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October 26, 2015
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Performance of Pharmacokinetic Models for Propofol in Early Phase of Target-Controlled Infusion
Kenichi Masui, M.D., Sayaka Ishigaki, M.D., Isao Yajima, Pharm.D, Tomiei Kazama, M.D.
National Defense Medical College, Saitama, Japan
Disclosures: K. Masui: None. S. Ishigaki: None. I. Yajima: None. T. Kazama: None.
Background: Target-controlled infusion (TCI) is applied to maintain a constant concentration of a drug based on the concept of vaporizer using a pharmacokinetic model. Although a compartmental pharmacokinetic model is generally used for TCI, the compartmental model assumes that an administered drug is instantaneously mixed in the central compartment. Therefore, the applied pharmacokinetic models may have a limitation in the early phase of TCI. The aim of the study was to investigate the performance of pharmacokinetic models for propofol, developed by Marsh1 or Schnider2, in the early phase of TCI.

Patients and Methods: After the institutional ethics committee approval and public registry, twenty patients were recruited with written informed consent. Exclusion criteria included older than 80 years old, body mass index >30, neurologic disorder, recent use of psychoactive medicine, and significant heart, hepatic, or renal impairment.

An 18- or 20-gauge catheter was inserted into a forearm vein. Acetate Ringer’s solution 10 ml/kg was infused before the start of TCI. All patients were receiving TCI of propofol using either of the Marsh or Schnider pharmacokinetic model. Rugloop II® (Demed Medical BVBA, Belgium) and Pump 22 (Harvard Apparatus, MA) was applied for TCI. Propofol was administered for 30 minutes using TCI at fixed targeted plasma concentration determined using the equation, 1.67•(2.9 − 0.022•age).[sup]3[/sup] Then, the infusion of propofol was terminated. For the propofol administration, a prefilled syringe of propofol and a three-way stopcock were connected with a small bore extension tube. The three-way stopcock was directly connected to the intravenous catheter. Acetate Ringer’s solution was infused simultaneously at 300 ml/h through the same intravenous catheter during the study period.

Arterial blood sample was taken from the radial artery every 10 s for 2 minutes, 140, 160, 180, 210 s, 4, 5, 7, 10, 15, 20, 25, 30, 30.5, 31, 31.5, 32, 33, 35, 37, 40, 45, 50, 60 minutes after the start of TCI. These blood samples were centrifuged within hours of collection. The plasma was transferred to polyethylene tube and kept at −30°C until assayed. Arterial plasma concentrations (Cp) of propofol were determined by high-performance liquid chromatography.

Predictive performance was assessed using prediction error (PE), calculated as (measured Cp - predicted Cp)/predicted Cp, derivatives, median prediction error (MDPE) and divergence PE. The MDPE was calculated for the first 5 minutes (MDPE0−5), from 5 to 30 minutes (MDPE5−30), from 30 to 35 minutes (MDPE30−35), and from 35 to 60 minutes (MDPE35−60). The divergence PE during 5 to 30 minutes was calculated as the slope of the linear regression of PE against time. Data was expressed as median [interquartile range] The MDPEs between the groups were compared using the Mann-Whitney test. The median of divergence PE was compared to zero using the Wilcoxon signed-rank test. P <0.05 was regarded as significant.

Results: The MDPE0−5, MDPE5−30, MDPE30−35, and MDPE35−60 were −11.7% [−22.5 to 0.9], −26.9% [−35.3 to −15.2], −49.2% [−55.5 to −42.9], and −59.5% [−62.5 to −54.0] for the Marsh model vs. −46.5% [−53.5 to −37.8] (P <0.001), −33.8% [−40.5 to −29.1] (P =0.046), −27.4% [−36.1 to −13.7] (P <0.001), −29.3% [−42.8 to −23.5] (P <0.001) for the Schnider model. The divergence PE was −17.8%/h [−23.0 to −1.8] for the Marsh model (P =0.001) or 7.7%/h [0.5 to 20.0] for the Schnider model (P =0.083).

Conclusions: Examined pharmacokinetic models overestimated the propofol Cp in 30-min TCI and subsequent 30-min after the stop of infusion except the first 5-min of plasma TCI using the Marsh model. In the Marsh model, the PE decreased from 5 to 30 minutes after the start of TCI.


1. BJA 1991;67:41-8, 2. Anesthesiology 1998;88:1170-82, 3. Anesthesiology 1999;90:1502-16.

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