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. 2021 Apr 1;22(4):e259-e269.
doi: 10.1097/PCC.0000000000002580.

Sedation With Midazolam After Cardiac Surgery in Children With and Without Down Syndrome: A Pharmacokinetic-Pharmacodynamic Study

Abraham J Valkenburg  1   2 , Sebastiaan C Goulooze  3 , Cormac V Breatnach  4 , Ron A A Mathôt  5 , Dick Tibboel  2 , Monique van Dijk  2   6 , Catherijne A J Knibbe  3   7 , Mariska Y M Peeters  7
Affiliations

Sedation With Midazolam After Cardiac Surgery in Children With and Without Down Syndrome: A Pharmacokinetic-Pharmacodynamic Study

Abraham J Valkenburg et al. Pediatr Crit Care Med. .

Abstract

Objectives: To compare the pharmacokinetics and pharmacodynamics of IV midazolam after cardiac surgery between children with and without Down syndrome.

Design: Prospective, single-center observational trial.

Setting: PICU in a university-affiliated pediatric teaching hospital.

Patients: Twenty-one children with Down syndrome and 17 without, 3-36 months, scheduled for cardiac surgery with cardiopulmonary bypass.

Interventions: Postoperatively, nurses regularly assessed the children's pain and discomfort with the validated COMFORT-Behavioral scale and Numeric Rating Scale for pain. A loading dose of morphine (100 µg/kg) was administered after coming off bypass; thereafter, morphine infusion was commenced at 40 µg/kg/hr. Midazolam was started if COMFORT-Behavioral scale score of greater than 16 and Numeric Rating Scale score of less than 4 (suggestive of undersedation). Plasma midazolam and metabolite concentrations were measured for population pharmacokinetic- and pharmacodynamic analysis using nonlinear mixed effects modeling (NONMEM) (Version VI; GloboMax LLC, Hanover, MD) software.

Measurements and main results: Twenty-six children (72%) required midazolam postoperatively (15 with Down syndrome and 11 without; p = 1.00). Neither the cumulative midazolam dose (p = 0.61) nor the time elapsed before additional sedation was initiated (p = 0.71), statistically significantly differed between children with and without Down syndrome. Population pharmacokinetic and pharmacodynamics analysis revealed no statistically significant differences between the children with and without Down syndrome. Bodyweight was a significant covariate for the clearance of 1-OH-midazolam to 1-OH-glucuronide (p = 0.003). Pharmacodynamic analysis revealed a marginal effect of the midazolam concentration on the COMFORT-Behavioral score.

Conclusions: The majority of children with and without Down syndrome required additional sedation after cardiac surgery. This pharmacokinetic and pharmacodynamic analysis does not provide evidence for different dosing of midazolam in children with Down syndrome after cardiac surgery.

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Conflict of interest statement

Drs. Valkenburg’s and Peeters’s institutions received funding from National Children’s Research Centre, Dublin, Ireland. The remaining authors have disclosed that they do not have any potential conflicts of interest.

References

    1. Down JL. On Some of the Mental Affections of Childhood and Youth: Being the Lettsomian Lectures Delivered Before the Medical Society of London in 1887. London, United Kingdom: J. & A. Churchill, 1887
    1. Terada Y, Tachibana K, Takeuchi M, et al. [Comparison of sedative and analgesic requirements in children with and without down syndrome following pediatric cardiac surgery]. Masui. 2016; 65:56–61
    1. Gakhal B, Scott CS, MacNab AJ. Comparison of morphine requirements for sedation in Down’s syndrome and non-Down’s patients following paediatric cardiac surgery. Paediatr Anaesth. 1998; 8:229–233
    1. Valkenburg AJ, Calvier EA, van Dijk M, et al. Pharmacodynamics and pharmacokinetics of morphine after cardiac surgery in children with and without down syndrome. Pediatr Crit Care Med. 2016; 17:930–938
    1. Goot BH, Kaufman J, Pan Z, et al. Morphine pharmacokinetics in children with down syndrome following cardiac surgery. Pediatr Crit Care Med. 2018; 19:459–467

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