- Email: [email protected]
PHARMACOKINETICS AND PHARMACODYNAMICS OF VERCURONUIUM IN PATIENTS WITH CHOLESTASIS
Br. J. Anaesth. (1986), 58, 983-987
PHARMACOKINETICS AND PHARMACODYNAMICS OF VECURONIUM IN PATIENTS WITH CHOLESTASIS C. LEBRAULT, P. DUVALDESTIN, D. HENZEL, M. CHAUVIN AND P. GUESNON
CLAUDE LEBRAULT, MJJ.; PHILIPPE DUVALDESTOJ, M.D.; MARCEL CHAUVIN, M JJ. ; PATRICK GUESNON.M.D. ; Departement
d'Anesthesie, Hdpital Ambroise Pare, University Paris 5, 92104 Boulogne BOlancourt Cedex, France. DANIELS HENZBL, M.D., Departemem d'Anesthesie, Hdpital Bichat, University Paris 7, 75018 Paris, France. Correspondence to C. L.
SUMMARY The pharmacokinetics and pharmacodynamics of vecuronium were studied in nine surgical patients with cholestasis, and in 14 patients without hepatic or renal disease. After the administration of vecuronium 0.2 mg kg-1 the plasma concentration of vecuronium and the degree of neuromuscular blockade were measured. The plasma clearance of vecuronium was decreased significantly (P < 0.01) from 4.30± 1.56mlmin-1 kg-1 (mean±SD) in normal patients to 2.36± 0.80 ml min-1 kg-1 in patients with cholestasis. The elimination half-life was of 58 ±22 min in normal patients and was prolonged to 98 ±57 min (P < 0.05) in patients with cholestasis. The total apparent volume of distribution was unchanged in patients with cholestasis. A prolonged neuromuscular blockade induced by vecuronium was observed in patients with cholestasis: the duration of effect from injection to 75% recovery of the twitch height was prolonged from 74 ± 19 min in normal patients to 111 ±13 min in patients with cholestasis. The plasma concentration corresponding to 50% recovery from paralysis did not differ significantly between the two groups. Vecuronium has a prolonged effect in patients with cholestasis which is caused by a delay in its elimination.
colleagues (1981). In the present study, we investigated the pharmacokinetics and the pharmacodynamics of vecuronium in patients with cholestasis undergoing biliary surgery. PATIENTS AND METHODS
Patients The pharmacokinetics and phannacodynamics of vecuronium were investigated in nine patients
Downloaded from http://bja.oxfordjournals.org/ at University of Glasgow on June 28, 2015
The short acting non-cumulative effect of vecuronium is explained by its high plasma clearance (Miller et al., 1984). However, its pathway of elimination in man is unclear, since the cumulative urinary and biliary excretion of vecuronium accounts for no more than 40 % of the dose after 24 h (Bencini et al., 1983). Unlike most other non-depolarizing neuromuscular blocking drugs which are predominantly eliminated in urine, vecuronium appears to be primarily eliminated by the liver. Several arguments plead in favour of a predominantly hepatic elimination: first, in the cat, the exclusion of the hepatic circulation potentiates the depth and the duration of vecuronium-induced neuromuscular blockade (Bencini, Houwertjes and Agoston, 1985); second, in several animal species the biliary excretion of vecuronium largely exceeds the urinary elimination (Upton et al., 1982; Bencini et al., 1985); third, in patients with cirrhosis a prolonged effect of vecuronium 0.2 mg kg"1 was observed which was explained by a decrease in the plasma clearance and an increase in the elimination half-life of vecuronium (Lebrault et al., 1985). Owing to its hepatic elimination, vecuronium will probably exert a prolonged effect in patients with cholestasis. It has been shown already (Somogyi, Shanks and Triggs, 1977) that the elimination half-life and the duration of the neuromuscular blockade of pancuronium were prolonged in patients with cholestasis. Three days after ligation of the common bile duct in rats, a three-fold increase in the duration of action of vecuronium was observed by Westra, Keulemans and
BRITISH JOURNAL OF ANAESTHESIA
984
Monitoring and analytical techniques
Before the induction of anaesthesia, a cannula was inserted to a fore-arm vein, and blood samples were collected before and at 5, 10, 15, 30, 45, 60, 75, 90, 120, 150, 180 and 210 min after the administration of vecuronium. The plasma concentration of vecuronium was measured using the Rose Bengale fluorimetric method for pancuronium assay (Kersten, Meijer and Agoston, 1973) with minor modifications which have been
described previously (Lebrault et al., 1985). This method is not specific and measures vecuronium and its metabolites. Data were fitted by both twoand three-compartment open pharmacokinetic models using a non-linear, least-squares regression. A two-compartment model was selected using the technique of Gomeni and Gomeni (1978). The following were calculated: the half-lives of distribution (Tf) and of elimination (7\P), the volume of the central compartment (F,), the total apparent volume of distribution measured in the steady state (Fb88) or according to the method of the area under the curve (FD P ) and the plasma clearance (C/)A Grass S-8 stimulator was used to administer supramaximal single stimuli of 0.2 ms duration at a rate of 0.1 pulse s"1 to the ulnar nerve at the wrist through thin wall electrodes. The evoked response of the adductor pollicis, that is the twitch height, was quantitated continuously using a Statham UC3 force transducer and recorded on a polygraph. Simultaneously with measurements of the plasma concentration, the degree of neuromuscular blockade was followed from onset to complete recovery. The concentration corresponding to 50 % paralysis (CP 60) during the recovery phase was determined in both groups. Statistical differences between the control group and the group of patients with cholestasis were analysed by the two-tailed non parametric Mann—Whitney U test.
RESULTS
The clinical characteristics of patients with cholestasis are shown in table I. Results of biochemical analyses are shown in table II. Most patients had almost complete biliary obstruction,
TABLE I. Clinical characteristics of the patients with cholestasis Duration nf
Patient
No. 1 2 3 4 5 6 7 8 9
Sex F M M M F F M F M
Age (yr)
Wt (kg)
81 65 50 72 49 69 44 73 70
50 45 64 74 60 60 70 59 65
UI
operation (h) 4 5 3 2.5 3 4.5 5 4 4
Surgical procedure Biliary-intestinal bypass (cholelithiasis) Biliary-intestinal bypass (cancer) Bile duct surgery (cholelithiasis) Bile duct surgery (cholelithiasis) Bile duct surgery (cholelithiasis) Cholecystectomy (cancer) Duodenopancreatectomy (cancer) Biliary-intestinal bypass (cancer) Biliary-intestinal bypass (cancer)
Downloaded from http://bja.oxfordjournals.org/ at University of Glasgow on June 28, 2015
with cholestasis who were between the ages 44 and 81 yr (64 ± 13, mean± SD) and weighed 45-74 kg (61 ±9), and in 14 patients without hepatic or renal dysfunction between the ages 21 and 68 yr (42±15) and weighing 57-107 kg (70±13). Informed consent was given by all the patients and the design of the study was approved by the Research Comittee of University Paris 5. Cholestasis was caused by extrahepatic biliary obstruction. All patients with cholestasis (table I) were scheduled for biliary surgery. Premedication consisted of diazepam 10 mg or lorazepam 2.5 mg given by mouth 90 min before the induction of anaesthesia with thiopentone 6-8 mg kg"1 i.v. A single bolus dose of vecuronium of 0.2 mg kg"1 was administered. General anaesthesia was maintained with 60 % nitrous oxide in oxygen delivered by mechanical ventilation plus incremental doses of fentanyl (total dose 0.25-1.5 mg) and thiopentone (total dose 350-750 mg). The duration of surgery exceeded the duration of the neuromuscular blockade induced by vecuronium in three patients with cholestasis and three controls. In these patients suxamethonium, the only neuromuscular blocker which does not interfere with the measurement of the plasma concentration of vecuronium, was given (total dose 50-500 mg).
VECURONIUM KINETICS IN CHOLESTASIS
985
TABLE II. LwtT function tests and serum creatinine concentrations in patients with cholestasis
Patient No.
92 82 100 91 100 100 79 95 69 >70
Serum bilirubin (nig Utre"')
Alkaline phosphatase (iu ml"')
45.1 136.9 157.9 67.3 118.8 40.4 169.1 175.5 204.2 < 10
123 286 170 46 276 118 76 98 258 > 13 <38
SGPT (iu ml-')
Serum creatinine (mg Utre-')
Total plasma protein (g Utre- 1 )
57 204 290 90 126 41 64 42 106 <20
10.2 6.2 9.0 11.3 7.9 17.0 8.2 10.2 10.7 < 12
63 46 77 75 78 80 71 75 79 >60 <72
Albumin plasma (g Utre-1) 32 28 51 36 41 40 36 34 29 >38 <53
TABLE III. Pharmacokinetic variables (mean values ± SD): serum half-lives of the distribution phase j and elimination phase (Ti^), initial volume of distribution (V,), total apparent volume of distribution at steady state ( V D " ) , total apparent volume of distribution measured by the method of the area under the curve (Vrr) and plasma clearance (CU). *P < 0.05; **P < 0.01, compared with normal patients
(nun) Normal patients 7.4±4.1 Patients with 11.8±8.0 cholestasis
(nun)
V, (litre kg"1)
Vrt* (Utre kg"1)
Vrf (Utre kg"1)
58±22 0.107±0.042 0.247±0.107 0.349±0.168 98±57* 0.094±0.037 0.206±0.099 0.289±0.111
Cl (ml min"1 kg"1) 4.30±1.56 2.36±0.80**
TABLE IV. Pharmacodynamic variables (mean values ± SD) established after the administration ofvecwonium 0.2 mg kg~'. CptQ is the plasma concentration ofvecwonium corresponding to 50% of recovery. *P < 0.05; **P < 0.01, compared with normal patients
Time (min) to recovery of the twitch height (TH)to: 25%
Normal patients Patients with cholestasis
53±13 80±16*
50%
62±16 88±19*
with the exception of two in whom the bilirubin concentrations were only moderately increased at the time of surgery. No patient had severe liver failure since the plasma prothrombin values were normal in all; only one patient (No. 8) was treated before operation with vitamin K. The plasma creatinine concentrations were within their normal values in all patients. The plasma clearance of vecuronium was decreased significantly (P < 0.01) in patients with cholestasis to (mean±SD) 2.36 ±0.80 ml min- 1 kg"1 compared with 4.30 ± 1.56 ml min"1 kg"1 in the controls (table III). The volume of the central
75%
74 ±19 111±13**
Recovery index (min)
(ng ml"1)
21±7
200±87 340±190
30±10
compartment and the total apparent volume of distribution were not significantly different between the two groups. The elimination half-life was prolonged from 58 ± 22 min to 98 ± 57 min in patients with cholestasis. No correlation could be found between the degree of impairment of biliary function, estimated by the bilirubin plasma concentration, and the alkaline phosphatase concentrations and the individual values of plasma clearance. The time interval from injection to recovery from neuromuscular blockade (to 75% of the control value) was prolonged significantly in
Downloaded from http://bja.oxfordjournals.org/ at University of Glasgow on June 28, 2015
1 2 3 4 5 6 7 8 9 Normal values
Prothrombin (%of normal)
BRITISH JOURNAL OF ANAESTHESIA
986 patients with cholestasis (table IV). The recovery index was not prolonged by cholestasis. The plasma concentration corresponding to 50 % paralysis during the recovery phase was not significantly different between the two groups. DISCUSSION
Patients with cholestasis were older than the controls, and ageing may have contributed to the pharmacokinetic alterations observed in association with cholestasis. The influence of age on the pharmacokinetics and the phannacodynamics of vecuronium is controversial, however. D'Hollander and co-workers (1982) observed a cumulative effect of vecuronium in elderly patients, whereas Rupp and associates (1983) reported no significant change in the pharmacokinetics and the pharmacodynamics of vecuronium in six patients older than 70 yr when compared with those in young adults.
Downloaded from http://bja.oxfordjournals.org/ at University of Glasgow on June 28, 2015
This study demonstrates that cholestasis caused a significant decrease in the plasma clearance of vecuronium. In patients with cholestasis, the plasma clearance of vecuronium was twice as low as that in the control group, and resulted in an increase in elimination half-life and a prolongation of neuromuscular blockade. The volume of the central compartment and the total apparent volume of distribution were not modified in the patients with cholestasis. These findings are similar to those that we previously observed in patients with cirrhosis (Lebrault et al., 1985). A prolonged elimination half-life, decreased plasma clearance and unchanged total apparent volume of distribution of vecuronium were observed in patients with cirrhosis together with a prolonged effect (Lebrault et al., 1985). The elimination half-lives of pancuronium and fazadinium were also shown to be increased in patients with cholestasis (Somogyi, Shanks and Triggs, 1973; Duvaldestin et al., 1980), despite the minor role of the liver in the elimination of these two drugs. The pharmacokinetics of gallamine, which is almost completely eliminated unchanged by the kidney, were unaltered in patients with cholestasis (Westra, Vermeer et al., 1981). In the present study the pharmacokinetic alterations remain relatively modest, despite the existence of complete biliary obstruction in most of the patients. No relationship could be found between the degree of biliary obstruction and the decrease in plasma clearance.
Until now the fate of vecuronium has not been completely clarified—probably because of the lack of an assay specific to vecuronium and its metabolites. It has been shown that exclusion of liver circulation greatly prolonged the duration of the blockade (Bencini et al., 1985). However, the limiting step in the hepatic elimination of vecuronium remains undefined. The relative contribution of metabolic degradation of vecuronium to its elimination is not clear as yet, nor is the tissue in which this degradation occurs. An extensive hepatic uptake of vecuronium may account for the high clearance and non-cumulative effect of vecuronium (Duvaldestin, Chauvin and Lebrault, 1985; Bencini et al., 1985). Hepatic uptake could be the limiting step of hepatic elimination, since biliary elimination occurs at a slow rate and accounts for a limited amount of the dose of vecuronium (Bencini et al., 1985). After the drug has been taken up by the liver it is possibly metabolized, stored in special liver organelles, like tubocurarine in the lysosomes (Meijer, Weitering and Vonk, 1976), and secondarily released slowly in the bile or in the hepatic venous blood. Therefore, in patients with cholestasis, hepatic uptake of vecuronium may still persist despite the absence of biliary secretion. Another factor which has been shown to diminish the hepatic uptake of several non-depolarizing neuromuscular blocking drugs is the increase in the plasma concentration of bile salts which is likely to occur in patients with cholestasis. Increases in the plasma concentrations of bile salts have been shown to prolong the effect of general neuromuscular blockers, including vecuronium, and to inhibit the hepatic uptake of tubocurarine and of vecuronium analogues (Westra, Keulemans et al., 1981). It was shown that vecuronium caused a prolonged effect only when a relatively high dose of 0.2 mg kg"1 was administered in patients with liver dysfunction caused by cirrhosis (Bell et al., 1985; Hunter et al., 1985). In the present study the same large dose of 0.2 mg kg"1 was used and it is likely that, after such a dose, the duration of action is influenced by elimination processes. After a large dose of vecuronium 0.2 mg kg~ l , the recovery from paralysis occurs during the elimination phase (Shanks, Somogyi and Triggs, 1979) and, therefore, a prolonged recovery index should be observed in patients with cholestasis, and indeed was observed in our patients with cholestasis. However, the change was not significant, because of the wide interindividual variation.
VECURONIUM KINETICS IN CHOLESTASIS
987
It is expected that, in patients with cholestasis, a single dose of vecuronium O.lmgkg" 1 will probably exhibit the same duration of action as in healthy patients, but that a cumulative effect will be observed in prolonged operations which require numerous additional doses.
Downloaded from http://bja.oxfordjournals.org/ at University of Glasgow on June 28, 2015
d'Hollander, A., Massaux, F., Nevelsteen, M., and Agoston, S. (1982). Age-dependant dose-response relationship of Org NC45 in anesthetized patients. Anesthesiology, 54, 653. Hunter, J. M., Parker, C. J. R., Bell, C. F., Jones, R. S., and Utting, J. E. (1985). The use of different doses of vecuronium in patient* with liver dysfunction. Br. J. Anaesth., 57, 758. Kersten, U. W., Meijer, D. K. F., and Agoston, S. (1973). Fluorimetric and chromatographic determination of pancuronium bromide and its metabolites in biological materials. Clin. Chan. Acta, 44, 59. ACKNOWLEDGEMENTS We are indebted to Miss Ursula Kersten for skilled technical Lebrault, C , Berger, J. L., d'Hollander, A. A., Gomeni, R., Henzel, D., and Duvaldestin, P. (1985). Phannacokinetics assistance and to Miss Nadine Creon-Lair for secretarial and pharmacodynamics of vecuronium (Org N C 45) in assistance. patients with cirrhosis. Anesthesiology, 62, 601. Meijer, D. K. F., Weltering, J. G., and Vonk, R. J. (1976). Hepatic uptake and biliary excretion of d-tubocurarine and REFERENCES trimethyltubocurarine in the rat in vivo and in isolated Bell, C. F., Hunter, J. M., Jones, R. S., and Utting J. E. perfused rat livers. J. Pharmacol. Exp. Ther., 198, 229. (1985). Use of atracurium and vecuronium in patients with Miller, R. D., Rupp, S. M., Fisher, D. M., Cronnelly, R., oesophageal varices. Br. J. Anaesth., 57, 160. Fahey,M. R.,and Sohn Y. J. (1984). Clinical pharmacology Bencini, A., Houwertjes, M. C , and Agoston, S. (1985). of vecuronium and atracurium. Anesthesiology, 61, 444. Effects of hepatic uptake of vecuronium bromide and its Rupp, S. M., Fisher, D. M., Miller, R. D., and Castagnoli, K. putative metabolites on their neuromuscular blocking (1983). Phannacokinetics and pharmacodynamics of vecuroactions in the cat. Br. J. Anaesth., 57, 789. nium in the elderly. Anesthesiology, 59, A270. Scaf, A. H. J., Agoston, S., Houwertjes, M. C , and Shanks, C. A., Somogyi, A. A., and Triggs, E. J. (1979). Kersten, U. W. (1985). Disposition of vecuronium bromide Dose—response and plasma concentration-response relationin the cat. Br. J. Anaesth., 57, 782. ships of pancuronhun in man. Anesthesiology, 51, 111. Sohn, Y. J., Kersten, U., and Agoston, S. (1983). Somogyi, A. A., Shanks, C. A., and Triggs, E. J. (1977). Clinical pharmacokinetics of vecuronium; in Clinical Disposition kinetics of pancuronium bromide in patients Experiences with Norcuron (Org NC 45, Vecuronium Bromide) with total biliary obstruction. Br. J. Anaesth., 49, 1103. (eds S. Agoston, W. C. Bowman, R. D. Miller and J. Viby- Upton, R. A., Nguyen, T. L., Miller, R. D., and Castagnoli, Mogensen), p. 115. Amsterdam: Excerpta Medica. N. (1982). Renal and biliary elimination of vecuronium (Org Duvaldestin, P., Chauvin, M., and Lebrault, C. (1985). NC 45) and pancuronium in rats. Anesth. Analg., 61, 313. Pharmacokinetics of muscle relazants in patients with liver Westra,P.,Keulemans,G. T. P.,Houweitjes,M. C.Hardonk, disease. Clin. Anaesth., 3, 293. M. J., and Meijer, D . K. F. (1981). Mechanisms underlying Saada, J., Henzel, D., and Saumon, G. (1980). the prolonged duration of action of muscle relaxants caused Fazadinium pharmacokinetics in patients with liver disease. by extrahepatic cholestasis. Br. J. Anaesth., 53, 217. Br. J. Anaesth., 52, 789. Vermeer, G. A., De Lange, A. R., Scaf, A. H. J., Meijer, Gomeni, C , and Gomeni, R. (1978). Interactive graphic D. K. F., and Wesseling, H. (1981). Hepatic and renal package for pharmacokinetic analysis. Comp. Biomed. Res., disposition of pancuronium and gallnmine in patients with 11, 345. extrahepatic cholestasis. Br. J. Anaesth., 53, 331.
PHARMACOKINETICS AND PHARMACODYNAMICS OF VECURONIUM IN PATIENTS WITH CHOLESTASIS C. LEBRAULT, P. DUVALDESTIN, D. HENZEL, M. CHAUVIN AND P. GUESNON
CLAUDE LEBRAULT, MJJ.; PHILIPPE DUVALDESTOJ, M.D.; MARCEL CHAUVIN, M JJ. ; PATRICK GUESNON.M.D. ; Departement
d'Anesthesie, Hdpital Ambroise Pare, University Paris 5, 92104 Boulogne BOlancourt Cedex, France. DANIELS HENZBL, M.D., Departemem d'Anesthesie, Hdpital Bichat, University Paris 7, 75018 Paris, France. Correspondence to C. L.
SUMMARY The pharmacokinetics and pharmacodynamics of vecuronium were studied in nine surgical patients with cholestasis, and in 14 patients without hepatic or renal disease. After the administration of vecuronium 0.2 mg kg-1 the plasma concentration of vecuronium and the degree of neuromuscular blockade were measured. The plasma clearance of vecuronium was decreased significantly (P < 0.01) from 4.30± 1.56mlmin-1 kg-1 (mean±SD) in normal patients to 2.36± 0.80 ml min-1 kg-1 in patients with cholestasis. The elimination half-life was of 58 ±22 min in normal patients and was prolonged to 98 ±57 min (P < 0.05) in patients with cholestasis. The total apparent volume of distribution was unchanged in patients with cholestasis. A prolonged neuromuscular blockade induced by vecuronium was observed in patients with cholestasis: the duration of effect from injection to 75% recovery of the twitch height was prolonged from 74 ± 19 min in normal patients to 111 ±13 min in patients with cholestasis. The plasma concentration corresponding to 50% recovery from paralysis did not differ significantly between the two groups. Vecuronium has a prolonged effect in patients with cholestasis which is caused by a delay in its elimination.
colleagues (1981). In the present study, we investigated the pharmacokinetics and the pharmacodynamics of vecuronium in patients with cholestasis undergoing biliary surgery. PATIENTS AND METHODS
Patients The pharmacokinetics and phannacodynamics of vecuronium were investigated in nine patients
Downloaded from http://bja.oxfordjournals.org/ at University of Glasgow on June 28, 2015
The short acting non-cumulative effect of vecuronium is explained by its high plasma clearance (Miller et al., 1984). However, its pathway of elimination in man is unclear, since the cumulative urinary and biliary excretion of vecuronium accounts for no more than 40 % of the dose after 24 h (Bencini et al., 1983). Unlike most other non-depolarizing neuromuscular blocking drugs which are predominantly eliminated in urine, vecuronium appears to be primarily eliminated by the liver. Several arguments plead in favour of a predominantly hepatic elimination: first, in the cat, the exclusion of the hepatic circulation potentiates the depth and the duration of vecuronium-induced neuromuscular blockade (Bencini, Houwertjes and Agoston, 1985); second, in several animal species the biliary excretion of vecuronium largely exceeds the urinary elimination (Upton et al., 1982; Bencini et al., 1985); third, in patients with cirrhosis a prolonged effect of vecuronium 0.2 mg kg"1 was observed which was explained by a decrease in the plasma clearance and an increase in the elimination half-life of vecuronium (Lebrault et al., 1985). Owing to its hepatic elimination, vecuronium will probably exert a prolonged effect in patients with cholestasis. It has been shown already (Somogyi, Shanks and Triggs, 1977) that the elimination half-life and the duration of the neuromuscular blockade of pancuronium were prolonged in patients with cholestasis. Three days after ligation of the common bile duct in rats, a three-fold increase in the duration of action of vecuronium was observed by Westra, Keulemans and
BRITISH JOURNAL OF ANAESTHESIA
984
Monitoring and analytical techniques
Before the induction of anaesthesia, a cannula was inserted to a fore-arm vein, and blood samples were collected before and at 5, 10, 15, 30, 45, 60, 75, 90, 120, 150, 180 and 210 min after the administration of vecuronium. The plasma concentration of vecuronium was measured using the Rose Bengale fluorimetric method for pancuronium assay (Kersten, Meijer and Agoston, 1973) with minor modifications which have been
described previously (Lebrault et al., 1985). This method is not specific and measures vecuronium and its metabolites. Data were fitted by both twoand three-compartment open pharmacokinetic models using a non-linear, least-squares regression. A two-compartment model was selected using the technique of Gomeni and Gomeni (1978). The following were calculated: the half-lives of distribution (Tf) and of elimination (7\P), the volume of the central compartment (F,), the total apparent volume of distribution measured in the steady state (Fb88) or according to the method of the area under the curve (FD P ) and the plasma clearance (C/)A Grass S-8 stimulator was used to administer supramaximal single stimuli of 0.2 ms duration at a rate of 0.1 pulse s"1 to the ulnar nerve at the wrist through thin wall electrodes. The evoked response of the adductor pollicis, that is the twitch height, was quantitated continuously using a Statham UC3 force transducer and recorded on a polygraph. Simultaneously with measurements of the plasma concentration, the degree of neuromuscular blockade was followed from onset to complete recovery. The concentration corresponding to 50 % paralysis (CP 60) during the recovery phase was determined in both groups. Statistical differences between the control group and the group of patients with cholestasis were analysed by the two-tailed non parametric Mann—Whitney U test.
RESULTS
The clinical characteristics of patients with cholestasis are shown in table I. Results of biochemical analyses are shown in table II. Most patients had almost complete biliary obstruction,
TABLE I. Clinical characteristics of the patients with cholestasis Duration nf
Patient
No. 1 2 3 4 5 6 7 8 9
Sex F M M M F F M F M
Age (yr)
Wt (kg)
81 65 50 72 49 69 44 73 70
50 45 64 74 60 60 70 59 65
UI
operation (h) 4 5 3 2.5 3 4.5 5 4 4
Surgical procedure Biliary-intestinal bypass (cholelithiasis) Biliary-intestinal bypass (cancer) Bile duct surgery (cholelithiasis) Bile duct surgery (cholelithiasis) Bile duct surgery (cholelithiasis) Cholecystectomy (cancer) Duodenopancreatectomy (cancer) Biliary-intestinal bypass (cancer) Biliary-intestinal bypass (cancer)
Downloaded from http://bja.oxfordjournals.org/ at University of Glasgow on June 28, 2015
with cholestasis who were between the ages 44 and 81 yr (64 ± 13, mean± SD) and weighed 45-74 kg (61 ±9), and in 14 patients without hepatic or renal dysfunction between the ages 21 and 68 yr (42±15) and weighing 57-107 kg (70±13). Informed consent was given by all the patients and the design of the study was approved by the Research Comittee of University Paris 5. Cholestasis was caused by extrahepatic biliary obstruction. All patients with cholestasis (table I) were scheduled for biliary surgery. Premedication consisted of diazepam 10 mg or lorazepam 2.5 mg given by mouth 90 min before the induction of anaesthesia with thiopentone 6-8 mg kg"1 i.v. A single bolus dose of vecuronium of 0.2 mg kg"1 was administered. General anaesthesia was maintained with 60 % nitrous oxide in oxygen delivered by mechanical ventilation plus incremental doses of fentanyl (total dose 0.25-1.5 mg) and thiopentone (total dose 350-750 mg). The duration of surgery exceeded the duration of the neuromuscular blockade induced by vecuronium in three patients with cholestasis and three controls. In these patients suxamethonium, the only neuromuscular blocker which does not interfere with the measurement of the plasma concentration of vecuronium, was given (total dose 50-500 mg).
VECURONIUM KINETICS IN CHOLESTASIS
985
TABLE II. LwtT function tests and serum creatinine concentrations in patients with cholestasis
Patient No.
92 82 100 91 100 100 79 95 69 >70
Serum bilirubin (nig Utre"')
Alkaline phosphatase (iu ml"')
45.1 136.9 157.9 67.3 118.8 40.4 169.1 175.5 204.2 < 10
123 286 170 46 276 118 76 98 258 > 13 <38
SGPT (iu ml-')
Serum creatinine (mg Utre-')
Total plasma protein (g Utre- 1 )
57 204 290 90 126 41 64 42 106 <20
10.2 6.2 9.0 11.3 7.9 17.0 8.2 10.2 10.7 < 12
63 46 77 75 78 80 71 75 79 >60 <72
Albumin plasma (g Utre-1) 32 28 51 36 41 40 36 34 29 >38 <53
TABLE III. Pharmacokinetic variables (mean values ± SD): serum half-lives of the distribution phase j and elimination phase (Ti^), initial volume of distribution (V,), total apparent volume of distribution at steady state ( V D " ) , total apparent volume of distribution measured by the method of the area under the curve (Vrr) and plasma clearance (CU). *P < 0.05; **P < 0.01, compared with normal patients
(nun) Normal patients 7.4±4.1 Patients with 11.8±8.0 cholestasis
(nun)
V, (litre kg"1)
Vrt* (Utre kg"1)
Vrf (Utre kg"1)
58±22 0.107±0.042 0.247±0.107 0.349±0.168 98±57* 0.094±0.037 0.206±0.099 0.289±0.111
Cl (ml min"1 kg"1) 4.30±1.56 2.36±0.80**
TABLE IV. Pharmacodynamic variables (mean values ± SD) established after the administration ofvecwonium 0.2 mg kg~'. CptQ is the plasma concentration ofvecwonium corresponding to 50% of recovery. *P < 0.05; **P < 0.01, compared with normal patients
Time (min) to recovery of the twitch height (TH)to: 25%
Normal patients Patients with cholestasis
53±13 80±16*
50%
62±16 88±19*
with the exception of two in whom the bilirubin concentrations were only moderately increased at the time of surgery. No patient had severe liver failure since the plasma prothrombin values were normal in all; only one patient (No. 8) was treated before operation with vitamin K. The plasma creatinine concentrations were within their normal values in all patients. The plasma clearance of vecuronium was decreased significantly (P < 0.01) in patients with cholestasis to (mean±SD) 2.36 ±0.80 ml min- 1 kg"1 compared with 4.30 ± 1.56 ml min"1 kg"1 in the controls (table III). The volume of the central
75%
74 ±19 111±13**
Recovery index (min)
(ng ml"1)
21±7
200±87 340±190
30±10
compartment and the total apparent volume of distribution were not significantly different between the two groups. The elimination half-life was prolonged from 58 ± 22 min to 98 ± 57 min in patients with cholestasis. No correlation could be found between the degree of impairment of biliary function, estimated by the bilirubin plasma concentration, and the alkaline phosphatase concentrations and the individual values of plasma clearance. The time interval from injection to recovery from neuromuscular blockade (to 75% of the control value) was prolonged significantly in
Downloaded from http://bja.oxfordjournals.org/ at University of Glasgow on June 28, 2015
1 2 3 4 5 6 7 8 9 Normal values
Prothrombin (%of normal)
BRITISH JOURNAL OF ANAESTHESIA
986 patients with cholestasis (table IV). The recovery index was not prolonged by cholestasis. The plasma concentration corresponding to 50 % paralysis during the recovery phase was not significantly different between the two groups. DISCUSSION
Patients with cholestasis were older than the controls, and ageing may have contributed to the pharmacokinetic alterations observed in association with cholestasis. The influence of age on the pharmacokinetics and the phannacodynamics of vecuronium is controversial, however. D'Hollander and co-workers (1982) observed a cumulative effect of vecuronium in elderly patients, whereas Rupp and associates (1983) reported no significant change in the pharmacokinetics and the pharmacodynamics of vecuronium in six patients older than 70 yr when compared with those in young adults.
Downloaded from http://bja.oxfordjournals.org/ at University of Glasgow on June 28, 2015
This study demonstrates that cholestasis caused a significant decrease in the plasma clearance of vecuronium. In patients with cholestasis, the plasma clearance of vecuronium was twice as low as that in the control group, and resulted in an increase in elimination half-life and a prolongation of neuromuscular blockade. The volume of the central compartment and the total apparent volume of distribution were not modified in the patients with cholestasis. These findings are similar to those that we previously observed in patients with cirrhosis (Lebrault et al., 1985). A prolonged elimination half-life, decreased plasma clearance and unchanged total apparent volume of distribution of vecuronium were observed in patients with cirrhosis together with a prolonged effect (Lebrault et al., 1985). The elimination half-lives of pancuronium and fazadinium were also shown to be increased in patients with cholestasis (Somogyi, Shanks and Triggs, 1973; Duvaldestin et al., 1980), despite the minor role of the liver in the elimination of these two drugs. The pharmacokinetics of gallamine, which is almost completely eliminated unchanged by the kidney, were unaltered in patients with cholestasis (Westra, Vermeer et al., 1981). In the present study the pharmacokinetic alterations remain relatively modest, despite the existence of complete biliary obstruction in most of the patients. No relationship could be found between the degree of biliary obstruction and the decrease in plasma clearance.
Until now the fate of vecuronium has not been completely clarified—probably because of the lack of an assay specific to vecuronium and its metabolites. It has been shown that exclusion of liver circulation greatly prolonged the duration of the blockade (Bencini et al., 1985). However, the limiting step in the hepatic elimination of vecuronium remains undefined. The relative contribution of metabolic degradation of vecuronium to its elimination is not clear as yet, nor is the tissue in which this degradation occurs. An extensive hepatic uptake of vecuronium may account for the high clearance and non-cumulative effect of vecuronium (Duvaldestin, Chauvin and Lebrault, 1985; Bencini et al., 1985). Hepatic uptake could be the limiting step of hepatic elimination, since biliary elimination occurs at a slow rate and accounts for a limited amount of the dose of vecuronium (Bencini et al., 1985). After the drug has been taken up by the liver it is possibly metabolized, stored in special liver organelles, like tubocurarine in the lysosomes (Meijer, Weitering and Vonk, 1976), and secondarily released slowly in the bile or in the hepatic venous blood. Therefore, in patients with cholestasis, hepatic uptake of vecuronium may still persist despite the absence of biliary secretion. Another factor which has been shown to diminish the hepatic uptake of several non-depolarizing neuromuscular blocking drugs is the increase in the plasma concentration of bile salts which is likely to occur in patients with cholestasis. Increases in the plasma concentrations of bile salts have been shown to prolong the effect of general neuromuscular blockers, including vecuronium, and to inhibit the hepatic uptake of tubocurarine and of vecuronium analogues (Westra, Keulemans et al., 1981). It was shown that vecuronium caused a prolonged effect only when a relatively high dose of 0.2 mg kg"1 was administered in patients with liver dysfunction caused by cirrhosis (Bell et al., 1985; Hunter et al., 1985). In the present study the same large dose of 0.2 mg kg"1 was used and it is likely that, after such a dose, the duration of action is influenced by elimination processes. After a large dose of vecuronium 0.2 mg kg~ l , the recovery from paralysis occurs during the elimination phase (Shanks, Somogyi and Triggs, 1979) and, therefore, a prolonged recovery index should be observed in patients with cholestasis, and indeed was observed in our patients with cholestasis. However, the change was not significant, because of the wide interindividual variation.
VECURONIUM KINETICS IN CHOLESTASIS
987
It is expected that, in patients with cholestasis, a single dose of vecuronium O.lmgkg" 1 will probably exhibit the same duration of action as in healthy patients, but that a cumulative effect will be observed in prolonged operations which require numerous additional doses.
Downloaded from http://bja.oxfordjournals.org/ at University of Glasgow on June 28, 2015
d'Hollander, A., Massaux, F., Nevelsteen, M., and Agoston, S. (1982). Age-dependant dose-response relationship of Org NC45 in anesthetized patients. Anesthesiology, 54, 653. Hunter, J. M., Parker, C. J. R., Bell, C. F., Jones, R. S., and Utting, J. E. (1985). The use of different doses of vecuronium in patient* with liver dysfunction. Br. J. Anaesth., 57, 758. Kersten, U. W., Meijer, D. K. F., and Agoston, S. (1973). Fluorimetric and chromatographic determination of pancuronium bromide and its metabolites in biological materials. Clin. Chan. Acta, 44, 59. ACKNOWLEDGEMENTS We are indebted to Miss Ursula Kersten for skilled technical Lebrault, C , Berger, J. L., d'Hollander, A. A., Gomeni, R., Henzel, D., and Duvaldestin, P. (1985). Phannacokinetics assistance and to Miss Nadine Creon-Lair for secretarial and pharmacodynamics of vecuronium (Org N C 45) in assistance. patients with cirrhosis. Anesthesiology, 62, 601. Meijer, D. K. F., Weltering, J. G., and Vonk, R. J. (1976). Hepatic uptake and biliary excretion of d-tubocurarine and REFERENCES trimethyltubocurarine in the rat in vivo and in isolated Bell, C. F., Hunter, J. M., Jones, R. S., and Utting J. E. perfused rat livers. J. Pharmacol. Exp. Ther., 198, 229. (1985). Use of atracurium and vecuronium in patients with Miller, R. D., Rupp, S. M., Fisher, D. M., Cronnelly, R., oesophageal varices. Br. J. Anaesth., 57, 160. Fahey,M. R.,and Sohn Y. J. (1984). Clinical pharmacology Bencini, A., Houwertjes, M. C , and Agoston, S. (1985). of vecuronium and atracurium. Anesthesiology, 61, 444. Effects of hepatic uptake of vecuronium bromide and its Rupp, S. M., Fisher, D. M., Miller, R. D., and Castagnoli, K. putative metabolites on their neuromuscular blocking (1983). Phannacokinetics and pharmacodynamics of vecuroactions in the cat. Br. J. Anaesth., 57, 789. nium in the elderly. Anesthesiology, 59, A270. Scaf, A. H. J., Agoston, S., Houwertjes, M. C , and Shanks, C. A., Somogyi, A. A., and Triggs, E. J. (1979). Kersten, U. W. (1985). Disposition of vecuronium bromide Dose—response and plasma concentration-response relationin the cat. Br. J. Anaesth., 57, 782. ships of pancuronhun in man. Anesthesiology, 51, 111. Sohn, Y. J., Kersten, U., and Agoston, S. (1983). Somogyi, A. A., Shanks, C. A., and Triggs, E. J. (1977). Clinical pharmacokinetics of vecuronium; in Clinical Disposition kinetics of pancuronium bromide in patients Experiences with Norcuron (Org NC 45, Vecuronium Bromide) with total biliary obstruction. Br. J. Anaesth., 49, 1103. (eds S. Agoston, W. C. Bowman, R. D. Miller and J. Viby- Upton, R. A., Nguyen, T. L., Miller, R. D., and Castagnoli, Mogensen), p. 115. Amsterdam: Excerpta Medica. N. (1982). Renal and biliary elimination of vecuronium (Org Duvaldestin, P., Chauvin, M., and Lebrault, C. (1985). NC 45) and pancuronium in rats. Anesth. Analg., 61, 313. Pharmacokinetics of muscle relazants in patients with liver Westra,P.,Keulemans,G. T. P.,Houweitjes,M. C.Hardonk, disease. Clin. Anaesth., 3, 293. M. J., and Meijer, D . K. F. (1981). Mechanisms underlying Saada, J., Henzel, D., and Saumon, G. (1980). the prolonged duration of action of muscle relaxants caused Fazadinium pharmacokinetics in patients with liver disease. by extrahepatic cholestasis. Br. J. Anaesth., 53, 217. Br. J. Anaesth., 52, 789. Vermeer, G. A., De Lange, A. R., Scaf, A. H. J., Meijer, Gomeni, C , and Gomeni, R. (1978). Interactive graphic D. K. F., and Wesseling, H. (1981). Hepatic and renal package for pharmacokinetic analysis. Comp. Biomed. Res., disposition of pancuronium and gallnmine in patients with 11, 345. extrahepatic cholestasis. Br. J. Anaesth., 53, 331.