D. P. Crankshaw

Concentrations of Desflurane and Propofol That Suppress Response to Command in Humans

The anesthetic concentration just suppressing appropriate response to command (minimum alveolar anesthetic concentration awake [MAC-awake] for volatile anesthetics or plasma concentration to prevent a response in 50% of patients [Cp50]-awake for intravenous anesthetics) provides three important measures. First, along with pharmacokinetics, the ratio of the awakening concentration to the anesthetizing concentration (MAC-awake/MAC or Cp50-awake/Cp50) determines time to awakening. Second, a correlation between MAC-awake and the anesthetic concentration sufficient to prevent learning suggests MAC-awake provides a surrogate measure of amnestic potency. Third, population values for MAC-awake provide evidence for or against commonality in anesthetic mechanisms. We studied 22 male volunteers twice to determine both MAC-awake for desflurane (2.60% +/- 0.46%) and Cp50-awake for propofol (2.69 +/- 0.56 micro gram/mL). Awakening with desflurane occurs at a concentration closer to its anesthetizing concentration (36% of MAC) than propofol (18% of Cp50); that is, 1) desflurane requires less of a decrement in anesthetic concentration at the effect site for arousal; and 2) if MAC-awake (Cp50-awake) values reflect the concentrations providing amnesia, propofol is a more potent amnestic. Of interest, the dose response curves of desflurane and propofol were equivalently steep, a finding consistent with a common mechanism of action. In contrast, sensitivity of each volunteer to desflurane did not correlate with sensitivity to propofol (r (2) < 0.01, P = 0.98) arguing against a common mechanism. (Anesth Analg 1995;81:737-43)

Plasma Drug Efflux-A New Approach to Optimization of Drug Infusion for Constant Blood Concentration of Thiopental and Methohexital

Plasma Drug Efflux is a time-varying measure of the rate of loss of drug from the plasma during conditions of constant plasma concentration. Its practical use is to define the parameters required for a programmed infusion to maintain a desired plasma concentration. The method of deriving the Efflux function, which does not depend on conventional pharmacokinetic models, was developed and tested using thiopental and methohexital in a total of 51 unselected surgical patients free of hepatic or renal disease. Throughout a predetermined, known, but arbitrary computer-controlled drug infusion, the rate of which was modified according to patient lean body mass (LBM) and the desired concentration, blood samples were taken and the plasma assayed for either drug by an HPLC method. By dividing the known variable infusion rate at the time of each sampling by the arterial plasma concentration at each time, an estimate of the rate of loss of drug from the plasma at each point, the Plasma Drug Efflux, was obtained. An error correcting iterative process was used with successive groups of patients until the optimum infusion profile was achieved. Only three iteration steps were required to optimize the infusion profile for each drug. The optimized infusion profile for thiopental was 25.35e−.145t + 4.85e−.0148t + 8.8 ml · min−.t · kgLBM−1, and, for methohexital, 22.21e−092t + 5.09e−.0121t + 15 ml · min−1 · kgLBM−1. It was concluded that the process of optimization under clinical conditions resulted in infusion profiles suitable for establishing and maintaining a designated arterial plasma concentration in adult surgical patients for periods up to 3 h.

Pharmacokinetics of thiopental and pentobarbital enantiomers after intravenous administration of racemic thiopental.

We studied the pharmacokinetics of thiopental enantiomers in 14 healthy patients aged 37-73 yr receiving racemic thiopental by intravenous (IV) bolus or IV infusion. Plasma concentration of each enantiomer was measured by chiral high-performance liquid chromatography. After IV bolus, the total plasma clearance (CL) (295 +/- 132 mL/min) and volume of distribution at steady state (Vss) (139 +/- 38.5 L) of R-thiopental were significantly greater than those of S-thiopental (230 +/- 104 mL/min and 114 +/- 47.5 L, respectively). The plasma unbound fraction (fu) was determined by ultrafiltration of plasma from six healthy volunteers. The fu of R-thiopental (12.4% +/- 0.6%) was significantly greater than that of S-thiopental (10.0% +/- 1.0%). When the CL and Vss of the two enantiomers were corrected for the difference in mean fu, there were no significant differences between enantiomers for these variables. As the 20%-30% difference between the enantiomers in total CL and total Vss could be accounted for by stereoselectivity in fu, these differences are not likely to be clinically significant. During 105-180 min IV infusion of racemic thiopental to the other patients, there was no difference between enantiomers in mean plasma concentrations of total or unbound thiopental or total pentobarbital, a major metabolite of thiopental (P > 0.05). Therefore, it is appropriate to relate pharmacodynamic effects to racemic plasma concentrations of thiopental during IV infusion of racemic thiopental. (Anesth Analg 1996;83:552-8)

The effects of cardiopulmonary bypass on plasma concentrations and protein binding of methohexital and thiopental

The effects of cardiopulmonary bypass (CPB) on plasma concentrations and protein binding of methohexital and thiopental were studied during continuous infusions in two groups of ten cardiac surgical patients. Patients were administered an infusion regimen designed to produce a stable total plasma concentration at 5 mg/L for methohexital and 10 mg/L for thiopental. Prior to the commencement of CPB the mean (+/-SD) total plasma methohexital concentration was 5.00 +/- 0.69 mg/L. This fell to 3.12 +/- 0.89 mg/L at two minutes after commencement of CPB, and rose to 4.67 +/- 1.11 mg/L by 75 minutes after commencement of CPB. The unbound fraction rose from 27.1 +/- 5.1% to 42.8 +/- 9.2% at five minutes after the start of CPB, and gradually decreased to 32.1 +/- 4.9% by 75 minutes. The unbound concentration (1.37 +/- 0.32 mg/L) was unaffected by the onset of CPB, being 1.51 +/- 0.49 mg/L at 75 minutes after the start of CPB. Thiopental followed a similar pattern to methohexital, with the total plasma thiopental concentration falling from 9.22 +/- 0.73 mg/L to 4.90 +/- 0.83 mg/L at two minutes after commencement of CPB, and rising again to 7.13 +/- 1.03 mg/L 75 minutes later. During the same period the unbound fraction of thiopental rose from 16.1 +/- 2.5% to 30.3 +/- 7.3% five minutes after the start of CPB, and fell gradually to 22.8 +/- 5.8% after 75 minutes. The unbound concentration (1.51 +/- 0.21 mg/L) was again unchanged by the onset of CPB, being 1.71 +/- 0.29 mg/L at 75 minutes. Plasma protein binding of both drugs correlated strongly with plasma albumin concentration, which decreased by 40% during CPB. It is concluded that hemodilution caused the reduction in total drug concentration and protein binding at the onset of CPB, but that the decrease in protein binding counteracted the dilution of unbound drug, resulting in a stable unbound concentration throughout CPB, and that this effect may be common for barbiturates.

Preprogrammed infusion of alfentanil to constant arterial plasma concentration

A variable rate infusion regimen, designed to rapidly achieve and maintain a target arterial concentration (CT) of 100 μg·L−1 of alfentanil, was developed using the method of Plasma Drug Efflux. This method uses a series of clearance values (Ep), calculated as the ratio of instantaneous infusion rate/arterial plasma drug concentration normalized to lean body mass (LBM), at various sampling times during a suboptimal infusion regimen. Values of Ep are used to calculate an infusion rate versus time profile to achieve CT, and the process is repeated in consecutive small groups of subjects to yield an optimal result, i.e., it is an iterative process. Thirty-three adult surgical patients were given alfentanil during anesthesia for approximately 1 h before cardiopulmonary bypass. In an initial group of four patients, who received a simple two-stage infusion, plasma alfentanil concentration was measured at frequent intervals and Ep(L·min−1·kg LBM−1) was estimated at each sampling time. The calculated infusion rate-versus-time profile to produce CT was obtained from the product Ep × CT for each time point and was transferred to the read-only memory of a computerized infusion pump. This new variable infusion profile was used in four patients, and the process was repeated in three further groups of 5, 8, and 12 patients using in fusion profiles calculated from the previous group. Each set of concentration data was assessed by calculating the performance error (PE), the median performance error (MDPE), i.e., bias, and the median absolute value of PE (MDAPE), i.e., inaccuracy. In the first group, bias and inaccuracy were 17% and 33%, respectively, but the iterative process reduced these to 3% and 10%, respectively, in the fifth group. This compares very favorably with results achieved in previous studies using conventional compartmental model-based pharmacokinetic techniques. The efflux method makes no assumptions about a model, linearity of plasma concentration with dose, or time invariance. It uses data generated only during the infusion and is not subject to the uncertainties of curve fitting. We conclude that the efflux method, combined with dosing based on calculated lean body mass, can be used readily and reliably to develop optimum infusion regimens for alfentanil.

Effect of body build on the clearance of atracurium: implication for drug dosing.

&NA; To determine factors that influenced the clearance (Cl) of atracurium, 80 adult patients of varying body build were given an atracurium infusion according to a predetermined profile, which was scaled by lean body mass (LBM). Cl was estimated at 50‐60 min by the constant infusion rate required to maintain the steady‐state plasma concentrations. The efficacy of scaling the absolute Cl estimates by body build variables, in which the absolute Cl estimate is divided by the body build variable to achieve similar scaled estimates in all patients, was assessed by the bias and precision of the individual scaled Cl estimates to those in patients with a “normal” body build (23%‐27% body fat). The efficacy of scaling the dose of atracurium by differing body build variables to achieve similar plasma concentrations was also assessed by bias and precision, in which the plasma concentrations from an infusion scaled by other body build variables were generated by linear simulation. Body size, as quantified by LBM, total body mass (TBW), height, and body surface area, had a significant influence on Cl, with the effect best described by LBM (respective R2, 0.487, 0.368, 0.265, 0.445). No other factors could be identified, including blood pH, serum creatinine, and drugs given during the perioperative period. The efficacy of scaling Cl by TBW (absolute Cl estimate divided by patient TBW) to achieve similar estimates in all patients was poor; Cl. TBW estimates varied inversely with patient body fat content and resulted in obese patients having smaller estimates, a mean bias of ‐29%, compared with those in patients with a normal body build (P = 0.002). Scaling Cl by LBM seemed optimal; it had the best precision compared to the other methods of scaling (LBM versus TBW, height; P < 0.05) and Cl.LBM estimates had no relationship with patient body fat content. LBM also seemed optimal for dosing with the best precision (LBM versus TBW, height, body surface area; P < 0.05). Dosing by TBW underdosed lean patients and overdosed obese patients (P < 0.001). We conclude that body size and build are important determinants of the disposition of atracurium. Dosage of atracurium, particularly in patients at the extremes of body build, should be adjusted by LBM. (Anesth Analg 1993;76:1296‐303)

Stability of Methoxyflurane Loaded Penthrox Inhaler

Methoxyflurane (MEOF), a non‐narcotic inhalational anaesthetic, administered with the Penthrox Inhaler is effective in managing acute pain. Despite widespread use by ambulance services, its use in emergency departments and hospital wards has been limited. MEOF storage to minimise evaporation would facilitate pre‐filling inhalers for multiple treatment use.