PHARMACODYNAMICS OF MIVACURIUM CHLORIDE IN PATIENTS WITH HEPATIC CIRRHOSIS

Transcription

1 British Journal of Anaesthesia 1993; 71: PHARMACODYNAMICS OF MIVACURIUM CHLORIDE IN PATIENTS WITH HEPATIC CIRRHOSIS J. C. DEVLIN, A. G. HEAD-RAPSON, C. J. R. PARKER AND J. M. HUNTER SUMMARY Ten healthy patients and 25 patients with cirrhosis of the liver (10, 10 and 5 Child's C) received a bolus dose of mivacurium chloride 150 fig kg~ 1. The electromyographic response was monitored throughout anaesthesia until recovery of the first twitch of the train-of-four (TOF) (T1/TO) to at least 85 % and the TOF ratio (T4: T1) to at least 80%. There was no significant difference between the two groups in the onset of neuromuscular block, but recovery was prolonged in the cirrhotic group compared with the healthy patients (respective mean times to recovery of T1/TO: to 5% = 20.2 vs 11.2 min (P<0.05); to 10% = 23.8 vs 13.4 min (P < 0.005); to 25% = 28.4 vs 16.6min (P < 0.005); to 50% = 41.1 vs 20.1 min (P < 0.005); to 75% = 43.8 vs 24.9min (P < 0.005). Recovery of T4: T1 to 70% = 48.1 vs 27.4 min (P < 0.005)). Recovery was most prolonged in the patients. Mean plasma cholinesterase activity was less in the cirrhotic compared with the healthy group (mean 582 (so 254) iu litre' 1 vs 1125 (303) iu Hue- 1 ) (P < 0.001) and there was a significant negative correlation between plasma cholinesterase activity and all the indices of recovery (P < for all except recovery index (P < 0.01)). We conclude that patients with hepatic cirrhosis may be sensitive to mivacurium, which could be explained, at least in part, by the lesser plasma cholinesterase activity. (Br. J. Anaesth. 1993; 71: ) KEY WORDS Neuromuscular relaxants: mivacurium. Pharmacodynamics liver disease. The new, short-acting, non-depolarizing neuromuscular blocking agent, mivacurium chloride, is metabolized by plasma cholinesterase. Early studies in vitro suggested that this occurs at a rate of 70-88% that of suxamethonium [1, 2]. It is known that the activity of this enzyme is reduced in liver disease [3]. We decided, therefore, to examine the pharmacodynamics of mivacurium in patients with hepatic cirrhosis in comparison with a control group of healthy patients. An early study of mivacurium failed to demonstrate a consistent relationship between plasma cholinesterase activity and duration of neuromuscular block in healthy patients, but in these subjects there was little variation in enzyme activity [1]. More recently, a significant negative correlation has been reported in three studies. Phillips and Hunter reported a negative correlation between plasma cholinesterase activity and recovery of T1/T0 to 5 % after a bolus of mivacurium 150 ug kg" 1 in a study comparing renal failure patients, in whom plasma cholinesterase activity was reduced, and healthy patients [4]. Ostergaard and colleagues also showed a negative correlation between plasma cholinesterase activity and time to return of the first twitch following a bolus dose of 200 ug kg" 1, although they could not demonstrate a correlation when a dose of 100 ug kg" 1 was used [5]. Ali and colleagues showed a negative correlation between plasma cholinesterase activity and the infusion rate of mivacurium required to maintain % depression of T1/T0 in healthy patients [6]. Therefore we also have attempted to correlate pharmacodynamic data with plasma cholinesterase activity. PATIENTS AND METHODS The study was approved by the Committee of Safety of Medicines and the Hospital Ethics Committee. All patients gave written, informed consent. We studied 25 patients with hepatic cirrhosis and 10 healthy patients undergoing intermediate, elective surgical procedures requiring neuromuscular block. All but one of the cirrhotic group were having injection sclerotherapy of oesophageal varices. The remaining patient in that group, and all the healthy patients, were undergoing general surgical or gynaecological procedures, such as inguinal hernia repair or laparoscopy. Hepatic cirrhosis is a chronic disease with a variable degree of functional impairment. Using Child's criteria [7], the cirrhotic group were classified further into three subgroups (A, B and C) in order to examine the influence of the severity of hepatic disease on the pharmacodynamic data. Patients were excluded if they had a clinical history of a neuromuscular disorder, asthma, renal failure, difficult tracheal intubation or were receiving drugs J. C. DEVLIN, M.B., F.R.C.A.; A. G. HEAD-RAPSON, B.SC., M.B., F.R.C.A. ; C. J. R. PARKER, M.A., M.D., F.R.C.A.; J. M. HUNTER, M.B., F.R.C.A.; University Department of Anaesthesia, Royal Liverpool University Hospital, Prescot Street, P.O. Box 147, Liverpool L69 3BX. Accepted for Publication: February 22, 1993.

2 228 BRITISH JOURNAL OF ANAESTHESIA TABLE I. Child's classification for assessing the severity of liver dysfunction [7] Serum bilirubin (umol litre" 1 ) Serum albumin (g litre" 1 ) Ascites Neurological disorder Nutrition Group A <34 >35 None None Excellent Group B Easily controlled Minimal Good Group C >50 <30 Poorly controlled Advanced Poor known to interfere with neuromuscular transmission or hepatic function. All patients with cirrhosis were receiving oral ranitidine 150 mg twice daily and vitamin K 10 mg daily. and C patients were also receiving oral spironolactone mg daily. All the patients had preoperative measurements of haemoglobin concentration, platelet count, urea, electrolytes and plasma albumin; liver function tests were also performed. Before operation, plasma cholinesterase activity was measured using a spectrophotometric method [8] and the dibucaine and fluoride numbers were determined [9]. The cirrhotic patients also had prothrombin time and activated partial thromboplastin time measured. Each cirrhotic patient was assigned to the appropriate Child's subgroup (table I). ASA II and III patients had a preoperative chest x-ray and electrocardiogram. Premedication was with either diazepam 10 mg orally, Cyclimorph (morphine sulphate 10 mg ml" 1 and cyclizine 50 mg ml" 1 ) 1 ml i.m. or no premedication (in the case of the cirrhotic patients). Anaesthesia was induced with fentanyl 1 ig kg" 1 and thiopentone 3-5 mg kg" 1, followed by a period of at least 15 min during which the patient breathed isoflurane and 70% nitrous oxide in oxygen, until a stable end-tidal isoflurane concentration of 0.5 % (measured using a Capnomac (Datex)) had been achieved. End-tidal carbon dioxide partial pressure was maintained in the range kpa, with positive pressure ventilation when needed, using the Capnomac. During this period, electromyographic monitoring was commenced, applying train-of-four (TOF) stimuli to the ulnar nerve at the wrist at 12-s intervals and recording the surface compound action potential over adductor pollicis using a Medelec MS6 [10]. The arm was wrapped in cotton wool padding, but skin temperature was not measured. When the end-tidal isoflurane concentration was stable, a bolus dose of mivacurium 150 ug kg" 1 was given into a fast flowing peripheral infusion in the other forearm. Electromyographic monitoring was continued throughout surgery and until the first twitch (T1/T0) had recovered to at least 85% and the TOF ratio (T4:T1) had reached at least 80%. No supplementary doses of mivacurium were given and no anticholinesterase was used. Increments of fentanyl, thiopentone, or both, were given when clinically indicated. Controlled ventilation was undertaken and tracheal intubation attempted 2 min after administration of mivacurium. Intubation was graded as excellent (no movement, vocal cords abducted), good (cords abducted, some diaphragmatic movement), poor (intubation achieved but cord and diaphragmatic movement present) or impossible [11]. If intubation was impossible at 2 min, another attempt was made 1 min later. After injection of mivacurium, evidence of cutaneous histamine release was sought at the injection site and over the face and trunk. Heart rate and indirect arterial pressure were recorded, using a Cardiocap (Datex), before induction, during anaesthesia immediately before the administration of mivacurium, and at 1-min intervals for a period of 5 min after the bolus of mivacurium and thereafter at 5-min intervals. After completion of surgery, and when T4:Tl was greater than 80 %, anaesthesia was discontinued and, when ventilation was considered adequate, the trachea was extubated. All patients were assessed in the recovery room for signs of residual curarization by their ability to maintain 5-s head-lift, tongue protrusion and cough [12]. The patients were seen also in the ward the next day to ensure that all cardiovascular variables had remained stable. They were asked specifically about muscle pain and weakness. Data analysis The electromyographic recording was analysed to determine the times to 95% and maximum depression of T1/T0 and the maximum depression of T1/T0 achieved. The times to recovery of T1/T0 to 5 %, 10 %, 25 %, 50 % and 75 %, the recovery index (time for T1/T0 to recover from 25 % to 75 %), and the time for T4:T1 to return to 70% were also noted. The onset and recovery data for the cirrhotic and the control groups were compared using the Mann- Whitney U test, as was the mean plasma albumin concentration in each group. Plasma cholinesterase activity was correlated with both onset and recovery data using Pearson's correlation coefficient. RESULTS The age, weight, sex, plasma cholinesterase activity and plasma albumin concentration of the patients are shown in table II. The patients in the control group were younger than those in the cirrhotic group and there was a slightly greater proportion of female patients in the cirrhotic group. The measured plasma cholinesterase activity was significantly less in the cirrhotic group (table II). Plasma cholinesterase activity was particularly reduced in the subgroup (mean 275 iu litre" 1, range iu litre" 1 ). One patient (Child's C) was found to be heterozygous for the dibucaine resistant gene (dibucaine number 68; normal range 77-83). This patient had a plasma cholinesterase activity of 236 iu litre" 1 and a fluoride number of 55 (normal range 55-65). All the other patients had normal dibucaine and fluoride numbers. Serum albumin concentration was significantly reduced in each cirrhotic subgroup compared with values in healthy patients (table II).

3 MIVACURIUM HEPATIC PHARMACODYNAMICS 229 TABLE II. Patient characteristics, plasma cholinesterase actwity and plasma albumin concentration (mean (SD) [range]) in the two groups and with Child's subgroups shown. *P < 0.05; **P < compared with healthy group CirrhorJc («= 25) (» = 5) Age (yr) Weight (kg) Sex(M:F) Plasma cholinesterase activity (iu litre" 1 ) Albumin (g litre" 1 ) 42.1 [27-59] 70.1(11.0) [53-84] 5:5 1125(303) [ ] 46.5 (2.6) [43-50] 52.8 [32-67] 65.7(10.7) [48-87] 10: (254)** [ ] 34.6 (5.9)** [24-16] 49.7 [32-60] 60.6 (6.2) [50-68] 4:6 687 (282)* [ ] 37.3 (5.6)** [24-14] 53.0 [43-60] 71.3(14.0) [48-«5] 4:6 595(178)** [ ] 34.2 (5.5)** [29-16] 58.4 [48-67] 64.6 (3.7) [60-70] 2:3 275 (78)** [ ] 30 (4.7)** [24-36] TABLE III. Pharmacodynamic onset data for the two groups and with Child's subgroups shown (mean (SD) [range]). P < 0.05: *compared with healthy patients; ^compared with patients Cirrhotics (n = 25) («= 5) Time to 95 % depression (min) Time to max. depression (min) Maximum depression (%) 2.8 (0.9) [ ] 5.2(1.4) [ ] 98.7(1.3) [ ] 2.3 (0.9) [ ] 6.1 (3.9) [ ] 98.1 (4.0) [ ] 2.2 (0.6) [ ] 4.7(1.0)+ [ ] 99.1 (0.6) [ ] 2.2 (0.6) [ ] (n = 9) 5.3(1.5)f [ ] 97.1 (6.3) [ ] 3.0(1.6) [ ] (n = 4) 10.7 (7.4)* [ ] 97.3 (3.4) [ ] TABLE IV. Pharmacodynamic recovery data for the two groups and with Child's subgroups shown (mean (SD) [range]). *P < 0.05; **P < compared with healthy patients; t+p < 0.01 compared with Times to (min) Cirrhotics (n = 25) 0 = 5) Tl/T0 = 5% Tl/T0= 10% Tl/T0 = 25% Tl/T0 = 50% Tl/T0 = 75% T4:T1 = 70% 25-75% T1/T0 11.2(3.1) [ ] 13.4 (3.0) [ ] 16.6 (3.3) [ ] 20.1 (3.9) [ ] 24.9 (6.5) [ ] 27.4 (4.8) [ ] 8.3(4.1) [ ] 20.2(8.1)* [ ] 23.8 (8.9)* [ ] 28.4(10.4)** [ ] 34.9(14.2)** [ ] 43.8 (20.8)** [ ] 48.1 (20.5)** [ ] 15.4(12.8) [ ] 17.0(6.7) [ ] 19.6(7.2)* [ ] 23.5 (8.2)* [ ] 27.9(10.1)* [ ] 33.5 (13.0)* [ ] 39.1 (15.4)* [ ] 9.9(5.2) [ ] 19.2 (4.9)* [ ] 22.3(5.1)** [ ] 26.1 (6.3)** [ ] 32.0 (7.0)** [ ] 40.7 (13.0)** [ ] 43.5 (8.5)** [ ] 14.6(12.8) [ ] 30.7(10.1)**f+ [ ] 34.9 (9.1)**ft [ ] 42.9 (8.9)**ft [ ] 54.6 (15.2)**tt [ ] 70.7 (25.4)**++ [ ] 75.0 (25.8)**tt [ ] 27.8(17.1)**++ [ ] There were no significant differences between the onset data in the two groups, although the patients had a significantly prolonged time to reach maximum depression of T1/T0 (10.7 min) compared with the other Child's subgroups and the healthy group (P < 0.05) (table III). Two cirrhotic patients showed resistance to the action of mivacurium: in one patient, the maximum block achieved was 80.3 % at 23 min, and in one patient it was 91.5 % at 7.5 min. There was no correlation between onset variables and plasma cholinesterase activity. In contrast, the recovery from neuromuscular block was significantly prolonged in the cirrhotic group for all variables except the recovery index which, although longer in the cirrhotic group, was not statistically significant (table IV). Even the subgroup with only minimal hepatic dysfunction had a prolonged recovery from block, of about 50% greater than the healthy group. The subgroup had a markedly prolonged recovery 150% greater than healthy patients and significantly longer even than the subgroup (table IV). In contrast with the onset data, there was a significant negative correlation between all recovery variables and plasma cholinesterase activity (5 % r = -0.71; 10% r = -0.74; 25% r =-0.79; 50% r = -0.71; 75% r =-0.63; 90% r =-0.62; 95% r = -0.71; recovery index r = {P < for all except recovery index P < 0.01)). This is demonstrated for the time to 25% recovery of T1/T0 in figure 1. The final recorded height of T1/T0 was greater than 95 % in 15 patients, % in 14 patients and 85-90% in six patients. Mean arterial pressure decreased after induction of anaesthesia in both groups, with a further small decrease after administration of mivacurium (table

4 m CM O t Cholinesterase activity (iu litre" 1 ) FIG. 1. Time to 25% recovery of T1/T0 (Tl/TO^) plotted against cholinesterase activity. Pearson's correlation coefficient: r = -0.79; P < = patients (controls); O = cirrhotic patients; = heterozygous patient. V). Tracheal intubation was performed after the 2 min recording. Mean arterial pressure and heart rate increased after intubation. Cutaneous histamine release was noted in five patients, two in the control group (20 %) and three in the cirrhotic group (12%). This was not associated with any significant cardiovascular change. In seven (70%) of the healthy patients and 19 (76 %) of the cirrhotic patients, intubation conditions were excellent or good at 2 min. Conditions were poor at this time in one (10%) healthy and five (20%) cirrhotic patients and impossible in two (20%) healthy and one (4%) cirrhotic patient. In two of this latter group, intubation was impossible until 5 min, because of clinically inadequate neuromuscular block. There was no indication of recurarization in the recovery room after anaesthesia. There were no complaints of muscle pains or weakness in the first 24 h after operation. All patients were satisfied with their anaesthetic. DISCUSSION The main finding of the present study was the increased duration of action of mivacurium in patients with hepatic cirrhosis. In healthy patients, mivacurium has a shorter duration of action than the BRITISH JOURNAL OF ANAESTHESIA older non-depolarizing agents: the time to 10% recovery of T1/T0 of 13 min contrasts with 27 min for vecuronium and 39 min for atracurium [13]. This difference was reduced in patients with mild to moderate cirrhosis, in whom the time to 10% recovery of T1/T0 of 20.8 min is little less than the times for vecuronium (23 min) or for atracurium (29 min) [14]. This therefore negates the main beneficial property of mivacurium in this group of patients. In severe cirrhosis (Child's group C), although the number of such patients in the present study was small, the duration of mivacurium appeared to be so prolonged and so unpredictable as to vitiate its use. Atracurium is currently the drug of choice in cirrhotic patients with severe liver dysfunction (Child's group C), because of its predictable duration of action, which is unrelated to the degree of hepatic dysfunction [14]. In these patients atracurium is clearly superior to mivacurium. This finding is supported by early reports of the use of mivacurium in patients with end-stage hepatic failure undergoing liver transplantation, in whom the duration of action was found to be three times greater than in healthy patients (25% recovery T1/T0: 57 min vs 19 min) [15]. Indeed, atracurium would seem to be the only non-depolarizing neuromuscular blocking agent in common use to have a duration of action independent of liver function. All the steroidal agents have been shown to have prolonged elimination or effect in end-stage liver disease [16-18]. The prolonged effect of mivacurium in patients with hepatic disease can probably be explained by the reduced plasma cholinesterase activity, which has long been recognized to occur in such patients [3]. It is unlikely that the differences between the groups in age or the slight difference in sex ratio would account for such a marked effect. This study has shown a significant negative correlation between several indices of recovery and the patient's preoperative plasma cholinesterase activity. Such findings have been reported in patients with chronic renal failure given mivacurium [4], but not in an earlier study of the drug given to healthy subjects [1]. This may result from a less variable plasma cholinesterase activity in healthy subjects than in a population with renal disease and, consequently, any relationship would be more difficult to detect. There are also differences in the methods used to assay plasma cholinesterase. Although plasma cholinesterase activity needs to be very markedly reduced before the duration of action of suxamethonium is TABLE V. Cardiovascular variable! before the bolus dose of mivacurium and percentage changes after mivacurium compared with post-induction values (mean [range]). Tracheal intubation was attempted after the 2-im'n recording MAP (mm Hg) Heart rate (beat min" 1 ) Time Before induction After induction After mivacurium (% change) 1 min 2 min Cirrhotic Cirrhotic 99.6 [90-108] 82.3 [65-111] 97.8 [77-115] 86.6 [70-113] -1.6 [-12 to +13] -6.6 [-30 to +42] -3.2 [-15 to +31] -8.0[-3O to +47] 83.2 [64-110] 70.6 [60-85] 80.6 [59-107] 78.0 [50-120] -6.0 [-23 to +10] -4.4 [-24 to +13] -3.3 [-23 to +24] -2.0 [-28 to +58]

5 MIVACURIUM HEPATIC PHARMACODYNAMICS 231 prolonged [19], it is not known if this is true also for mivacurium. This study would suggest, however, that potentiation of neuromuscular block produced by mivacurium may occur even if the plasma cholinesterase activity is only slightly reduced. The onset of action of mivacurium in patients with hepatic cirrhosis compared with normal control subjects is also of interest. There was a tendency in this study for onset of block, as measured by time to 95 % depression, to be more rapid in the and B patients, although this was not statistically significant (table III). Patients with hepatic cirrhosis have altered haemodynamics, in particular increased cardiac output [20], which may enhance delivery of the drug to the site of action [21] and hasten the onset of block. This explanation is less plausible, however, in Child's group A patients, in whom cardiac output and speed of circulation are not likely to be substantially increased. In contrast, two patients with severe liver dysfunction showed considerable resistance to the action of mivacurium, similar to that reported by Dundee and Gray for tubocurarine [22]. It may be that the increased volume of extracellular fluid known to occur in severe cirrhosis could have led to an increase in the volume of distribution of mivacurium, as occurs with pancuronium, fazadinium and atracurium, and hence to a less intense block [16,23,24]. Pharmacokinetic studies of mivacurium are required to establish the relationship between volume of distribution and effect. ACKNOWLEDGEMENTS We acknowledge help with the cholinesterase assay from Mrs E. Lawton in the Department of Chemical Pathology, and the Wellcome Foundation pic for providing the mivacurium. REFERENCES 1. Savarese JJ, Ali HH, Basta SJ, Embree PB, Scott RPF, Sunder N, Weakly JN, Wastila WB, El-Sayad HA. The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U). 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