Clinical Pharmacology of Midazolam in Neonates and Children: Effect of Disease—A Review

Table 1

Demographic data of patients and pharmacokinetic parameters of midazolam in neonates and children.

Comments	GA (weeks)	PNA (days)	BW (g)	Dose of midazolam	Number of infants	𝑡1/2 (hours)	Cl (mL/kg/min)	Vd (L/kg)	Reference
Healthy neonates
Intravenous administration	26 to 34	3 to 11	na	100 µg/kg Bolus IV	24	6.3^a	1.8^a	1.1^a	[26]
Critically ill neonates and children
Oral administration, the values are corrected for 𝐹=49%	26 to 31	3 to 13	1,076 ± 240	100 µg/kg; Bolus PO	15	7.6^b	2.7^b	1.4^b	[6]
Note A	2 days 17 years	—	3.8 to 24.5 (kg)	90 µg/kg/h; Infusion	21	na	0.14^a L/kg/h (diseased); 0.28^a L/kg/h (healthy) 𝑃=0.0350	na	[27]
Infants required mechanical ventilation. Some drugs were administered	33 ± 3.3	1 to 5	1,900 ± 700	Infusion; 60 µg/kg/h	15	12 ± 0.6	1.7 ± 1.8	1.2 ± 0.6	[28]
Respiratory distress syndrome (𝑛=5) and neonatal infection (𝑛=5)	37 ± 2.3	2 to 5	3,150 ± 520	200 µg/kg; Bolus; IV	10	6.5 ± 2.3	2.0 ± 1.2	0.9 ± 0.3	[29]
Neonates undergoing “extracorporeal membrane oxygenation” (ECMO)
Note B	39.5 ± 1.9	3.8^a	3,400 ± 600	50 to 250 µg/kg/h Infusion	10	6.8^a Initial	1.4^a Initial	3.1^a; (L); Initial	[30]
	39.5 ± 1.9	3.8^a	3,400 ± 600	50 to 250 µg/kg/h Infusion	10	33.3^a Terminal	4.1  Terminal	14.2^a; (L); Terminal
Median ECMO duration was 70 to 275 hours	40.4^a	0.79^a	3,000^a	200 µg/kg; Bolus; IV	20	1.8^a  Initial	2.6^a Initial	1.4^a; Initial	[31]
𝑡1/2 from the onset to steady-state was prolonged 5-fold	40.4^a	0.79^a	3,000^a	200 µg/kg; Bolus; IV	20	na	7.6^a Terminal	4.9^a; Terminal
Population pharmacokinetics of midazolam in neonates and children
Note D	26 to 42	0 to 9	700 to 5,200	Note C	187	9.9^a	1.2 ± 0.2	1.0 ± 0.2	[32]
Note E	24 to 31	2 to 15	523 to 1,400	100 µg/kg; Bolus; IV	60	14.1^a	0.938^a	1.15^a	[33]
Age ranged from 2 days to 17 years	—	—	3.5 to 60	50 to 400 µg/kg/h Infusion	18	5.5 ± 3.5	5.0 ± 3.9	1.7 ± 1.1	[34]
Adult subjects
Adults	—	—	—	—	—	1.9 ± 0.6	6.6 ± 1.8	1.1 ± 0.6	[5]

Figures are the mean ± SD unless otherwise stated. In some cases, results are given as a range. F: oral bioavailability which is 49% [6]; ^amean, standard deviation is not available; ^bmedian; GA: gestational age; PNA: postnatal age; BW: body weight; 𝑡_1/2: β-phase elimination; Cl: clearance; Vd: apparent volume of distribution; na: not available; IV: intravenously; PO: by mouth; Note A: neonates were suffering from congenital heart disease (𝑛=4), upper airway infection (𝑛=4), pneumonia (𝑛=2), postcardiac surgery (𝑛=2), pulmonary hypertension (𝑛=2), and other (𝑛=7); Note B: midazolam was administered via a central or peripheral venous catheter; Note C: midazolam was administered intravenously as a continuous infusion to 109 infants, as a bolus dose to 22 infants, and as a combination of both to 56 infants. The bolus dose was 210 ± 239 µg/kg. The continuous infusion was 69 ± 63 µg/kg per h; Note D: all neonates received midazolam during artificial ventilation; Note E: neonates undergoing mechanical ventilation had a body weight <1,500 g.