Straight-tip guidewire versus J-tip guidewire for central venous catheterisation in neonates and small infants: A randomised controlled trial. Population Pharmacokinetics of Intranasal Dexmedetomidine in Infants and Young Children.

Study summary

This is a single-centre prospective study looking at the pharmacokinetic profile of 2 mcg/kg intranasal (IN) dexmedetomidine administered to 137 ASA 1-2 Chinese children aged 3-36 months, with simple vascular malformations undergoing interventional radiological procedures between June 2016 to November 2017 at Guangzhou Women and Children’s Medical Center, China. Exclusion criteria were dexmedetomidine allergy or hypersensitivity; severe hepatic impairment; haematological, cardiovascular, endocrine, metabolic, and gastrointestinal diseases; any sedative exposure including dexmedetomidine within a week; presence of active respiratory symptoms, rhinorrhoea and vascular malformations in or near the nasal cavity that might influence nasal drug absorption.
All enrolled patients were given a standardised general anaesthetic consisting of induction with 2 mg/kg propofol, 0.3 mg/kg sufentanil and 0.2 mg/kg cisatracurium besylate; followed by intubation or a LMA placement; then 2 mcg/kg IN dexmedetomidine administered by a same paediatric anaesthetist, Dr B.L. Li; and anaesthesia maintained on sevoflurane. IN dexmedetomidine is used here as an anaesthetic adjuvant to decrease risk of emergence delirium, and thus, risk of rebleeding from the interventional puncture site. Vital signs and sedation score (UMSS) were measured at baseline and every 5 minutes until discharge criteria were reached.
IN dexmedetomidine pharmacokinetic data from healthy adults were extrapolated to children based on allometric scaling. The children in the study were divided into 3 groups based on age: 3-12 months (Group 1), 13-23 months (Group 2), and 24-36 months (Group 3); and 5 blood samples were taken from an IV cannula into heparin sodium tubes from each patient at 6, 18, 120, 180 and 360 minutes for Group 1; 6, 18, 60, 240 and 360 minutes for Group 2; and 6, 18, 120, 240 and 360 minutes for Group 3. Plasma dexmedetomidine concentrations were quantified using validated ultrahigh performance liquid chromatography-tandem mass spectrometry with a stable isotope-labelled internal standard. Of the 685 scheduled blood samplings, 586 were successfully collected; 37 samples were not collected due to clash with the investigator’s other commitments, 45 missed due to blocked cannula and 17 were refused by parents.
The median duration of anaesthesia was 30.0 min (interquartile range, IR = 24.0-44.5 min), and wake-up time (defined as start of anaesthesia to UMSS 0-1) was 43.5min (IR = 32.5 – 55.8min). 8 patients had hypotension with 1 patient requiring epinephrine for SBP = 58mmHg.
A two-compartment model used to describe dexmedetomidine pharmacokinetics with first order elimination from the central compartment yielded a smaller improvement in fit compared to a single-compartment model. Addition of maturation of dexmedetomidine based on postmenstrual age improved modelling to a greater extent than a 70-kg standardised allometric model. This study found a target plasma of 0.3 ng/ml will be reached within 20 minutes in 95% of simulated individuals treated with 2 mcg/kg IN dexmedetomidine and Cmax of 0.563 ng/ml will be reached at 61 minutes. These findings are similar to a study by Miller et al. with a similar age group, but different to a study by Wang et al. who recruited older children. The difference seen is postulated to be from patient age range, clinical status and bioavailability of dexmedetomidine from different administration routes. The terminal half-life of 1.8 hours is similar in all 3 studies.
Using the pharmacokinetic modelling in this study, IN dexmedetomidine dose at 2 mcg/kg or above will give moderate to deep sedation at 20 minutes after administration, and be adequate for non-painful procedural sedation lasting up to 2 hours.

Take home message

This study appears to be of robust design and adds to the understanding of IN dexmedetomidine. Personally, whilst this is a pharmacokinetic study, I am disappointed that there were no comments on incidence of emergence delirium for which the IN dexmedetomidine was administered for in this study, and it was unclear if the patient in this study with SBP of 58mmHg needing epinephrine had the SBP drop due to dexmedetomidine or another cause.
Nevertheless, we now have some evidence IN dexmedetomidine at dose of 2 mcg/kg would give clinically significant sedation without unduly prolonging time for emergence. It would be interesting to repeat this study to look at the dexmedetomidine pharmacodynamic profile specifically for pre-anaesthetic anxiolysis/sedation, pain relief, and any significant adverse effects or cardiorespiratory risks.

Reviewed by Dr K.C. Law