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Mivacurium arteriovenous gradient during steady state infusion in anesthetized patients
Samia Ezzine1, François Donati, France Varin
1Faculté de Pharmacie, Université de Montréal, Québec, Canada.
Background:
Mivacurium and isomers undergo rapid hydrolysis by plasma cholinesterase. As this enzyme is largely distributed, it cannot be excluded that these isomers might undergo peripheral elimination. This hypothesis was investigated in patients by measuring the difference between arterial and venous concentrations under a constant-rate continuous infusion of mivacurium.
Methods:
During propofol-remifentanil anesthesia, eight adult consenting patients received an intravenous bolus dose of 0.2 mg/kg mivacurium, followed by a constant infusion (3, 5, or 7 microg. kg. min ) into the brachial vein. One hour after starting the infusion, arterial (radial artery) and venous (contralateral brachial vein) blood samples were drawn simultaneously at 15-min intervals for 45 min. Mivacurium isomers and metabolite plasma concentrations were determined by stereospecific high-performance liquid chromatography. Using the corresponding arterial and venous concentrations, the tissue extraction coefficient as well as total body clearance were calculated.
Results:
During steady state conditions, the venous concentrations of the and isomers were 34 +/- 13% and 42 +/- 11% (mean +/- SD) lower than the corresponding arterial concentrations (P < 0.05), respectively. For the isomer, the difference between venous and arterial concentrations was 3 +/- 4% (P = 0.063). Total body clearances of the and isomers were greater when based on venous sampling (P < 0.05).
Conclusion:
Pharmacokinetic parameters derived from a constant infusion of mivacurium depend heavily on the sampling site (arterial or venous) for the rapidly hydrolyzed isomers. These results strongly suggest a significant metabolism of mivacurium within muscle tissue that may account for the large interpatient variability in response to mivacurium.
Insights
Mivacurium isomers are rapidly metabolized in muscle tissue, not just plasma. This peripheral elimination significantly impacts pharmacokinetic calculations, explaining patient response variability.
Area of Science:
- Pharmacology
- Drug Metabolism
- Clinical Anesthesia
Background:
- Mivacurium and its isomers are rapidly hydrolyzed by plasma cholinesterase.
- Peripheral elimination of mivacurium isomers was hypothesized due to widespread enzyme distribution.
Purpose of the Study:
- To investigate peripheral elimination of mivacurium isomers.
- To determine if muscle tissue contributes to mivacurium metabolism.
Main Methods:
- Eight adult patients received mivacurium infusion during propofol-remifentanil anesthesia.
- Arterial and venous blood samples were collected to measure isomer concentrations.
- Stereospecific HPLC was used to quantify mivacurium isomers and metabolites.
Main Results:
- Venous concentrations of mivacurium isomers were significantly lower than arterial concentrations (34-42%).
- Total body clearance calculations varied significantly based on arterial versus venous sampling.
- A trend towards lower extraction was observed for one isomer.
Conclusions:
- Pharmacokinetic parameters for mivacurium are highly dependent on blood sampling site (arterial vs. venous).
- Significant metabolism of mivacurium occurs within muscle tissue.
- Peripheral metabolism may explain interpatient variability in mivacurium response.