Charles Darwin University Clonidine for pain-related distress in Aboriginal children on a penicillin regimen to prevent recurrence of rheumatic fever

Context:  Indigenous children and adolescents in Australia and globally bear the burden of acute rheumatic fever (ARF). It has been virtually eliminated in well-resourced, developed settings. ARF is an autoimmune response to infection with group A Streptococcus. The mainstay of management is long-acting intramuscular penicillin injections to prevent recurrence of ARF and development of rheumatic heart disease (RHD), comprising valvular pathology and attendant complications. In Australia, penicillin injections are currently prescribed every 28 days for 5–10 years after diagnosis of ARF, depending on cardiac involvement. Adherence to this regimen reduces ARF recurrences and RHD progression. ‘Days at risk’ of ARF recurrence are calculated as the number of days after day 28 that an injection is not received. Adherence to the injection schedule has been reported as difficult in most global locations due to the painful nature of the injections, the long timeframes of the prescription, young age of patients, access problems and costs in some locations. The newly updated Australian guideline on the prevention, diagnosis and management of ARF and RHD has a chapter dedicated to secondary prophylaxis. This chapter takes into account cultural considerations and advises on ways to minimise pain and distress of injections in children such as pain gate strategies, distraction techniques and concurrent injection of local anaesthetic. Issues:  Some children continue to find the injection regimen traumatising despite strategies to reduce pain and fear. Clinicians providing the injections to children also find the injecting episodes distressing if pain is not effectively minimised. An Aboriginal Community Controlled Health Service in a remote setting in northern Australia addressed the issue of severe trauma of injection episodes experienced by an Aboriginal boy aged 7 years. Usual strategies were not effective, so advice was sought from an expert anaesthetist at a tertiary hospital. As a result, oral clonidine 3 μg/kg was trialled 45 minutes prior to the penicillin injection. Procedural coaching and monitoring protocols specific to administration of clonidine in children under their care were created by the health service. The initial dose of clonidine was delivered with the child as an inpatient. Lessons learned:  Clonidine was successful in reducing pain related distress and facilitating adherence to the penicillin regimen. Subsequent doses were delivered and monitored in a remote setting by nurses. After 18 months, the boy no longer required clonidine due to his increased coping capacity. A second child was recognised with similar trauma and has been taking clonidine for pre-procedural sedation for 6 months with good effect and no adverse effects. An additional child was similarly prescribed clonidine without success. Failure in that instance was attributed to lack of procedural coaching and receiving the initial dose of clonidine in an emergency department in hurried circumstances. Individualised child-focused and culturally appropriate care in remote settings is feasible: in this instance team planning for use of clonidine and procedural coaching when other measures have failed. However, for children with RHD, or other comorbidities, advice from the child’s treating cardiologist is required prior to prescribing clonidine due to possible adverse consequences. These include hypotension and atrioventricular block, which could lead to haemodynamic compromise in the setting of moderate to severe RHD.


Context
Acute rheumatic fever (ARF) and its sequela, rheumatic heart disease (RHD), are prevalent among Australian Aboriginal people, with the most common ages of ARF acquisition being between 5 years and 14 years . The mainstay of medical management in Australia for a confirmed or probable case of ARF is a regimen of long-acting benzathine benzylpenicillin G (BPG) injections. Oral penicillin has been shown to be inadequate as secondary prophylaxis in this instance . The Australian guideline currently recommends that the regimen is continued for 5-10 years after the last known episode of ARF, depending on cardiac involvement, or until the person reaches the age of 21 years, whichever is longer .
The long-term nature of this management is due to the high risk of reinfection with group A Streptococcus in northern Australia.
BPG injections are given at no later than 28-day intervals to maximise protective serum levels of benzathine penicillin. 'Days at risk' of recurrence are calculated as the number of days after day 28 that an injection is not received and the person is therefore susceptible to ARF . Some children are prescribed a 21-day regimen if an ARF recurrence occurs on the 28-day regimen.
Physiological pain of the injections is assumed to be caused by high viscosity and the large volume of medication injected.
Children who are prescribed the regimen face a long-term 'repeated painful procedure'. Online guidelines from the Royal Children's Hospital in Melbourne state that for procedural pain 'it is often difficult to distinguish between pain, fear and anxiety', therefore 'the combination is often referred to globally as pain related distress' . ARF is most often diagnosed in children, The Laynhapuy clinical team discussed the boy's case to determine availability of further options. Although all recommended strategies were being used to alleviate the boy's severe distress, they were concerned as a group that it was not adequate in this instance. In a collegial approach, the team discussed analgesia commonly used to manage strong pain and/or severe distress in hospitalised children (such as ketamine, nasal midazolam or fentanyl and nitrous oxide) and considered how the remoteness of their practice impacted potential use of such pharmacological interventions. The boy's family were also keen to try something new to address the severe trauma.
The director of anaesthesia in the tertiary referral hospital (Darwin) was contacted for advice. The recommendation of oral clonidine was made as a safe and effective option for children experiencing procedural trauma. Oral clonidine is an alpha-2 adrenergic receptor agonist with broad cardiovascular and central nervous system effects in children and adults, including analgesia and sedation. Clonidine produces sedation by decreasing sympathetic nervous system activity and the level of arousal due to activation of central nervous system alpha-2 receptors. The result is 'a calm patient who can be easily aroused to full consciousness' . Use of clonidine has not been reported in primary healthcare settings locally or internationally for children prescribed the BPG regimen; however, it is increasingly used as an adjunct in anaesthesia and to reduce postoperative pain in children as well as with good effect for a range of other conditions such as sleep and behavioural disorders and secondary dystonia .
Under guidance of the director of anaesthesia, a starting dose of 3 µg/kg given 45 minutes prior to the penicillin injection and a 2-hour observation time was planned. A dose of ibuprofen 10 mg/kg was recommended to be given concurrently to assist with muscular pain post-procedure. If the child was stable and rousable after 2 hours and awake enough to protect the airway, then they could be discharged home. The health team decided to commence the first dose of clonidine with the boy as an inpatient in the regional hospital in January 2018. The starting does was just under 3 µg/kg (100 µg for child weighing 38.5 kg) along with oral ibuprofen and paracetamol. These were given 45 minutes prior to the penicillin injection. The episode was assessed as successful: the boy declined to have the injection in the buttock but accepted the thigh. He watched the needle throughout the procedure. Blood pressure, respiratory rate, level of consciousness and emotional state were monitored for 3 hours with no adverse events being recorded.
The next phase was to deliver the new strategy in the remote homeland setting with no doctor present and the clonidine being administered by experienced nurses. The nursing team created a procedural counselling protocol specifically for use with the clonidine strategy (Box 1). This comprises six elements as sourced from the Royal Children's Hospital, Melbourne clinical nursing guideline for procedural pain management .
The homeland dose of clonidine was reported to cause mild sedation with relief of the boy's anticipatory anxiety; he was calm prior to and during the injection. Sedation was no longer evident with repeated dosing. Anxiety was greatly reduced in the boy although he continued to show overt signs of emotional relief post-injection. Six months into the new clonidine strategy, the boy had just one 'day at risk' compared with 4 days at risk prior to the strategy. 'Days at risk' of recurrent streptococcal infection/ARF are counted as every day after day 28 that a BPG dose is not administered . After 18 months on the strategy, clonidine was ceased due to the boy's decreased fear and anxiety around injections. He continues to cope well with the regular injections with good adherence: in the 12-month period after ceasing clonidine, 4 days at risk were recorded, attributed to patient movements over the school holiday period rather than to fear of needles.
Two other children aged 9 years and 8 years on the BPG injection regimen were subsequently diagnosed with pain related distress and were commenced on the clonidine strategy. The second child commenced the clonidine strategy in the local clinic rather than in hospital and at the time of writing had been receiving clonidine for 6 months with effective reduction in anxiety, no adverse effects and complete adherence to the penicillin regimen. The third case to commence the strategy was unsuccessful. This failure was attributed to starting clonidine in the emergency department of the regional hospital in rushed circumstances without procedural counselling. This third child has temporarily stopped the penicillin regimen (with oral penicillin substitution in the interim) and will recommence as soon as feasible with a new injection care plan.
Box 1: Procedural counselling protocol specifically for use with clonidine strategy for long-acting benzathine benzylpenicillin G administration.

Health service protocol and new Australian guideline
In consultation with the director of anaesthesia, the health service completed an in-house protocol for prescription and administration of clonidine in cases of pain related distress in children on the penicillin regimen. Administration of clonidine in this health service is typically carried out by two nurses, or one nurse and one Aboriginal health practitioner, who are trained in paediatric basic life support, in the absence of a doctor. Monitoring was consistent with the Australian safe practice for administration of sedation . The children in this case study had probable and definite ARF with no cardiac damage.
Due to insights gained from this case study, authors were invited to contribute to the third edition of the Australian guideline for prevention, diagnosis and management of acute rheumatic fever and rheumatic heart disease published online in February 2020 .
We refer readers to chapter 10 of the guideline and pages 179 and 180 specifically on clonidine use for BPG injections. The new guideline alerts practitioners to possible adverse effects of clonidine, which include hypotension and atrioventricular block, necessitating discussion with the child's specialist in cases of RHD prior to prescribing clonidine.

Lessons learned
In determining what enabled improved and effective care for the plan with other regional health practitioners in primary healthcare and hospital settings is important given the likelihood that a patient may receive their BPG from other healthcare providers at times.
Good planning for initial injections at ARF diagnosis needs to include procedural coaching, ideally with staff that children and adolescents already know. This may prevent or reduce pain related distress.
Clonidine is a feasible option for reducing aversion to BPG injections in children and adolescents experiencing pain related distress, which may facilitate adherence to the longterm regimen and prevent ARF recurrences. However, for children with RHD, discussion with their specialist is required before prescribing clonidine.
Approaching repeated painful procedures in children proactively, informed by current best practices, means it is feasible for children and adolescents on the penicillin regimen and their families, as well as healthcare staff, to provide and receive optimum care within remote locations. Good adherence to the injection regimen reduces the overall risk of heart damage, which in turn reduces morbidity and mortality from RHD. Ultimately, eradication of ARF in Australia should be possible. REFERENCES: