British Journal of Anaesthesia 1990; 65: 177-183

PHARMACOKINETICS OF PROPOFOL INFUSIONS IN PATIENTS WITH CIRRHOSIS F. SERVIN, I. D. COCKSHOTT, R. FARINOTTI, J. P. HABERER, C. WINCKLER AND J. M. DESMONTS

We have compared the pharmacokinetics of propofol as an infusion in 10 control and 10 patients with cirrhosis. Anaesthesia was induced within 3-4 min during administration of an infusion of propofol 21 mg kg'1 h~1. After 5 min, the infusion was decreased in a stepwise manner to 12 mg kg'1 h~1 and subsequently 6 mg kg'1 h'1. The mean recovery time after discontinuation of the infusion was significantly longer in the cirrhotic group; however, when patients opened their eyes, blood concentrations of propofol were similar in both groups (1 fxg ml'1). Pharmacokinetic analysis was performed from the beginning of infusion to 8 h after termination. Total body clearance was not reduced significantly in cirrhotic (1.56 (SD 0.48) litre min-1) compared with control (1.75 (0.32) litre min-1) patients. The volume of distribution at steady state was significantly greater in patients with cirrhosis than in control patients (202 (82) litre vs 121 (49) litre). However, this difference did not change terminal elimination half-life. The pharmacokinetics of propofol given by infusion to maintain general anaesthesia were not affected markedly by moderate cirrhosis.

[1]. The disposition of propofol was similar after single bolus injection and infusion for maintenance of anaesthesia. Propofol is cleared from the body primarily by metabolism [2], but no significant differences in disposition were observed after single bolus administration to patients with cirrhosis and control patients [3]. However, this finding cannot be extrapolated confidently to infusions, as propofol concentrations were only transiently within the range required to maintain anaesthesia. The aim of this study was to compare the pharmacokinetics of propofol administered as an infusion for maintenance of anaesthesia in control patients and others with cirrhosis. PATIENTS AND METHODS

The pharmacokinetics of propofol in 10 patients with cirrhosis aged 37-64 yr (mean 53.5 (SD 8.8) yr) and weighing 51-80 kg (64.7 (9.0) kg) were compared with those for patients with normal renal and hepatic function (24-56 yr (mean 41.9 (SD 11.7) yr) and 50-96 kg (65.6 (14.9) kg)). All patients were undergoing elective surgical procedures and gave informed consent. For all cirrhotic patients, cirrhosis had been established

KEY WORDS Anaesthetics, intravenous, propofol. Anaesthetic techniques. intravenous infusion. Liver: cirrhosis. Pharmacokinetics: propofol.

Propofol is used to maintain anaesthesia by continuous infusion. Although distributed extensively into tissues, the drug is known to be cleared rapidly and linear pharmacokinetics have been observed with infusion to healthy patients

F. SERVIN,

M.D., J. M. DESMONTS,

M.D.

(Departement

d'Anesthesie ct de Reanimation Chirurgicale); R. FARINOTTI, PH.D. (Service de Toxicologie); Hopital Bichat, 46, rue HenriHuchard, 75878 Paris. J. P. HABHRER, M.D., Departement d'Anesthesie et de Reanimation Chirurgicale, Hopitaux de Brabois, Alice du Morvan, 54511 Vandoeouvre Cedex. C. WiNaciiR, M.D., Departement d'Anesthesie et de Reanimation Chirurgicale, Hopital Charles Nicolle, 1, rue de Germont, 76031 Rouen Cedex, France. I. D. COCKSHOTT, B.SC., PH.D., ICI Pharmaceuticals Division, Mereside Alderley Park, Macclesfield Cheshire SK10 4TG. Accepted for Publication: January 17, 1990.

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SUMMARY

178

BRITISH JOURNAL OF ANAESTHESIA

TABLE I. Characteristics and liver function tests of patients with cirrhosis. SGPT = Serum glutamic pyruvic transaminase (normal value < 30 iu ml'1). Normal values: * < 20 fimol litre'1; \ < 180 iu ml'1

Patient No. 1 2 3 4 5

Serum alkaline phosphatasef (iu ml-1)

Surgical procedure

Age

(yr)

Sex

Hip replacement Wound dehiscence Colectomy Laparotomy Peritonco-jugular shunt Splenorenal shunt Portocaval shunt Portocaval shunt Portocaval shunt Portocaval shunt

64 62 55 58 60

M F M M F

B B B A A

34 29 29 48 34

13 20 35 25 23

170 20 28 14 39

100 81 61 100 75

235 122 210 66 91

57 42 37 48 52

M F

A B B A A

43 32 29 29 27

39 21 41 139 78

3 21 23 21 26

78 66 67 78 64

108 197 286 104 84

F M M

by liver biopsy; all these subjects had suffered previously from clinical decompensation. None of the patients with cirrhosis had ascites or encephalopathy at the time of the study and none had ingested alcohol for at least 2 weeks before the study. The degree of liver dysfunction, as estimated from liver function tests, was moderate and compatible (group A or B according to Child's classification) with elective surgery (table I). All patients were premedicated orally with diazepam 10 mg and atropine 1 mg l h before anaesthesia. An i.v. cannula was placed in a large forearm vein for injection of propofol. Following infiltration with lignocaine, a cannula was inserted in an artery in the contralateral arm for monitoring arterial pressure and collection of blood samples for pharmacokinetic analysis. Anaesthesia was induced and maintained using a stepwise infusion regimen of propofol 21 mg kg"1 h"1 for 5 min, 12 mg kg"1 h"1 for 10 min and 6 mg kg"1 h"1 for the rest of the procedure, which lasted for a minimum of 2 h. When the patient lost consciousness, muscle relaxation was produced with vecuronium 0.1 mg kg"1 and the trachea was intubated. Small incremental doses of fentanyl (50 ug) were given i.v. as required throughout the procedure. The patient's lungs were ventilated to normocapnia with a mixture of 66 % nitrous oxide in oxygen. At the end of the procedure, the propofol infusion and nitrous oxide administration were stopped simultaneously. The time from the beginning of infusion to the loss of consciousness, time to opening eyes on verbal command after stopping the infusion, the duration of the infusion and the total amount of propofol infused were recorded.

For pharmacokinetic analysis, 5-ml arterial blood samples were collected before infusion of propofol and at 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 15, 20, 25, 30, 40, 50, 60, 75, 90, 105 and 120 min thereafter. For infusions continuing beyond 120 min, additional samples were obtained every 15 min. A sample was taken as the infusion was stopped, and further samples were collected 2, 4, 6, 8, 10, 20, 40, 60, 90, 120, 180, 240, 300, 360, 420 and 480 min after the end of the infusion. An additional sample was drawn when the patient opened the eyes to verbal command. After thorough mixing, the samples were cooled immediately to 4 °C and stored at that temperature until subsequent analysis. "Whole blood concentrations of propofol were measured by high pressure liquid chromatography [4]. Two- and three-exponential models of the following form, derived from Colburn [5], were fitted to the data using the extended least squares curve-fitting program Elsfit version 3.1 [6]: c, = 3.5* £ c ( *(l-e-^* T ')*e- v< '- B) + 2.0* f]c(*(l-e-x

Pharmacokinetics of propofol infusions in patients with cirrhosis.

We have compared the pharmacokinetics of propofol as an infusion in 10 control and 10 patients with cirrhosis. Anaesthesia was induced within 3-4 min ...
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