Atomized Intranasal Dexmedetomidine in Children with Congenital Heart Disease: Defining the Optimal Dose
Viviane Nasr MD, James DiNardo MD, Lindsey Loveland Baptist MD, Susan Nicolson MD
Original article
Grogan K, Thibault C, Moorthy G, Prodell J, Nicolson SC, Zuppa A. Dose Escalation Pharmacokinetic Study of Intranasal Atomized Dexmedetomidine in Pediatric Patients With Congenital Heart Disease. Anesth Analg. 2023 Jan 1;136(1):152-162. PMID: 35446797 1
Original article
Miller JW, Balyan R, Dong M, Mahmoud M, Lam JE, Pratap JN, Paquin JR, Li BL, Spaeth JP, Vinks A, Loepke AW. Does intranasal dexmedetomidine provide adequate plasma concentrations for sedation in children: a pharmacokinetic study. Br J Anaesth. 2018 May;120(5):1056-1065. PMID: 29661383 2
Dexmedetomidine (DEX), an alpha-2-agonist most commonly administered by the intravenous (IV) route, has gained popularity in children as a premedicant, sedative, anxiolytic and adjuvant to analgesia. Atomized DEX has been increasing administered via the intranasal (IN) route as a premedicant and for non-painful procedural sedation which obviates the need for IV access that can be technically challenging and associated with distress and pain for the child. IN DEX in doses between 1-4 mcg/kg alone or in conjunction with other sedatives have been studied. The quality of the sedation, time to onset of action and peak effect and the ability to complete the procedures are highly variable. Determining the optimal dosing for a predictable onset and peak effect while not exceeding the maximal plasma concentration requires PK studies in different subset of pediatric patients.
In today’s PAAD Grogan et al.1 use a creative study design to delineate the PK of IN DEX in children with congenital heart disease (CHD) between 2-6 years of age undergoing elective cardiac catheterization. IN DEX was administered after induction and IV placement. Blood samples were prior to and 10, 15, 20, 30, 45, 90, 120, 180, 240 and 300 after administration of IN DEX. The study was designed for dosing of 2 ug/kg, 4 ug/kg and 6 ug/kg with an interim PK analysis after each cohort before proceeding to the next dose. However, 3 patients in the 4 ug/kg cohort achieved a dose limiting toxicity (DLT), defined as a plasma dexmedetomidine concentration above 1000 pg/mL. This threshold comes from IV DEX PK data obtained from previous studies conducted at the Children’s Hospital of Philadelphia (CHOP) that looked at neonates and infants undergoing cardiac surgery during which the incidence of bradycardia increased significantly above this level.3-5 This DLT was determined in conjunction with FDA guidance under IND 69758. None of 3 patients in the Grogan study with plasma concentrations above 1000 pg/mL had any significant hemodynamic consequences. No patients were enrolled in the 6 ug/kg cohort. Children receiving 4 µg/kg had higher concentrations then children who received 2 µg/kg (1000pg/ml [978-1050] vs 413 pg/ml [311-565], p=0.003). The time to reach maximum concentration between the two-dosing regimen was not statistically significantly different (54 min [45-106] vs 91min [44-120], p=0.67). However, even though the difference is not statistically significant, a difference of 33 minutes may affect workflow in a busy operating room or procedural area. Simulation with a virtual population of 1000 children based on the patient characteristics in the study showed that subjects who receive 3 µg/kg would not reach a plasma concentration > 1000pg/mL.
Another study by Miller et al.2 evaluating IN DEX used lower dosing of 1 µg/kg and 2 µg/kg and compared IN administration to intravenous DEX 1 µg/kg in patients with CHD. The mean arterial plasma concentrations of DEX in infants and toddlers approached 100 pg/mL. This is the low end reported for sedative efficacy and was reached within 20 min of an atomized intranasal administration of 1 μg/kg. Doubling the dose to 2 μg/kg resulted in the same plasma concentration within 10 min and was associated with almost twice the peak concentration. Peak plasma concentrations with both doses were reached within 47 min of IN administration.5 The time to reach plasma concentration was lower than the study by Grogan et al.1
A follow-up, phase 2 prospective study of plasma concentrations after IN (3 µg/kg and 4 µg/kg) and buccal (2 µg /kg) DEX to determine the early pharmacokinetics peak concentration, time to maximum concentration and bioavailability of a single IN or buccal dose in 18 pediatric patients has been completed. This study is currently in the analysis phase and the results will add to our current knowledge of DEX PK. It will be interesting to see if this in vivo testing of the simulation model performed by Grogan et al demonstrates that a 3 µg/kg dose is safe and efficacious in pediatric patients with CHD.
References
1. Grogan K, Thibault C, Moorthy G, Prodell J, Nicolson SC, Zuppa A. Dose Escalation Pharmacokinetic Study of Intranasal Atomized Dexmedetomidine in Pediatric Patients With Congenital Heart Disease. Anesthesia and analgesia. Jan 1 2023;136(1):152-162. doi:10.1213/ane.0000000000005988
2. Miller JW, Balyan R, Dong M, et al. Does intranasal dexmedetomidine provide adequate plasma concentrations for sedation in children: a pharmacokinetic study. British journal of anaesthesia. May 2018;120(5):1056-1065. doi:10.1016/j.bja.2018.01.035
3. Su F, Gastonguay MR, Nicolson SC, DiLiberto M, Ocampo-Pelland A, Zuppa AF. Dexmedetomidine Pharmacology in Neonates and Infants After Open Heart Surgery. Anesthesia and analgesia. May 2016;122(5):1556-66. doi:10.1213/ane.0000000000000869
4. Su F, Nicolson SC, Gastonguay MR, et al. Population pharmacokinetics of dexmedetomidine in infants after open heart surgery. Anesthesia and analgesia. May 1 2010;110(5):1383-92. doi:10.1213/ANE.0b013e3181d783c8
5. Su F, Nicolson SC, Zuppa AF. A dose-response study of dexmedetomidine administered as the primary sedative in infants following open heart surgery. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. Jun 2013;14(5):499-507. doi:10.1097/PCC.0b013e31828a8800