Pharmacokinetics and haemodynamic effects of prolonged methohexitone infusion

Br. J. clin. Pharmac. (1988), 26, 589-594 Pharmacokinetics and haemodynamic effects of prolonged methohexitone infusion Y. LE NORMAND', C. de VLLEPOX1, M. PNAUD2, J. M. BERNARD2, J. P. FRABOUL2, A. ATHOUEL', M. RBEYROL3, N. BENEROSO3 & C. LAROUSSE' 'Department of Pharmacology, Faculty of Medicine, 44035 Nantes Cedex, France, 2Department of Anesthesiology and ntensive Care, H6tel-Dieu, CHU, 44035 Nantes Cedex, France, 3Department of Clinical Pharmacology, H6tel-Dieu, CHU, 44035 Nantes Cedex, France 1 The use of continuous infusion anaesthesia has only been of interest since the development of short-acting, less cumulative and less toxic drugs. 2 This study aimed to compare pharmacokinetics and haemodynamic effects during and after long time methohexitone constant rate infusion. Sixteen patients were given either 60 or 90 p,g kg-' min-1 methohexitone during 14 h. Blood samples were taken hourly during this time and 12 h following the end of infusion. 3 nfusion period was analysed by a single exponential model; post-infusion time showed a three compartment model, the intermediate phase parameters corresponding to those of the infusion period. 4 Methohexitone was haemodynamically well tolerated; prolonged infusion decreases oxygen consumption, mainly by a decrease in oxygen demand. 5 Many patients remained unconscious for unacceptably long periods of time after postoperative sedation by methohexitone. Keywords methohexitone infusion pharmacokinetics haemodynamics ntroduction Most patients in an intensive care unit (CU) require sedation at some time. Short acting anaesthetic agents alphaxolone-alphadolone, etomidate and thiopentone are unsuitable for continuous intravenous infusion because of their side effects (high incidence of allergic reactions for the former, suppression of cortisol production in adrenal cortex for the second and cumulative properties for the latter). Methohexitone might be a suitable replacement for these agents for sedating patients receiving intensive care, because this drug demonstrated great potency, an ultra-short action time and a rapid recovery. This barbiturate is considered to be safe and effective but some EEG modifications and convulsive seizures have been reported (Gumpert et al., 1969; Rockoff et al., 1981; Metriyakool, 1981). While the pharmacokinetics of a single bolus V injection is now well known (Hudson et al., 1983; Sear, 1983), only few data are available for conditions of continuous infusion (Breimer, 1976). The haemodynamic consequences of highdose methohexitone infusion (400,ug kg-' min-') have been related to plasma concentrations (Todd et al., 1984) but only over 1 h. Doserelated haemodynamic effects of infusions (60 and 120,ug kg-' min-') lasting up to 4.4 h were also documented (Prys-Robert et al., 1983), but without measurements of plasma concentration. We have used methohexitone in this way to provide sedation for patients who required artificial ventilation in the postoperative period. Correspondence: Dr Yves Le Normand, Department of Pharmacology, Faculty of Medicine, 1 rue Gaston Veil, F-44035 Nantes Cedex, France. 589

590 Y. Le Normand et al. The aims of our post-operative investigation were to determine for two different infusion rates: 1. the pharmacokinetics of methohexitone a) during a constant rate infusion lasting 14 h and b) during the 12 h post-infusion period. 2. the relationship between methohexitone plasma concentration and haemodynamics from starting infusion to steady-state plasma concentration. Methods Patients After approval by the local Human Studies Committee, informed consent was obtained from sixteen patients suffering from systemic disease with definite functional limitations (ASA in the classification of the American Society of Anesthesiologists). Following benzodiazepinefentanyl anaesthesia for major thoracic, abdominal or orthopaedic surgery, patients were transferred before recovery to intensive care units. Patients were assigned randomly to receive continuous infusion of methohexitone: 60 (group ) or 90 jig kg-' min-' (group ) during 14 h via the venous infusion port of a Swan Ganz catheter. Mean age was 67 years (range 50-85) in group and 64 years (51-77) in group. Mean body weights were respectively 69.4 ± 15.9 kg (50-100) and 67.5 ± 11.4 kg (52-85). None of the patients had renal or hepatic dysfunction or enzyme inductor treatment. Study design Controlled ventilation with air and 02 was adjusted to maintain Paco2 between 28 and 35 mm Hg, and to ensure adequate oxygenation. The levels of sedation were assessed with the scale defined by Ramsay et al. (1974), level 1 to 6. Heart rate was monitored by a V5 ECG lead. An indwelling teflon cannula was inserted into a radial artery for systolic (SAP) and diastolic (DAP) blood pressure measurement. A 7.5-F triple lumen thermodilution catheter was inserted via the right internal jugular vein to measure the right atrial pressure (RAP), systolic (SPAP) and diastolic (DPAP) pulmonary arterial pressures, pulmonary capillary wedge pressure (PCWP) and cardiac output (CO) (iced injectate in triplicate). HR and pressures were recorded simultaneously on a polygraph (Mingograph 803 Siemens Elema). Po2, Pco2, ph, (ABL 30 Acid-base analyzer, Radiometer), haemoglobin concentration and haemoglobin saturation (OSM2 Hemoximeter, Radiometer) were measured in arterial blood and in mixed venous blood. Derived values : mean arterial pressure (MAP), cardiac index (C), stroke index (S), systemic vascular resistance index (SVR), pulmonary vascular resistance index (PVR), oxygen content, oxygen consumption index (VO21) and oxygen extraction ratio (EOR) were computed according to standard formulae. Temperature of blood in the pulmonary artery was monitored by the thermistance of the Swan Ganz catheter. Arterial blood samples for haemodynamic data and methohexitone plasma concentration were collected before infusion (when the PCWP was in the range 6-9 mm Hg by intravascular volume expansion and blood temperature reached at least 36 G), each hour during infusion (h 1 to h 14), and each hour after the end of infusion (h 15 to h 26). After immediate centrifugation of blood samples, plasma was separated and stored at 18 C until analysed. Blood gas analysis was performed before infusion and at h6, h12, h14, h20 and h26 after the beginning of infusion. Methohexitone assay Methohexitone concentration was measured by a g.l.c. method using single-step extraction with internal standard (mephobarbitone) and capillary column with nitrogen-specific detection : to 1 ml plasma were added 1 ml distilled water and 10 ml chloroform containing internal standard (mephobarbitone, 10,ug). After 30 s vortexing and centrifugation (4000 g, 10 min), the organic layer was evaporated to dryness under nitrogen at 40 C. The final residue was reconstituted without derivatization in 100,ul chloroform, and aliquots of 1-3,ul were then deposited on the glass needle of the solid injector. A Delsi 300 gas-chromatograph equipped with a fused-silica quartz capillary column (OV-1 WCOT: 20 m x 0.3 mm i.d, 0.20 pum film thickness, Spiral) was used. The carrier gas was helium (column flow-rate : 2 ml min-'), and a make-up of helium provided a constant flow of 30 ml min-' throughout the detector. Oven was heated isothermally at 200 C, injection port and detector temperatures were respectively 270 and 250 C. Nitrogen-specific detection was obtained with a rubidium-type thermoionic detector (Delsi). Calibration was run by extraction of spiked plasma on each analysis day. Linearity was excellent in the range of 0.125-50 p.g ml-' (r = 0.998) and the limit of sensitivity was 6 ng ml-' in plasma. The absence of interference of drugs or endogenous compounds was checked for all

patients by extracting a blank plasma sample collected before the beginning of methohexitone infusion. Calculation Pharmacokinetics parameters were calculated with G-PHARM computer program using a nonlinear regression model. Monoexponential (infusion period) and triexponential (postinfusion period) equations were fit to the total serum concentration versus time data for all subjects. The area under the plasma concentration curve (AUC tot) was calculated by the trapezoidal rule. Extrapolation to infinity was not valid during infusion period. Plasma clearance was then calculated using the formula: Dose CL = AUC tot Statistical analysis was performed using a two way ANOVA and non paired t-test with Bonferroni corrections. Pharmacokinetics ofprolonged methohexitone infusion 591 Results Clinical effects All patients in group and only two patients in group were at the level 6 of sedation (no response to a light glabellar tap or auditory stimulus) at the end of methohexitone infusion; in group, two were at the level 5 (a sluggish response with the patient asleep and two at the level 4 (a brisk response with the patient asleep). Time taken for recovery was in the range of 4-24 h in the group and 2-9 h in group. No seizures were noted during the period of drug administration and after complete recovery. Pharmacokinetics Pharmacokinetic parameters are shown in Table 1. AUC was determined between 0-14 h during infusion and between 0-12 h after. Clearance and volume of distribution were calculated with availability assumed as complete. During the post-infusion period, plasma concentration vs time kinetics were represented by a triexponential Table 1 Pharmacokinetic data (mean s.d.): intragroup comparison between infusion and post-infusion periods, and intergroup comparison During infusion Postinfusion ntergroup group group ANOVA P values nfusion rate (p.g kg-' min-') 60 90 Cmax (p.g ml-') 7.86 ± 2.83 10.70 ± 2.74 - - < 0.05 AUC tot (p.g ml-' min) 4.52 ± 1.77 6.23 ± 1.63 1.30 ± 0.32** 1.72 ± 0.60** < 0.05 t,,, (min) - _ 30.0 ± 22.3 27.3 ± 13.7 NS t,, 2 (min) 144 41 144 44 142 ± 59 NS 159 ± 95 NS NS t½,z (min) 460 ± 257 412 ± 160 NS Vl (1 kg-') - - 0.44 ± 0.33 0.42 ± 0.26 NS V (1 kg-') 1.88 0.74 1.88 0.40 5.27 ± 1.63** 5.14 ± 2.02** NS VS (1 kg-1) 1.90 0.76 1.91 +0.41 4.51 ± 1.47** 4.69 ± 1.92** NS CL (ml min-' kg-') 9.33 ± 4.05 9.42 ± 2.49 9.58 ± 4.32 NS 9.76 ± 3.21 NS NS MRT (min - - 549 ± 322 522 ± 213 NS ** P < 0.005 model (Figure 1); during infusion, zero order input kinetics did not allow this type of analysis. For this reason, the two periods were analysed separately. Haemodynamics Some haemodynamic data are shown in Table 2. Haemodynamic profiles were significantly different during infusion period. n both groups, methohexitone infusion decreased significantly in the same manner C(a-v)o2 and Vo2 without changes in the haemodynamic values (Table 3). Discussion Post-infusion period is represented by a three exponential model, the first phase showing a fast distribution throughout the body. Brand et al. (1963) described this rapid decrease during the first thirty minutes with high dosages, with an equivalent half-life (30 min). With lower dosages, Breimer (1976) and Hudson et al. (1983) observed shorter half-lives (6.3 and 5.6 min, respectively). During infusion, zero order infusion rate masks this short distribution phase. n our study, half-life of elimination phase is

592 Y. Le Normand et al. L E -i.c 0 2 6 1f 14 18 22 26 Figure 1 Mean ± s.e. mean plasma methohexitone concentrations in group 1 (U) and group 2 (e) Table 2 Haemodynamic data (mean ± s.e. mean): intragroup comparison vs control and intergroup comparison (group vs group ) Heart rate (beats min-') MAP (mm Hg) C (1 min-' m-2) S (ml beats-' m-2) RAP (mm Hg) PCWP (mm Hg) SRV (U m-2) 89 ± 6 81 ±7 107 ± 8 97 ± 5 Control h 6h 14h 2.99 ± 0.31 3.16 ± 0.33 36 ± 5 40 ± 3 4.2 ± 0.7 4.2 ± 1.1 6.9 ± 0.8 7.5 ± 1.0 36.2 ± 3.5 30.1 ± 2.1 90±5 84± 6 91 ± 4 84 ± 8 97±8 89±5 106±7 95±5 3.07 ± 0.37 2.69 ± 0.30 3.24 ± 0.21 3.26 ± 0.24 35±4 32±2 36±2 41±4 4.1 ± 0.7 2.5 ± 1.1 5.5 ± 0.9 3.6 ± 0.7 6.2 ± 0.7 4.2 ± 0.9 6.6 ± 0.7 5.1 ± 0.7 85 ± 3 83 ± 5 106 ± 5 90 ± 6 2.95 ± 0.24 3.06 ± 0.27 35 ± 3 38 ± 3 4.2 ± 0.6 2.6 ± 0.8 6.7 ± 0.8 4.2 ± 1.0 33.0 ± 4.0 31.8 ± 2.3 36.5 ± 2.9 33.2 ± 2.8 28.6 ± 2.4 29.1 ± 3.2 ntergroup ANOVA P values < 0.01 < 0.001 <0.05 NS < 0.01 <0.001 <0.05 identical for both dosages and periods. n other studies, shorter half-lives have been observed in normal subjects (Breimer (1976): 97 min) in a shorter protocol, or with i.v. injection in minor surgery patients (Hudson et al. (1983): 58.3 min). n our experiment, blood sampling lasted up to 720 min after the end of infusion; a slow elimination phase was then observed as reported by Hudson et al. (1983) and by Breimer (1976) for some patients. This slower elimination phase may be a result of elimination by metabolism, or sequestration by fat or combination of these two processes. We analysed plasma concentrations for a sufficient period to conclude that, during long time infusion, the drug uptake by the poorly perfused tissues play a role in methohexitone elimination and can explain this long terminal half-life. As low concentrations are observed during this last phase, this phenomenon does not seem to have any clinical implication.

Pharmacokinetics ofprolonged methohexitone infusion 593 Table 3 Metabolic data (mean ± s.e. mean): intragroup comparison vs control (** P < 0.001) and intergroup comparison vs group ). ntergroup Control 1 h 6 h 14 h ANOVA P values C(a-v) 02 (ml 02 dl-) 5.12 ± 1.25 6.09 ± 1.15 4.25 ± 0.52 4.30 ± 0.99 3.29 ± 0.90** 3.82 ± 0.86** 4.04 ± 0.82** 3.27 ± 0.92** NS Vo2 (mlo2min-m-2) 146 ± 17 179 ± 54 135 ± 15 129 ± 30 94 ± 20** + 20** 116 ± 12** 92 ± 22** NS EOR (%) 24.3 ± 2.1 27.6 ± 2.8 23.7 ± 1.8 25.0 ± 1.2 21.3 ± 1.6 24.1 ± 1.9 23.5 ± 1.4 23.2 ± 1.6 NS Clearance was similar for both rates and periods. Clearance values are in the same range that those qublished by Breimer (1976): 12.4 ml kg-1 min-, and Hudson et al. (1983): 10.9 ml kg-1 min-1. Sear (1983) reviewed that clearance in healthy volunteers is higher than in patients. This most important clearance value indicates a greater metabolism of the drug by the liver in healthy subjects. This parameter is therefore sensitive to hepatic extraction and the lower value in surgical patients may be attributed to the effects of surgery and anaesthesia on cardiac output and liver blood flow. nitial volume of dilution is similar to those published by Breimer (1976): 0.29 1 kg-', and Hudson and colleagues (1983): 0.35 1 kg-'). V,, after infusion is greater than during infusion (Table 1) and than those generally observed in other studies (Breimer (1976): 1.13 1 kg-', Hudson et al. (1983): 2.2 1 kg-1). After the end of infusion, the long sampling time has shown a slow elimination phase for all of our subjects and this last phase increases Vss values. n patients undergoing surgery, volume of distribution may be altered by a decrease in protein binding, either by drug interaction or pathological processes. This may be another reason for our higher value of Vs, compared to Breimer (1976) whose study was performed in healthy volunteers. Moreover both our dosages were higher than dosage used by Breimer (1976) in the same route of administration (3.6 and 5.4 mg kg-1 h-1 vs 2.76 mg kg-' h-1. Since an attempt was made to increase PCWP in the range 6 to 9 mm Hg by infusing fluids prior to methohexitone infusion and since drug levels during infusion changed slowly compared with a bolus injection, cardiovascular function was stable in contrast to previous haemodynamic studies. But some differences in the haemodynamic course appeared between the two groups. t is not surprising that the highest dosage of methohexitone resulted in lower preload and afterload. However the combination of more profound venous pooling and reduced arterial impedance allowed a maintained comparable stroke index. Fluid loading must be emphasized to avoid a deleterious effect on stroke index and cardiac index. This haemodynamic response gives no suggestion of impairment characteristic of drugs that depress ventilation performance. n this study, we showed that methohexitone infusion can decrease oxygen consumption. t is critical to know whether this decrease is related to a decrease in oxygen demand or in oxygen delivery. The oxygen extraction ratio is an index of efficiency of the circulation, with normal values around 25%. n our patients, the oxygen extraction ratio remained stable during methohexitone infusion. This suggests that the decrease in oxygen consumption was mainly caused by decreased oxygen demand rather than by inadequate oxygen delivery. Unfortunately, methohexitone is not an ideal agent for prolonged sedation in an CU because many of these patients remained unconscious for unacceptably long periods of time with impossibility to assess the mental state. References Brand, L., Mark, L. C., Snell, M. McM., Vrindten, P. & Dayton, P. G. (1963). Physiologic disposition of methohexital in man. Anesthesiology, 24, 331-335. Breimer, D. D. (1976). Pharmacokinetics of methohexitone following intravenous infusion in humans. Br. J. Anaesth., 48, 643-649. Gumpert, J., Hansotrje, P., Paul, R. & Lipton, A. (1969). Methohexitone and the EEG. Lancet, ii, 110. Hudson, R. J., Stanski, D. R. & Burch, P. G. (1983). Pharmacokinetics of methohexital and thiopental in surgical patients. Anesthesiology, 59, 215-219. Metriyakool, K. (1981). Seizures induced by methohexital. Anesthesiology, 55, 718.

594 Y. Le Normand et al. Prys-Robert, C., Sear, J. W., Low, J. M., Phillips, K. C. & Dagnino, J. (1983). Hemodynamic and hepatic effect of methohexital infusion during nitrous oxide anesthesia in humans. Anesth. Analg. 62, 317-323. Ramsay, M. A. E., Savege, T. M., Simpson, B. R. J. & Goodwin, R. (1974). Controlled sedation with alphadolone-alphadolone. Br. med. J., 2, 656-659. Rockoff, M. A. & Goudzouzian, N. G. (1981). Seizures induced by methohexital. Anesthesiology, 54, 333-335. Sear, J. W. (1983). General kinetic and dynamic principles and their application to continuous infusion anaesthesia. Anaesthesia, 38, 10-25. Todd, M. M., Drummond, J. C. & Hoi Sang, U. (1984). The hemodynamic consequences of highdose methohexital anesthesia in humans. Anesthesiology, 61, 495-501. (Received 1 December 1987, accepted 14 June 1988)