Determining the Pharmacogenetic Basis of Non-responsiveness to the Sedative Effects of Dexmedetomidine in Children

Overview

Intranasal Dexmedetomidine is one of the sedative drugs of choice commonly used as an anxiolytic premedication for children for diagnostic or therapeutic procedures. However, some children do not achieve the level of sedation expected with the usual dose after an expected timeframe, leading to distress and costly time wasted. In this study, we would try to identify a genetic basis to non-responders of Dexmedetomidine by comparing a chosen gene panel of 250 relevant genes between responders and non-responders to a standardized 3mcg/kg intranasal Dexmedetomidine.

For most children, having to endure a diagnostic or therapeutic procedure in a hospital environment is a frightening and distressing experience, especially if it is accompanied by pain or discomfort. In an attempt to minimise the trauma and to maximise co-operation from the child, administration of a sedative is often requested by either the parent or the proceduralist. Some sedative agents may have the side effect reducing the child's efforts in breathing, causing inadequate oxygen to be delivered to and carbon dioxide removed from the body, a state that can be life threatening if left untreated. Other sedative agents may cause unpleasant sensations such as hallucinations or nausea while still others may have a paradoxical effect of exciting rather than sedating the child. Among the available agents that may be administered without the presence of an attendant anaesthesiologist, dexmedetomidine is an agent of choice with minimal incidence of the aforementioned effects. However, we have observed in a small proportion of children that dexmedetomidine does not see to be able to elicit a sedative response in the expected time and with the usual dose. It is possible that there is a genetic bas to this resistance and it would be of great use to be able to predict the non-responders ahead of time so an appropriate alternative may be selected without a trial and error approach. In this project, children who would require Precedex as first-line sedation for radiological or pre-anaesthesia sedation are asked to participate by providing a buccal swab sample and have their genome (genetic makeup) characterised by target sequencing. They are standardized into receiving 3mcg/kg intranasal Precedex and are observed every 5 minutes afterwards for their level of sedation. They would be identified as 'fast responder', 'normal responder', 'slow responder' and 'definite non-responder'. A gene panel of 250 relevant genes is chosen and compared between the different groups of responders and non-responders. We will then try to look for the differences between these groups and we will use this information to build a predictive model. This model will help to identify non-responders in the future and this would allow clinicians to prepare for an alternative approach to sedation. This would save time, distress to the child and parent and ultimately cost to the institution.