The role of α2 agonists in paediatric critical care sedation

Background There are two α2 agonists used in sedation in paediatric critical care in Ireland. Firstly, the older medication clonidine and secondly the newer, more selective, α2 agonist dexmedetomidine. Neither agent is licensed for use in paediatrics despite both being in routine clinical use. Not being licensed in children has meant both medications bypassed formal efficacy and safety studies in children during their development. This thesis aimed to address current knowledge deficits and provide an evidence base for the use of α2 agonists as sedatives in mechanically ventilated children. Methods The thesis consists of four studies. An initial systematic review aimed to describe existing evidence for the efficacy of α2 agonists from previously published randomised controlled trials and observational studies. The study aimed to investigate the impact of the addition of an α2 agonist on time at sedation target as measured by a validated sedation scale. Secondary outcomes measured concomitant opioid and benzodiazepine dosage. Lessening concomitant use of other opioids and benzodiazepines could reduce adverse effects associated with their use. Following the systematic review, a descriptive observational study was conducted. The purpose of this study was to establish baseline sedation outcomes and establish if routinely gathered sedation scores could be used to assess the effectiveness of sedative regimens. The study was conducted in the PICU at Our Lady’s Children’s Hospital, Crumlin (OLCHC). This PICU is the largest in Ireland with over 1200 annual admissions. Children over 18 months admitted from January to June 2016 were included.Sedation was assessed using the validated COMFORT Behaviour scale. The descriptive study informed the design of a comparative effectiveness study of α2 agonists at OLCHC and Temple Street, Children’s University Hospital (TSCUH). The comparative effectiveness study examined the effect of exposure to an α2 agonist on time adequately sedated alongside concomitant morphine and midazolam use. Exposed children were matched to unexposed children using propensity score matching. Results of the comparative effectiveness study and from the systematic review suggested clonidine is underdosed in Irish PICUs. A final study investigated optimising dosing of clonidine. A pharmacokinetic simulation study examined the therapeutic plasma clonidine concentrations obtained by a variety of potential dosage regimens. Results This systematic review included the results of six trials of α2 agonists (three trials of each agent) alongside twelve observational studies of dexmedetomidine use. Overall, clonidine has shown efficacy as an opioid-sparing agent in mechanically ventilated neonates while dexmedetomidine may shorten time to extubation and opioid requirements. Dexmedetomidine trials were smaller and of lower methodological quality. Included studies of both α2 agonists typically did not use primary outcomes based on validated sedation scores. Instead, they focussed on other outcomes such as concomitant opioid use and time to extubation. The descriptive observational study reported sedation outcomes in mechanically ventilated children addressing the limitations of previous studies identified in the systematic review. It showed that routinely collected nursing sedation scores could be used to quantify sedation success for research purposes. Approximately three-quarters of included children had less than 80% of the time at sedation target, the chosen definition of sedation failure. Oversedation was more common than undersedation. The subsequent comparative effectiveness study found those exposed to an α2 agonist had a higher time adequately sedated versus the unexposed group. This benefit was observed in clonidine-treated children and not in children treated with dexmedetomidine. Opioid and benzodiazepine sparing were not observed. Dexmedetomidine use was infrequent and not associated with improved sedation outcomes. The pharmacokinetic simulation study found that the dosages of clonidine used in Irish PICUs are unlikely to attain sufficiently high plasma concentrations for a full therapeutic effect. The study supported a dosage regimen of an initial loading dose of 2 μg/kg (with intermittent rescue doses if insufficient sedation achieved) followed by a continuous infusion of up to 2 μg/kg/hr titrated according to sedation scores. Doses should be halved in neonates. Conclusion The published evidence base to support the use of α2 agonists is limited. Clonidine has shown efficacy as an opioid-sparing agent in mechanically ventilated neonates while dexmedetomidine may shorten time to extubation and reduce opioid requirements. Sedation outcomes in current clinical practice are currently relatively poor, with most children requiring multiple agents to maintain adequate sedation. The results of the comparative effectiveness study suggest clonidine is a useful alternative sedative agent for use in sedation regimens; however, the hypothesised opioid-sparing effects are not seen at the doses used in Irish PICUs. The pharmacokinetic simulation study found that current clonidine dosage regimens are often insufficient. This thesis provides an up-to-date evidence base for α2 agonist use in paediatric critical care and should inform future studies to optimise their use