Contribution of midazolam and its 1-hydroxy metabolite to preoperative sedation in children: a pharmacokinetic-pharmacodynamic analysis

Johnson, Trevor N.; Rostami‐Hodjegan, Amin; Goddard, J.M.; Tanner, M S; Tucker, Geoffrey T.

doi:10.1093/bja/89.3.428

Cited by 64 publications

(27 citation statements)

References 44 publications

(33 reference statements)

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“…There are PKPD relationships described for short‐term intravenous midazolam in adults, using an EEG signal as an effect measure (31–33). These relationships are more difficult to describe after midazolam infusion administration over longer term in intensive care because the 1‐hydroxy metabolite has approximately half the activity of the parent drug (34).…”

Section: Discussionmentioning

confidence: 99%

A maturation model for midazolam clearance

Anderson

Larsson

2011

Pediatric Anesthesia

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Previously published pharmacokinetic parameters can be used to develop maturation models that address gaps in current knowledge regarding the influence of age on a drug's disposition. If a midazolam sedation target concentration of 0.1 mg·l(-1) , similar to that given to adults, is assumed, then we might anticipate steady-state infusion rates of 0.014 mg·kg(-1) ·h(-1) in neonates, 0.05 mg·kg(-1) ·h(-1) in a 1-year-old, 0.06 mg·kg(-1) ·h(-1) in a 5-year-old and 0.05 mg·kg(-1) ·h(-1) in a 12-year-old child. Age-related pharmacodynamic differences that will affect dose and the impact of active metabolites on response are not yet quantified.

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Section: Discussionmentioning

confidence: 99%

A maturation model for midazolam clearance

Anderson

Larsson

2011

Pediatric Anesthesia

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“…Although LC-UV has been used for decades for the above purpose, these methodologies typically represent relatively poor sensitivity and low throughput, with a reported sensitivity of 1.0-100 ng/mL, sample size of up to 2.0 mL, and analysis cycle time of up to 18 min (Blackett et al, 1988;Carrillo et al, 1998;El Mahjoub and Staub, 2000;Ha et al, 1993;Johnson et al, 2002;Lee and Charles, 1996;Odou et al, 1997;Mastey et al, 1994;Portier et al, 1999;Puglisi et al, 1985;Sautou et al, 1991;ter Horst et al, 2003;van Brandt et al, 1997;Vletter et al, 1990;Yasui-Furukori et al, 2004). GC-MS methods appear to be more sensitive than HPLC-UV with a reported LLOQ of 20 pg/ mL for both midazolam and 1′-hydroxymidazolam when 1 mL of human plasma was used.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous determination of midazolam and 1′‐hydroxymidazolam in human plasma by liquid chromatography with tandem mass spectrometry

Li¹,

Luo²,

Smith³

et al. 2007

Biomedical Chromatography

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A sensitive and simple liquid chromatography-tandem mass spectrometry method for the determination of midazolam and 1'-hydroxymidazolam in human plasma has been developed and validated with a dynamic range of 0.1-250 ng/mL. The analysis was based on semi-automated liquid-liquid extraction followed by evaporation of the extraction solvent, reconstitution and chromatography on a reversed-phase C(18) column. The mobile phase consists of 5 mm ammonium acetate and methanol and runs in gradient at a flow rate of 0.25 mL/min with column temperature of approximately 20 degrees C. The entire column effluent was transferred into the LC-MS/MS interface operated in positive electrospray ionization mode. The chromatographic run time was 4.3 min per injection, with retention times for midazolam, 1'-hydroxymidazolaml and the internal standard, triazolam, of 2.5, 2.3 and 2.1 min, respectively. The intra-day and inter-day precision (RSD %) and accuracy (bias %) of the quality control samples were <15.0% and within +/-13%, respectively. The current method has been applied to a clinical drug-drug interaction study in human.

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“…Pre- and post-operative blood samples in previously cannulated children (median age 5 years) receiving a general anaesthetic were taken and compared with the preoperative sedation score (1 = awake; 2 = drowsy/asleep). It was known that children have an increased weight-normalised clearance of midazolam (via CYP3A4) 8. These data showed that, despite a significant contribution to preoperative sedation by an active metabolite of midazolam (1-hydroxy-midazolam), a dose increase of up to 50% may be necessary to avoid therapeutic failure 8…”

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confidence: 98%