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Atracurium and severe hepatic disease: Henry K. Gyasi Ma CH B FFARCSI, Mohamed Naguib Ma a CH M SC a case report

Atracurium is a new non-depolarising neuromuscular venous pressure was 0.9 KPa (9 cmH20). Haemo- blocking agent, metabolized through Hofmann elimina- globin was 8.9 g.d1-1 and the test for sickle cell tion. A case is presented in which a 45-year-old patient haemoglobin was negative. with severe liver disease showed a decreased response This was his first general anaesthetic and there to atracurium. The possible causes of resistance to was no family history of anaesthetic problems. atracurium are discussed. We conclude that atracurium Preoperative serum urea, sodium, potassium may be used in patients with severe hepatic disease. and chloride were within normal limits but total bilirubin was 73.5 txmol'L -I (normal 1.71-18.81 Key words l.Lmol.L -~) total protein 85g.L -t (normal 60-80 NEUROMUSCULAR RELAXANTS: atracurium, g.L -1) and albumin 27 g'L -1 (normal 35-48 g.L-I). succinylcholine; ENZYMES" plasma ; The preoperative chest x-ray and ECG were normal. LIVER: function. He was started on a course of metronidazole 250 mg, gentamycin 80 mg and Vitamin K 10mg intravenously. No prernedication was given. The patient arrived in the operating room with a Atracurium besylate is a new non-depolarising solution of Ringer's Lactate in five per cent dextrose neuromuscular blocking agent. It is broken down running via a peripheral vein. A baseline blood in the body through Hofmann elimination, a spon- pressure was measured and subsequently, every taneous non-enzymatic process which is pH and five minutes by an electronic oscillotonometer temperature dependent.~'2 The molecule of atra- (Dinamap). The ECG was monitored continuously curium may, however, undergo non-specific ester by a Medishield M1 monitor. hydrolysis, especially under acidic conditions. The thumb of a restrained arm was attached to a In plasma of patients deficient in plasma force-displacement transducer to record the re- cholinesterase activity, the degradation of atra- sponse of the adductor pollicis to peripheral nerve curium is unaffected. 3 stimulation of the ulnar nerve at the elbow via We present a case of decreased response to surface electrodes using a myotest nerve stimulator atracurium in a patient with severe liver disease. (Biometer) and a continuous pen and paper recorder (Myograph, Biometer). Train of four (TOF) stimula- Case history tion of 0.2msee duration and 2 hertz frequency A 45-year-old male presented for emergency every 12 sec was used. Temperature was measured laparatomy for drainage of a liver abscess due to an by means of a nasopharyngeal thermistor probe. infected hydatid cyst. He weighed 84 kg, looked After pre-oxygenation for three minutes, anaes- very ill, was pyrexial (temperature 38.1~ and thesia was induced with thiopentone 300 mg, suc- icteric. His blood pressure was 16/10.6 KPa (120/ cinylcholine 80 mg and the trachea was intubated 80mmHg), pulse 120/min and respiratory rate with a cuffed oral tube after complete suppression 30/min. He had no peripheral oedema. His central of twitch response. Anaesthesia was maintained with 70 per cent in oxygen and From the Department of Anaesthesiology, King Faisal phenoperidine 3 mg intravenously. Ventilation was University, King Fahd Hospital, P.O. Box 2208, controlled to maintain an end-tidal carbon dioxide AI-Khobar 31952, Saudi Arabia. tension of 4.0 KPa (30 mmHg) as measured by a Address correspondence to: Dr. H.K. Gyasi. Datex Normocap infra-red carbon dioxide analyser.

CAN ANAESTH SOC J 1985 I 32: 2 / pp [61-4 162 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL

TABLE Dose, onset, duration and intensity of block with atracurium

Dose of atracurium (mg) 42 8.4 8.4 8.4 8.4 8.4 8.4* Onset of action (s) 30 33 30 57 32 32 45 Duration of action (rain) 13.65 4.65 2.35 8.4 5.5 3.85 4.08 Twitch height at time of injection(% of control) 40 12 12 16 12 16 16 Minimum twitch height following injection 0 8 10 4 8 8 4 Duration of incremental doses: 4.8 • 1.8 min (Mean -+ S.D.)

An initial bolus of atracurium 0.5 mg.kg-j was given followedby incrementsof 0.1 mg.kg-j as required (see text). *The last dose of atraeurium was given 4.08 min beforereversal with neostigmineand atropine.

There was no response to peripheral nerve minutes after reversal. The patient regained con- stimulation for 19 minutes following succinylcho- sciousness ten minutes after completion of . line injection and after 21 minutes twitch response He was extubated and sent to the recovery room had recovered to only 20 per cent of control twitch where his progress was uneventful. height. There was no fade to TOF stimulation. Samples of venous blood were taken for plasma Neuromuscular blockade was subsequently main- cholinesterase estimation during surgery and on tained with atracurium 0.5mg.kg -I body weight the third and fifth postoperative days. The and incremental doses of 0.1 mg.kg-i whenever the enzyme activity was measured with the plasma first twitch of TOF stimulation exceeded ten per cholinesterase pack (PChE pack, Dupont) and cent of control twitch height on at least three the Dupont Automatic Clinical Analyser.* Plasma successive stimulations. cholinesterase activities were 4.4, 4.6 and 4.2 Thirty seconds after the initial dose of atracurium, units.L -1 respectively (normal values 7-19 there was complete suppression of the twitch units.L-J). No qualitative studies of plasma response. Recovery of the first twitch of TOP eholinesterase were done because the necessary re- stimulation to ten per cent of control twitch height agents were not available. took 13.65 minutes. Subsequently, six incremental The subsequent postoperative course was un- doses of atracurium were given (Table) and the eventful and the patient was discharged 14 days mean duration of effect of each dose was 4.8 postoperatively. minutes. At no time following the first incremental dose did complete twitch inhibition recur. Discussion During surgery, a large liver abscess was drained, Foldes et al. found that the duration of action of later found to be an infected echinococcus cyst. 0.5 mg'kg -t atracurium in normal patients was 43.6 Two units of blood were transfused in addition to minutes and for 0.1 mg'kg -I increments, 20.9 two litres of Ringer's Lactate solution. Blood minutes. 4 This is in agreement with our own ob- pressure, pulse and CVP readings were unchanged servations with atracurium in patients with normal throughout surgery. Arterial blood gases were: pH liver function. In contrast, the duration of action of 7.39, PaCOz 3.85K Pa, PaO2 12.1kPa, oxygen atracurium in this patient was considerably shorter: saturation 97 per cent, bicarbonate 16 mmol'l-i and 13.65 minutes for the initial dose and 4.8 minutes base excess - 6.6 mmol'l- i. for each incremental dose. Anaesthesia lasted for 70 minutes and residual There are no previous reports of the use of neuromuscular block was reversed by neostigmine atracurium in patients with severe hepatic disease 3 mg and atropine 1.5 mg. At the time of reversal, but the use of other non-depolarising muscle re- only the first response to TOF stimulation was laxants in such patients is well documented,s-~l present and this was 20 per cent of control twitch height. The response to neostigmine was rapid and *Plasma cholinesterase activity is measured by the the TOF ratio, the ratio of the fourth response to the change in absorbance at 600 nm following the reduction first of TOF stimulation, had recovered to 0.75, six of butyrylthiocholine to thioeholine. Gyasi and Naguib: ATRACURIUM AND HEPATIC DISEASE 163

Dundee and Gray reported resistance to d-tubo- levels tend to parallel serum albumin levels in curarine in the presence of liver disease s and this has chronic liver disease.16 The nephrotic syndrome is been attributed to increased binding to globulins .6,7 the only condition in which hypoalbuminaemia and There is increased sensitivity to alcuronium in pa- a high plasma cholinesterase activity regularly tients with hypoalbuminaemia. 8 In clinical studies co-exist. 17 with pancuronium, Stovner found no relationship Other causes of plasma cholinesterase deficiency between this relaxant and serum protein fractions. 9 have been described, and these may be physiological, In obstructive liver disease, total body clearance of inherited, acquired or iatrogenic. For a full review pancuronium is decreased,~~ resulting in a slower of these causes, the reader is referred to an excellent rate of recovery from the drug. In patients with article by Whittaker. is cirrhotic liver disease, there is an increased distribu- This case shows that atracurium can be safely tion volume for pancuronium, resulting in a slow used in patients with severe hepatic disease. Dose onset of paralysis, an increased dose to maintain the requirements may be greater than in normal patients same degree of paralysis and a delayed rate of and monitoring of neuromuscular function is recom- recovery because of the prolonged elimination half mended in order to determine each patient's re- life. 1i quirements for atracurium. It also confirms the ob- Foldes and Deery found that 82 per cent of servation that in patients with plasma cholinesterase atracurium was bound to plasma proteins, com- deficiency, the metabolism of atracurium is not pared to 77 per cent of d-tubocurarine.~2 prolonged. 1.3 In chronic liver disease, hypoalbuminaemia is accompanied by hyperglobulinaemia. 13 Increased Acknowledgements binding of atracurium to globulin could therefore The authors wish to thank Prof. R. Bodman and Dr. explain the resistance to atracurium observed in this Y. Adu Gyamfi for their advice and Mr. Emmanuel patient. Hyperbilirubinaemia, hypoalbuminaemia Lapak for typing the manuscript. and low plasma cholinesterase activity, all of which were present in this patient, collectively indicate References severe hepatic dysfunction. Increased globulin will I Stenlake JB, Waigh RD, Urwin J, Dewar GH, mean that more binding sites for atracurium will be Cooker CG. Atracurium: conception and inception. available and it is when these sites are saturated that Br J Anaesth 1983; 55 (Suppl. I): 3S-10S. excess drug will be available for action at other 2 Chapple DJ, Clark JS. Pharmacological action of sites, including the neuromuscular junction. breakdown products of atracurium and related An increased distribution volume cannot explain substances. BrJ Anaesth. 1983; 55 (Suppl. 1): I1S- the decreased response to atracurium since unlike 15S. the effect with pancuronium, both onset and re- 3 Merrett RA, Thompson CW, Webb FW. In vitro covery were normal. degradation of atracurium in human plasma. Br J Prior administration of succinylcholine increases Anaesth 1983; 55: 61-6. the intensity but not the duration of atracurium 4 Foldes FF, Nagashima H, Boros M, Tasfonyi E, blockade. 1,, However, in our patient, the intensity Fitzal S, Agoston S. Muscular relaxation with of atracurium blockade was not affected by the prior atracurium, vercuronium and duador under administration of succinylcholine and the duration balanced anaesthesia. Br J Anaesth 1983; 55 (Suppl. was shorter. l): 97S-103S Electrolytes and pH were normal and would 5 Dundee JW, Gray TC. Resistance to d-tubocurarine therefore not alter the metabolism of atracurium in chloride in the presence of liver damage. Lancet this patient. 1953; 2, 16-7. The slow recovery following the administration 6 AladjemoffL. Dilestein S, Shafir E. Binding of of succinylcholine in our patient may be due to d- to plasma proteins. J. plasma cholinesterase deficiency from chronic liver Pharmacol Exp Ther 1958; 123: 43-8. disease. The enzyme is synthesised in the liver and 7 Baraka A, Gabali F. Correlation between tubo- the enzyme levels tend to fall in chronic liver curarine requirements and plasma protein pattern. Br disease.15 Furthermore, plasma cholinesterase J Anaesth 1968; 40: 89-93. 164 CANADIAN ANAESTHETISTS ~ SOCIETY JOURNAL

8 StovnerJ, Theodorsen L, Bjelke E. Sensitivity to R6sum~ tubocurarine and alcuronium with special reference L'atracurium est un nouveau bloqueur neuro-musculaire to plasma protein pattern. Br J Anaesth 1971; 43: non-dJpolarisant m~tabolisd par ~limination de Hof- 385. mann. Un cas est prdsent~ dans lequel un patient de 45 9 Stovner J, Theodorsen L, Bjelke E. Sensitivity to ans avec une atteinte h~patique s~v~re a pr~sent~ une gallamine and pancuronium with special reference diminution de la rgponse ft I'atracurium, Les causes to serum proteins. Br J Anaesth 1971 ; 43: 953. possibles de la rdsistance d l' atracurium sont discutges. 10 Somogyi AA, Shanks CA, Triggs El. Disposition On conelut que l'atracurium peat ~tre utilis~ chez les pa- kinetics of in patients with tients avec une atteinte h~patique s~vdre. total biliary obstruction. Br J Anaesth 1977; 49:1103-8. 11 Duvaldestin P, Agoston S, Henzel D et al. Pancuronium in patients with liver cirrhosis. Br J Anaesth 1978; 50: 131-6. 12 Foldes F, Deery A. Protein binding of atracurium and other short acting neuromuscular blocking agents and their interaction with human cholinesterase. Br J Anaesth 1983; 55 (Suppl, 1): 31S-34S. 13 MacleodJ. Principles and Practice of Medicine. 2nd Ed. Edinburgh, Churchill Livingstone: 1978; 430. 14 Stirt JA, Karz RL, Murray AL, Schelhl DL, Lee C. Modification of atracurium blockade by and suxamethonium. A review of clinical ex- perience. BrJ Anaesth 1983; 55 (Suppl. 1): 71S-5S. 15 Kaufman K. Serum eholinesterase activity in the normal individual and in people with liver disease. Ann int Med 1954; 41: 533-45. 16 Faber M. The relationship between serum cholinesterase and serum albumin. Acta Med Scand 1943; 114: 72-91. 17 KunkelHG, WardSM. Plasma esterase activity in patients with liver disease and nephrotic syndrome. Journal of Experimental Medicine 1947; 86:325 - 37. 18 Whittaker M, Plasma cholinesterase variants and the anaesthetist. Anaesthesia 1980; 35: 174-97.