PLASMA CONCENTRATIONS OF ALPHAXALONE DURING CONTINUOUS INFUSION OF ALTHESIN

Transcription

1 Br.J. Anaesth. (1979), 51, 861 PLASMA CONCENTRATIONS OF ALPHAXALONE DURING CONTINUOUS INFUSION OF ALTHESIN J. W. SEAR AND C. PRYS-ROBERTS SUMMARY Plasma concentrations of alphaxalone have been measured during various rates of continuous infusion of Althesin used to supplement nitrous oxide-oxygen anaesthesia in man. There was an approximately linear relationship between the plasma concentration of alphaxalone and the rate of infusion of Althesin. The rate of uptake of alphaxalone into the liver did not appear to be impaired in the presence of the steroid myoneural blocking agent pancuronium, or in patients with hepatic cirrhosis. The use of a continuous i.v. infusion of Althesin for the maintenance of anaesthesia was described first by du Cailar (1972) and developed further by Savege and his colleagues (1975). The advantages of i.v. anaesthesia using Althesin are rapid awakening on cessation of the infusion, minimal cardiovascular depression and the elimination of the need for volatile anaesthetic gases. Several authors have described the clinical features of continuous Althesin anaesthesia. Although a gas-liquid chromatographic method (GLC) for the measurement of the plasma concentration of alphaxalone was described by Child and colleagues (1972) and used by Dubois, Allison and Geddes (1975) to measure the plasma concentrations of alphaxalone after a single dose of Althesin, there have been no reports of the pharmacokinetics of continuous infusions of Althesin. We describe a study in which the alphaxalone concentrations in human plasma have been measured during various rates of continuous Althesin anaesthesia. METHODS Patients and anaesthetic management The plasma concentrations of alphaxalone were measured during the continuous infusion of Althesin as a supplement to nitrous oxide-oxygen anaesthesia in 28 patients. Twenty-two patients without evidence of liver disease and six patients with cirrhosis of the liver were studied. The latter group of patients was undergoing surgery for the relief of portal hyperten- J. W. SEAR, B.SC, M.B., D.R.C.O.G., F.F.A.R.C.S.; C. PRYS- ROBERTS, M.A., D.M., PH.D., F.F.A.R.C.S.; Department of Anaesthetics, University of Bristol, Royal Infirmary, Bristol. Correspondence to J. W. S /79/ sion. Some of the patients were also being studied independently to determine the cardiovascular effects of the infusions of Althesin. All patients were premedicated with papaveretum mg i.m. 1 h before operation. Consent was obtained from every patient, after each had received an explanation of the nature of study. Anaesthesia was induced with fentanyl 8 fxg kg" 1 and Althesin (6-24 mg total steroid). The trachea was intubated following neuromuscular blockade with either pancuronium 0.1 mg kg" 1 or alcuronium 0.25 mg kg" 1, and the patients were ventilated artificially through a circle system without a soda-lime absorber, the fresh gasflowbeing adjusted to maintain Pa C02 within the range kpa. Of the 22 normal patients, 12 received alcuronium and 10 received pancuronium. All of the patients with cirrhosis of the liver received pancuronium. Anaesthesia was maintained with nitrous oxide 66% in oxygen, supplemented by Althesin administered as an infusion of 2.4 mg ml" 1 total steroid in Compound Sodium Lactate solution. The infusion rates of Althesin in this and the subsequent paper (Sear and Prys-Roberts, 1979) were multiples of a minimum rate of infusion (MIR) determined in a separate pilot study (Prys-Roberts, unpublished data) in 15 patients. These patients, like those in the present study, had been premedicated with papaveretum mg, and were breathing spontaneously a mixture of nitrous oxide 66% in oxygen during inguinal herniorrhaphy. The minimum rate of infusion of Althesin in these patients which would just suppress movement in response to surgical stimulus ranged between 15 and 20 (ig min" 1 kg" 1 as the total steroid. In the present studies we used a nominal minimum infusion rate of Althesin of 18 [xg min" 1 kg" 1 (table Macmillan Journals Ltd 1979

2 862 BRITISH JOURNAL OF ANAESTHESIA II), which represents an infusion rate for alphaxalone of 13.5 y.g min" 1 kg" 1. The infusion was established at this nominal rate for a period of min to obtain a steady-state plasma concentration. Each patient had an arterial cannula in place to monitor the arterial pressure throughout surgery, thus all blood samples were withdrawn from this source. A sample of arterial blood was withdrawn to determine the plasma alphaxalone concentration at this nominal infusion rate. Incremental increases in the rate of the Althesin infusion were made during the period of surgery and further blood samples withdrawn at min intervals after each step change in the rate of infusion. By sampling blood at 5-min intervals after a step change of the infusion rate, we have determined that a steady concentration of alphaxalone in the plasma is achieved after 20 min. The plasma was separated within 2 h of collection of the samples, and stored at 20 C until assayed for the alphaxalone concentration. Assay of plasma alphaxalone concentration The concentration of alphaxalone in plasma was measured by a GLC assay. It is possible also to measure alphadolone by GLC, but the sensitivity of the method is less than that for alphaxalone. Trimethyl silyl esters were formed using a modification of the method of Chambaz and Horning (1967). To 1 ml of plasma, a known amount of internal standard, (3-alphaxalone (3(3-hydroxy,-5a-pregn-16- ene-11, 20 dione), was added, with 0.5 ml of 2.5% w/v NaOH. Ten millilitre of freshly distilled diethyl ether was used to extract the drug by manually shaking the test tube for 30 s. The ethereal layer was taken and evaporated to dryness. Reference standards of alphaxalone were obtained by adding known amounts of drug to blank plasma and extracting as for the plasma samples. The silylation reagent consisted of N,0 bis-trimethylsilyl acetamide, pyridine and trichloromethylsilane (100 vol : 20 vol : 1 vol). Twenty microlitre of this mixture was added to the dried extracts and incubated for 15 min at 50 C. Samples were injected on to a Perkin Elmer Fll gas chromatograph containing a column of 3% OV 17, and using a flame ionization detector. The oven temperature was 250 C, injection temperature 260 C and detector temperature 300 C. Nitrogen 45 ml min" 1 was used as the carrier gas. For each patient, a blood sample obtained before anaesthesia was assayed in a similar manner, as a small interference peak with retention characteristics identical to those of alphaxalone has been observed in the plasma of some patients. Using a 1-ml sample of plasma, a linear relationship between the alphaxalone concentration and flame ionization detector response has been found over the clinical range 100 ng ml" 1 to 10 \Lg ml" 1. Repeated analysis of separate samples gave a mean coefficient of variance of 7.87%. The chemical nature of the measured peak, namely trimethylsilyl alphaxalone, has been confirmed using gas chromatograph : mass spectroscopy (GC : MS). No chromatographic interference has been seen from any other of the anaesthetic drugs used. RESULTS In every patient, there was an approximately linear relationship between the alphaxalone concentration in the plasma and the rate of infusion of alphaxalone. Linear regression analysis was used to determine the regression equation for each patient between the plasma concentration of alphaxalone and the infusion rate of alphaxalone (r>0.9; P<0.01). Table I shows the values for the mean slope of the regression equation between the plasma concentration of alphaxalone and the rate of infusion of alphaxalone for the 22 normal patients and six patients with cirrhosis of the liver. There was no statistical difference between the slopes of the mean regression lines for the 12 patients who received alcuronium and the 10 who received pancuronium. The patients with cirrhotic liver disease showed a similar relationship between the plasma concentration of alphaxalone and the rate of infusion of alphaxalone, although the mean value for the slope of the regression line was significantly less than that in normal subjects (t = 3.579; P< 0.002). TABLE I. Slope of regression equation (mean + SEM) of plasma concentration of alphaxalone against rate of infusion of Althesin {fig. 1). 'Difference between patients receiving alcuronium and patients receiving pancuronium: not significant; ^difference between all 22 normal patients and six patients with cirrhosis of the liver: t = 3.579; P< Patients Normal (n = 22) 12 receiving alcuronium 10 receiving pancuronium With cirrhosis of liver («= 6) Slope of regression equation ± ± \, / ±0.002f

3 CONCENTRATIONS OF ALPHAXALONE 863 Because of small variations in the infusion rates of Althesin within the patients studied, we have grouped plasma concentrations of alphaxalone in relation to infusion rates of alphaxalone close to the multiples of the nominal infusion rate. The results are shown in table II, in which it can be seen that a fivefold increase in the rate of infusion causes the plasma concentration of alphaxalone to be approximately doubled. TABLE II. Plasma concentration of alphaxalone at varying rates of infusion of Althesin {mean ± SEM) Rate of infusion (ng min" 1 per kg) Althesin ±3.2 Alphaxalone Plasma concn of alphaxalone (ng ml- 1 ) Figure 1 shows the values for the 22 normal patients of the mean plasma alphaxalone concentration at various rates of infusion of alphaxalone, and the individual values of plasma concentration of alphaxalone in the six patients with cirrhosis of the liver. The plasma concentration of alphaxalone for a given infusion rate was lower in the patients with cirrhosis of the liver than in the group of patients with normal liver function. DISCUSSION In man, it is believed that there is a rapid uptake of the constituents of Althesin, alphaxalone and alphadolone, from the blood into the liver, and perhaps muscle and kidney. In the liver, alphaxalone is probably metabolized by microsomal enzymes, and then conjugated to a glucuronide which is excreted in the bile. Strunin and co-workers (1977) studied the pharmacokinetics of alphaxalone in the blood following the injection of a single dose (10-20 (xci) of 14 C-labelled alphaxalone. In both healthy patients and those with obstructive bile duct disease, Strunin and colleagues were able to show a triphasic decay pattern of the plasma radioactivity. Fifty-nine per cent of the radioactivity appeared in the urine within 24 h in the healthy patient. In the patients with obstructive biliary disease, only 38% appeared in the urine within the same time. This suggests that the water-soluble glucuronide conjugates of alphaxalone or its metabolites are reabsorbed in the small intestine and excreted in the urine. Gas chromatography may be coupled with mass spectroscopy to detect specific mass fragments. Using this technique, alphadolone, unchanged alphaxalone and its reduced metabolite, 3a,20 di hydroxy 5apregnane, have been detected in the urine of both normal patients and those with cirrhotic liver disease (H. Makin and J. Sear, unpublished data) RATE OF INFUSION OF ALTHESIN ( pg min' 1 per kg bodyweight) FIG. 1. Mean ( + SEM) plasma alphaxalone concentrations at various rates of infusion of Althesin in 22 normal patients, and the individual values of the plasma concentration of alphaxalone in six patients with cirrhosis of the liver. 90

4 864 BRITISH JOURNAL OF ANAESTHESIA The slope of the regression equation between the plasma concentration of alphaxalone and the infusion rate of alphaxalone may be taken as an index of drug uptake into the liver. From our results, there appears to be linear uptake over the range of rates of infusion studied. There is no evidence of any decreased uptake of alphaxalone in the patients with cirrhotic liver disease; indeed our results would suggest that alphaxalone uptake may be enhanced in cirrhosis. In the group of patients with cirrhotic liver disease, there was a lower plasma concentration of alphaxalone for a given rate of infusion of alphaxalone when compared with the control values. This may be explained in several ways. In cirrhosis of the liver, there is usually an accompanying hepatosplenomegaly until end-stage cirrhosis is reached. Thus, the volume of distribution of any drug within the hepatic circulation is enlarged, with an increase in drug sequestration. This leads to an effective increase in the rate of clearance of the drug by the liver. Similarly, there may be abnormalities of the hepatosplenic vasculature, such as arterio-venous shunts. These also may facilitate drug clearance. The role of the plasma proteins in drug binding may affect the amount of free drug in the blood. Alphaxalone has been shown to bind with high affinity to albumen and p-lipoproteins (Jones, 1972). Although the former are decreased usually in cirrhotic liver disease, the (3-lipoproteins may increase in biliary cirrhosis, so increasing the amount of bound alphaxalone. A similar high affinity binding of alphaxalone has been demonstrated for the IgG immunoglobulins. These immunoglobulins exist both intravascularly and in the extracellular fluid. Both of these protein pools increase in cirrhosis of the liver, and the latter may act as a ready source for drug binding and sequestration. The data presented here would suggest that a reduction in the dose of Althesin in chronic liver disease may not be necessary, in view of the apparent ability of the liver to clear the drug adequately. In each of the six patients, there was no prolongation of recovery time compared with the normal group. This is in contrast to the experience of du Cailar (1972), who observed a prolonged recovery of up to 2 h in two patients with hepatic failure. An impairment of radiolabelled alphaxalone clearance from the plasma has been seen also by Ward, Adu-Gyamfi and Strunin (1975) in a patient in acute hepatic failure. Pancuronium is a quaternary ammonium-substituted steroid with non-depolarizing neuromuscular blocking properties. The uptake of many steroids into tissues depends on their combination with a specific cellular receptor molecule. The data presented here may indicate that there is no competition between pancuronium and alphaxalone for the same tissue uptake mechanism. The alternative hypothesis is that there is an adequate reserve receptor capacity within these tissues. If pancuronium was to- inhibit the uptake of alphaxalone, it would be seen as an increase in the slope of the regression line between the plasma alphaxalone concentration and the infusion rate of alphaxalone. This has not been observed in our patients. ACKNOWLEDGEMENTS Glaxo-Allenburys Research Ltd kindly supplied the continuously variable-speed Harvard Infusion Pump. We are grateful to Mr R. N. Baird, M.CH., F.R.C.S., for the opportunity to study patients under his care. Dr J. Sear is in receipt of a Research Training Fellowship from the Medical Research Council. REFERENCES du Cailar, J. (1972). The effects in man of infusions of Althesin with particular regard to the cardiovascular system. Postgrad. Med. J., 48, (Suppl. 2), 72. Chambaz, E. M., and Horning, E. C. (1967). Steroid trimethyl silyl esters. Anal. Lett., 1, 301. Child, K. J., Gibson, W., Harnby, G., and Hart, J. W. (1972). Metabolism and excretion of Althesin (CT 1341) in the rat. Postgrad. Med. J., 48, (Suppl. 2), 37. Dubois, M., Allison, J., and Geddes, I. C. (1975). The determination of alphaxalone in human blood by gasliquid chromatography. Br. J. Anaesth., 47, 902. Jones, B. C. (1972). The protein binding of alphaxalone. Postgrad. Med. J., 48, (Suppl. 2), 47. Savege, T. M., Ramsay, M. A. E., Curran, J. P. J., Cotter, J., Walling, P. T., and Simpson, B. R. (1975). Intravenous anaesthesia by infusion. A technique using alphaxalone/ alphadolone (Althesin). Anaesthesia, 30, 757. Sear, J. W., and Prys-Roberts, C. (1979). Dose-related haemodynamic effects of continuous infusions of Althesin in man. Br. J. Anaesth., 51, 867. Strunin, L., Strunin, J. M., Knights, K. M., and Ward, M. E. (1977). Metabolism of 14 C-labelled alphaxalone in man. Br. J. Anaesth., 49, 609. Ward, M. E., Adu-Gyamfi, Y., and Strunin, L. (1975). Althesin and pancuronium in chronic liver disease. Br.J. Anaesth., 47, CONCENTRATIONS D'ALPHAXALONE DANS LE PLASMA PENDANT UNE INFUSION CONTINUE D'ALTHESINE RESUME On a mesure les concentrations d'alphaxalone dans le plasma pendant l'infusion continue d'althesine, a differents debits, utilisee pour completer chez 1'homme l'anesthesie induite a l'aide d'oxygene-protoxyde d'azote. II y a eu une relation a peu pres lineaire entre la concentration d'alphaxalone dans le plasma et le taux d'infusion de l'alth -

5 CONCENTRATIONS OF ALPHAXALONE 865 sine. Le taux de fixation de l'alphaxalone dans le foie n'a pas semble etre gene en presence du pancuronium, agent de blocage steroide myoneuralj ou chez les malades souffrant d'une cirrhose du foie. ALPHAXALONKONZENTRATIONEN IM BLUTPLASMA WAHREND UNUNTERBROCHENER ALTHESININFUSION ZUSAMMENFASSUNG Es wurden die Alphaxalonkonzentrationen im Blutplasma bei verschiedenen Raten ununterbrochener Althesininfusion, zur Erganzung der Lachgas/Sauerstoffharkose im Menschen eingesetzt, gemessen. Zwischen der Alphaxalonkonzentration im Blutplasma und der Althesininfusionsrate bestand ein annahernd lineares Verhaltnis. Die Aufnahmegeschwindigkeit von Alphaxalon in die Leber schien in der Gegenwart des neuromuskularen Blockierungssteroiden Pankuronium oder bei Patienten mit Leberzirrhose nicht beeintrachtigt zu sein. CONCENTRACIONES DE ALFAXALONA EN EL PLASMA DURANTE INFUSION CONTINUA DE ALTESINA SUMARIO Se midieron las concentraciones de alfaxalona en el plasma durante varios ritmos de infusion continua de Altesina, utilizada para suplir la anestesia oxigeno-oxido nitroso en el hombre. Existia una relation aproximadamente lineal entre la concentration de alfaxalona en el plasma y el ritmo de infusi6n de Altesina. El ritmo de captation de alfaxalona dentro del higado no parecio ser trastomado en presencia del pancuronio, agente bloqueador mioneural esteroide, ni tampoco en pacientes con cirrosis hepatica.