outside the drug's product licence and requires use in an unlicensed manner. Specially prepared medications are also produced at a greater cost than the equivalent tablets; however, they are more desirable as they allow smaller, more accurate doses to be administered. The cost of specially prepared medications can also act as a barrier to children's access to their medication locally. Table 3 identifies the cost differences between some commonly prescribed antiarrhythmic medications for children.

Specials are also ordered on a named patient basis and usually take at least 5 working days to be produced; therefore, parents need to request repeat prescriptions in sufficient time to ensure they do not run out of the current supply. Specially prepared medication is also unstable for long periods. Close observation of the expiry date and any changes in the consistency of the liquid are important. Bottles should be well shaken before administration to ensure the drug is well distributed. When local access to specially prepared medications is not possible, an alternative method of prescribing and dispensing medication to the child at home can be arranged via an external company; therefore, prescribing responsibility remains with the tertiary or specialist centre, thus improving the child's access to medication.

Local prescribing of unlicensed and specialist medications

The General Medical Council (GMC, 2014) recognise that unlicensed medication is often used in areas such as paediatric care and that unlicensed medications can be prescribed by GPs following an assessment of the individual, with the conclusion that for medical reasons it is necessary to prescribe the unlicensed medication. This includes medication licenced for use in adults, but that meets the needs of the child. It is also applied to patients who need medicine in a formulation that is not specified in an applicable licence ie, specially prepared medication made in liquid form. However, advice is given to ensure that when prescribing unlicensed medication, the prescriber is satisfied there is sufficient evidence to do so or that they have experience using the medicine to demonstrate its safety and efficacy. Once these issues are addressed the prescriber should take responsibility for prescribing the medicine and overseeing the patient's care, monitoring the patient including any follow-up treatment, or they must ensure that arrangements are made for another suitable doctor to do so (GMC, 2014). Despite this guidance there remains a continued problem in clinical practice with some infants and children experiencing a problem accessing their antiarrhythmic medication.

An additional challenge in ensuring children can access their medication locally is the classification of some antiarrhythmic drugs or those that are unlicensed or prescribed off-label being classified under specialist prescribing guidance. Local clinical commissioning groups (CCG) provide prescribing guidance to GPs regarding the prescribing of specialist medications.

Antiarrhythmic medications are often prescribed for children by a specialist cardiologist in a specialist centre, whereas cardiac pharmacological therapy for adults is often prescribed by GPs (Lawrenson et al, 2011). Shared care agreements between GP and specialist centres can be requested to overcome the problems encountered with specialist drugs; however, different CCGs have differing rules regarding shared care agreements and not all CCGs will agree to GPs taking on the prescribing of specialist antiarrhythmic medications. NHS England (2018) suggest shared care prescribing is inappropriate in the case of unlicensed and off-label medications without an associated evidence base or being recognised as standard treatment; however, prescribing antiarrhythmic medications to children that are used unlicensed or off-label for recognised childhood arrhythmias is common practice and is well described with medications identified in the BNFc for arrhythmia management.

Ease of access to medications

NHS England (2018) set out guidance for those prescribing between primary, secondary and tertiary care. The guidance aims to ensure the continuation of good professional practice so that patients receive seamless care including the transition of prescribing care provision, so they are never placed in a position where they are unable to obtain the medicines they need. Misunderstandings around professional prescribing responsibilities, prescribing cost, prescribing unfamiliar treatments and lack of consultation during the transfer of prescribing responsibility are often cited as reasons for patients not being able to access their medicines promptly (NHS England, 2018). Optimising patient experience, particularly for those on long-term treatment or those less able to attend a tertiary centre for prescriptions requires prescribing closer to home.

When children are left without access to their medication it is stressful for parents and poses a risk that their medication may not be administered in a timely fashion, potentially resulting in arrhythmia development. The prescribing responsibility remains with the specialist centre or specialist prescriber to source alternative options. If a GP refuses to prescribe locally, written confirmation of the refusal is requested with the reason for refusal included so this is documented in the child's medical record. The refusal is also recorded by the tertiary pharmacy team who are then able to reclaim some funding from the CCG for the continuation of prescribing. Alternative options for supplying prescriptions are then considered and agreed upon with the child's parents. Supplying prescriptions direct from the tertiary centre, if the family live close enough to be able to come and collect a prescription between outpatient appointments, is one option. Supplying a prescription that will last until the child attends their next planned outpatient appointment is also an option; however, this may only provide a limited supply of medication in the case of specially prepared medications or liquid medication, which may expire before the next outpatient appointment. With the additional implementation of virtual consultations because of COVID-19, this is not always an option either. A further and often preferred option for those living further away from the specialist tertiary centre is to send an FP10 prescription, which parents can take to their local pharmacy, to collect a supply of medication closer to home.

Formulation and route of administration

Children are usually able to manage to swallow tablets by the age of 9 years, some a little earlier. Tablets taken by adults are not an option for an infant or younger child, however, this poses a challenge as some antiarrhythmic medication is only manufactured in tablet form. Arrhythmias can occur in very small infants; therefore, producing medication in liquid form that is palatable is paramount to ensure ease of administration and optimise adherence to therapy. Infants and small children very easily spit medication out; therefore, the taste of the liquid preparation is also highly important to ensure the drug is administered as intended (Keith, 2015). Some beta-blockers are routinely produced in liquid form and are easily sourced including atenolol and propranolol (BNFc, 2022; Joint Formulary Committee, 2022). Switching to tablets once children are old enough reduces the potential for refusal to prescribe based on the cost of more expensive liquid preparations, eg flecainide. It also makes travel easier, as carrying liquid medication can be problematic, particularly in airports, because of the risk of bottle breakage.

Sourcing syringes locally can also be a challenge for parents. Regular replacements are required as the numbers wash off with repeated use, preventing accurate volume measurements for administration. Parents are often expected to pay for syringes which can be a problem for families on a low income. Medication for children until the age of 18 years is free on the NHS, so it is odd that the ancillaries used to safely administer medications are not.

Frequency of administration

The timing of administration is also an important factor to consider. Medications that are administered frequently, or that should be taken before or after food can prove a challenge. Flecainide is thought to cause a local anaesthetic effect when taken with food. The advice given is to avoid giving with milk and to give at least 30 minutes before or after food, which for infants who are breastfed is completely unrealistic given the frequency of feeding.

When children are of school age, prescribing medications that can be given at home is preferable, either once or twice daily. For example, atenolol can be given once or twice daily versus propranolol, which is given three times a day. Children requiring medication during school hours can prove challenging, with some schools refusing to administer lunchtime doses of medication, despite guidance intended to support children with medical needs requiring medications at school (Department of Health, 2005).

Safe prescribing

Fundamental differences between children and adults are a cause of errors when prescribing medication to children and should be considered to ensure safe prescribing. These differences include variable and rapidly changing size and weight; physiological and metabolic changes; the pharmacokinetic and pharmacodynamics of medications being prescribed; varying disease states and prematurity; and the child's level of development and cognitive ability (Ferro, 2015; Conn et al, 2019).

Prescribing errors have the potential to cause harm and contribute 21% of the total drug errors in the UK per annum, with potentially harmful errors in children being three times more likely (Kaushal et al, 2001; Elliot, 2005). Therefore, minimising potential drug errors in children is paramount.

Children's medications are prescribed predominantly with prescribing guidance from the BNFc (Paediatric Formulary Committee, 2022). This guidance includes indications for treatment, contraindications, cautions, safety, side effects, dosing relative to age and weight, monitoring requirements, preparation type and cost. However, some antiarrhythmic medications are not listed in the BNFc and are prescribed from the BNF, often using modified ‘small’ adult dosing (Joint National Formulary, 2022) (Table 2).

Where possible, prescribing based on the BNFc should occur; however, when this is not possible, dosing may require an estimated dose reduction, with further local guidance taken from a specialist paediatric pharmacist to support safe prescribing.

Prescribing liquid antiarrhythmic medication produced in varying concentrations also poses a risk of error. An example is the beta-blocker Propranolol which is commercially produced in four different strengths with varying cost (Table 4).

A concentrated solution of propranolol is preferred for infants and small children as it provides the smallest volume of liquid to be administered, is easier for parents to manage and is less likely to be spat out. For example, an infant receiving 5 mg of propranolol at a strength of 50 mg in 5 ml receives 0.5 ml per dose. Potential drug errors arise when the strength of the liquid is changed and parents are not well informed about the concentration and volume change ie, 5 mg in 5ml. The resulting volume to be administered is 5ml, which is a considerable difference and one which makes a difference in ease of administration. Equally, if an inadequate explanation is provided, there is potential for under-dosing with a risk of subsequent arrhythmia return. This is a commonly occurring error during the transition to local prescribing, with general practitioners often prescribing a more dilute solution, resulting in the volume to be administered needing adjustment, but which is often poorly explained to parents.

Prescribing guided by the BNFc also reduces the potential for adverse reactions. There is a potential for side effects no matter what medication is prescribed; however, monitoring side effects in infants and young children can be more problematic as they are unable to verbalise how medications affect them (Conn et al, 2019). Consideration of the side effects with differing beta-blockers may influence which type is prescribed in childhood. Propranolol is known to cause nightmares because of its lipid-soluble profile, crossing the blood–brain barrier. Atenolol is water–soluble and therefore less likely to cause this side-effect.

Proarrhythmic effects are an important consideration when prescribing antiarrhythmic medication for children (McComb, 1993). The potential to cause unwanted effects on the electrocardiogram (ECG), including PR, QRS or QT prolongation, are evident with most antiarrhythmic medication; therefore, all antiarrhythmic medication other than beta-blockers are initiated in hospital with 12-lead ECG monitoring performed daily. Additional blood level monitoring is also indicated for some medications; however, obtaining blood samples from infants and children can be difficult because of compliance during blood sampling, accessing small veins and the development of needle phobia due to repeated blood testing (Ferro, 2015). Therefore, careful planning during the initiation of antiarrhythmic medications should be used to reduce the need for blood sampling.

Antiarrhythmic medications requiring therapeutic blood monitoring at initiation include flecainide and digoxin. Additional blood monitoring is performed when doses are up titrated as an outpatient, with further ECG monitoring performed, and if toxicity is suspected (Dan et al, 2018). Regular outpatient appointments with 12-lead ECG and ambulatory Holter monitoring are also used to monitor efficacy and adverse effects. Therapeutic ranges aim to prevent toxicity and ensure sufficient blood levels and arrhythmia control are achieved (Yang et al, 2012; Karmegaraj et al, 2017). The toxicity of antiarrhythmic medications are potentially life-threatening; therefore, methods to reduce toxicity are paramount. Toxicity may occur as a result of altered metabolism of medication and errors in dosing and administration.

Amiodarone requires regular monitoring of liver, thyroid and renal function during treatment (Siddoway, 2003) with withdrawal therapy recommended if adverse effects develop. Side effects occurring with antiarrhythmic therapy usually resolve once therapy has been discontinued. In the event of side effects, alternative antiarrhythmic medication may be initiated, with yellow card reporting required to report the side effects, in addition to a documentation in the child's medical records.

Conclusion

This article has identified many challenges when prescribing antiarrhythmic medication for infants and children. Despite guidance to support the prescribing of unlicensed and off-label medications used during childhood, access to medications for some infants and children remains sub-optimal. Methods to improve access to medications should be implemented where possible. There is a definite need to improve the processes in place to support local access to medication and promote continuity of care and ensure safe prescribing of these specialist medications.