PROLONGED NEUROMUSCULAR BLOCKADE FOLLOWING VECURONIUM

Br. J. Anaesth. (1985), 57, 807-810

PROLONGED NEUROMUSCULAR BLOCKADE FOLLOWING VECURONIUM A Case Report

A. B. SHANKS, T. LONG AND A. R. AITKENHEAD Among the virtues of vecuronium bromide (Norcuron; Organon Teknika Ltd), a relatively recent addition to the range of non-depolarizing neuromuscular blocking agents, are said to be a short duration of action and easy reversibility (Marshall et al., 1980). We report a case of prolonged neuromuscular blockade following the administration of vecuronium, and discuss the possible aetiological factors. CASE REPORT

A 77-yr-old lady was admitted as an emergency, complaining of abdominal pain and absolute constipation for the previous 5 days. Sixty-one years previously she had suffered from poliomyelitis which had resulted in permanent muscle wasting in the right leg, but no other evidence of muscle weakness. She had also suffered from mild cardiac failure and severe varicose ulcers for some years. At the time of her admission, her current medication comprised ibuprofen 400 mg 8 hourly and Moduretic (amiloride 5 mg and hydrochlorthiazide 50 mg) 2 tablets each morning. A clinical diagnosis of small bowel obstruction was made and she was scheduled for laparotomy. The patient was small and obese, with an estimated weight of 65 kg. She was obviously unwell, but apyrexial: her heart rate was 105 beat min"1 and her arterial pressure 150/ 80 mm Hg. The apex beat was ill-defined and on auscultation a third heart sound was heard with a loud systolic murmur, predominantly in the aortic area. Jugular venous pressure was increased. She was grossly kyphotic and had signs of a left pleura! effusion, andfinecrepitations were audible A. B. SHANKS, B.SC., M.B., B.S., F.FJVJI.CJ.; T. LONG, B.SC., B.M., B.S.J A. R. AITKENHEAD, B.SC., M.B., CH.B., F.P.A.R.C.S.;

University Department of Anaesthesia, Leicester Royal Infirmary, Leicester LEI 5WW. Correspondence to A. R. A.

SUMMARY Vecuronium was used to provide muscle relaxation in a patient who subsequently developed prolonged neuromuscular blockade (8 h) after anaesthesia. The aetiology of this condition, and the possible role of vecuronium, are discussed.

at the right lung base. Her haemoglobin concentration was 13.7 g dl"1, her white blood count 31.7 x 109 litre"1 with 94% neutrophils, and the concentrations of sodium, potassium and urea were 128 mmol litre"1, 3.9 mmol litre"1 and 12.2 mmol litre"1, respectively. The ECG demonstrated multiple supraventricular premature contractions and ischaemic changes were present in the infero-lateral leads. Chest x-ray revealed a left pleural effusion. A central venous catheter was inserted before surgery; the CVP was + 10 cm H2O. Bumetanide 1 mg was administered i.v., and following a rapid diuresis the CVP decreased to +6 cm H a O. Arterial blood-gas analysis revealed pH 7.42, PaOt 9.23 kPa,Pa COt 4.85 kPa, base excess 0(Fi Ot 0.21). Gentamicin 80 mg was administered i.v. In the anaesthetic room, her heart rate was 106 beat min"1 and her arterial pressure 115/ 70 mm Hg. Following preoxygenation, anaesthesia was induced with etomidate 8 mg, and the trachea intubated following suxamethonium 100 mg i.v. Anaesthesia was maintained with 67 % nitrous oxide in oxygen supplemented with fentanyl 100 \ig and intermittent 0.5 % isoflurane. Ventilation was controlled and adjusted to maintain an end-tidal carbon dioxide concentration of 5 % as measured by infra-red capnography. ECG was monitored continuously and arterial pressure measured repeatedly (Dinamap 845, Critikon Ltd). When signs of recovery from the suxamethonium (gagging and swallowing) were apparent, vecuronium 6 mg was administered to provide

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adequate muscular relaxation for surgery. Laparotomy was performed through a mid-line incision and a necrotic volvulus of the sigmoid colon was revealed. This was removed and a Paul-Mickulicz double-barrelled colostomy fashioned. The patient's condition remained stable during surgery and a single supplementary dose of vecuronium 2 mg was required to maintain adequate relaxation. This was administered 40 min after the initial dose because the surgeons were of the opinion that the relaxation of the abdominal muscles was poor. There was no objective evidence of inadequate neuromuscular blockade. At the end of surgery, 125 min after induction of anaesthesia and 70 min after the supplementary dose of vecuronium, glycopyrrolate 0.6 mg and neostigmine 5 mg (in two doses of 2.5 mg each) were given to antagonize residual neuromuscular blockade. At this time the patient gagged on the endotracheal tube and made finger movements, but spontaneous respiration was not established. Subsequently, naloxone 0.4 mg was administered to antagonize any respiratory depression caused by opioid drugs, but with no apparent effect. In addition, at this time, the patient developed some ventricular premature contractions and lignocaine 40 mg was administered i.v. A peripheral nerve stimulator was applied over the right ulnar nerve at the wrist, using surface electrodes. Whilst all four twitches were visible on train-of-four stimulation, the fourth twitch was markedly reduced in force in comparison with the first. Marked tetanic fade and post-tetanic facilitation were present. A diagnosis of persistent non-depolarizing neuromuscular blockade was made and the patient transferred to the Intensive Therapy Unit (ITU). In the ITU the patient's circulation was stable, peripheral perfusion and urine output were adequate, and she was drowsy but rousable. At this time the Na + concentration was 133 mmol litre"1, and other biochemical values were: K+ 3.7 mmol litre"1, urea 13.2 mmol litre"1, Cas+ 2.16 mmol litre"1, PO4 1.41 mmol litre"1, Mg1+ 0.74 mmol litre"1, total proteins 50 g litre"1, albumin 30 g litre"1. Liver function tests were normal. Arterial blood-gas analysis revealed pH 7.36, 13.8 kPa, Paco, 5.18 kPa, base excess 3.2 ^ 0.5). Intermittent positive pressure ventilation was continued and at 8 h after the last dose of vecuronium, electromyography was performed and revealed a train-of-four ratio of 20 % which improved to 30 % after atropine 0.6 mg and

BRITISH JOURNAL OF ANAESTHESIA neostigmine 2.5 mg. Ventilation was continued for a total of 32 h from the induction of anaesthesia, after which time adequate spontaneous respiration was established. The trachea was extubated 49 h after the induction of anaesthesia. Electromyography repeated 53 h after induction demonstrated a normal response to train-of-four stimulation. The patient was returned to a general surgical ward where, apart from a mild chest infection, she made an uneventful recovery. Her renal function was apparently normal before discharge from hospital. She remained well when seen 5 weeks following surgery. DISCUSSION

Although prolonged neuromuscular blockade is a well-known entity, this would appear to be the first time it has been reported in a patient receiving vecuronium. Vecuronium is a monoquarternary homologue of pancuronium and became generally available in the United Kingdom in 1983. It is a competitive antagonist at the neuromuscular junction with preand post-junctional effects similar to those of pancuronium (Bowman, Gibb and Marshall, 1983). It is also said to exhibit minimal cumulation in normal man (Booij and Crul, 1983). Pharmacokinetic data suggest that the rapid termination of action results predominantly from hepatic uptake (Bencini et al., 1983). Various estimates of its duration of action, which is dose dependent, have been made. Clarke (1982) found a duration to 75 % recovery of 49 min with a dose of 0.15 mg kg"1 and 71 min with a dose of 0.2 mg kg"1. D'Hollander and colleagues (1983) reported that the duration of action increased with age: the duration to 90% recovery was 84 min in subjects younger than 40 yr, compared with 119 min in subjects older than 60 yr with a dose of 0.2 mg kg"1. They also noted that the recovery index was slower in the older age group. The patient described in the present report had a total dose of approximately 0.16 mg kg"1 and it would be expected that, in the absence of complicating factors, she should have recovered from the effects of vecuronium spontaneously within 3 h. However, electromyographic evidence ofprolonged neuromuscular blockade was obtained 8 h after its administration. Previous administration of suxamethonium has been reported to increase the potency of vecuronium by a factor of 1.66 and to increase its duration

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PROLONGED NEUROMUSCULAR BLOCKADE of action by approximately 25 % (Krieg, Hendrickx and Crul, 1981). However, the recovery index following infusion of vecuronium was not affected by suxamethonium given 90 min before the termination of the infusion (D'Hollander, Bomblet and Esselen, 1982). Inhalation anaesthetics prolong neuromuscular blockade caused by non-depolarizing agents in vitro (Vitez et al., 1974) and in vivo (Miller et al., 1971). Of all the neuromuscular blocking drugs, vecuronium is said to be affected least (Lee, Tran and Nguyen, 1983). In addition, isoflurane is thought to be intermediate between enflurane and halothane in potency for potentiation of the effect of muscle relaxant drugs (Rupp, Miller and Gencarelli, 1982). However, it would seem unlikely that any residual effect of isoflurane would be signincant 7 h after the administration of a dose of 0.4 MAC h. Acid-base abnormalities affect the duration and reversibility of neuromuscular blockade produced by non-depolarizing agents (Feldman, 1963): metabolic acidosis has been implicated in the pathogenesis of "neostigmine-resistant curarisation" (Vickers, Schneiden and Wood-Smith, 1984). In the present case report, pre- and postoperative arterial blood analyses failed to demonstrate significant acid-base abnormality. Hypokalaemia, hypocalcaemia, hypermagnesaemia and hyperphosphataemia have also been implicated (Feldman, 1963), but our patient had no evidence of any such abnormality. She did exhibit a mildly increased serum urea concentration, reflecting probably the dehydration which may have been associated with alterations in fluid compartment volumes, and in turn this might have affected the pharmacokinetics of vecuronium. However, the increase in serum urea concentration was relatively modest. In addition, it has been reported that the pharmacokinetics of vecuronium are unaltered in patients with chronic renal failure (Fahey et al., 1981). Lignocaine has been shown to produce mild augmentation of neuromuscular blockade in doses greater than 3 mg kg"1 (Telivuo and Katz, 1970), but this is unlikely to be clinically relevant. Frusemide has also been reported to enhance neuromuscular blockade (Miller, Sohn and Matteo, 1976), but there have been no reports on the effect of other diuretics. Aminoglycoside antibiotics have neuromuscular blocking properties resulting from a presynaptic effect on the release of acetylcholine and a

post-junctional effect on receptor sensitivity (Torda, 1983). Our patient received one dose of approximately 1.5 mg kg"1 of gentamicin 5 h before surgery and hence 13 h before the time when electromyographic evidence of neuromuscular blockade was obtained. During this period urine output was 40-70 ml h"1 and, following surgery, her renal function was normal. Thus, although the serum gentamicin concentration was not measured, we consider it unlikely that this drug was a major contributory factor in the genesis of the prolonged neuromuscular blockade. Certain diseases, such as myasthenia gravis, myasthenic syndromes and familial periodic paralysis, render patients abnormally sensitive to non-depolarizing neuromuscular blocking drugs (Feldman, 1982). There was no evidence of these conditions in this patient. Lower motor neurone disease has been reported to alter the response to neuromuscular blocking drugs (Rosenbaum, Neigh and Strobel, 1971). Rosenbaum has suggested that this may result from limited re-innervation ofmuscle by unaffected neurones, with the subsequent formation of abnormal motor end-plates. These patients are reported to exhibit electromyographic responses similar to those seen in myasthenia gravis (Rosenbaum, Neigh and Strobel, 1971). Similar electromyographic findings have been reported in some patients following poliomyelitis (Hodes, 1948; Rook et al., 1961). Our patient's electromyographic responses were normal before discharge from the ITU, although it is possible that electromyography of the muscles of respiration might have recorded different responses from those measured as normal in the right arm. In conclusion, we feel that the most likely cause of this patient's prolonged neuromuscular blockade was abnormal distribution and elimination of vecuronium. It is possible that her previous poliomyelitis, and the previous administration of suxamethonium and gentamicin may have been contributory factors, but their significance is uncertain. REFERENCES Bencini, A., Scaf, A. H. J., Sohn, Y. J., Kersten, U., and Agoston, S.(1983). Clinical phannacokinetics of vecuronium; inClimcalExperiencestvithNorcuron(OrgNC 45,vecuronium bromide) (eds S. Agoston, W. C. Bowman, R. D. Miller and J. Viby-Mogensen), Current Clinical Practice Series, 11, p. 115. Amsterdam: Excerpta Medica. Booij, L. D. H. J., and Crul, J. F. (1983). A comparison of

810 vecuronium with the hypothetical neuromuscular blocking drug; in Clinical Experiences with Norcuron (Org NC 45, vecuronium bromide) (eds S. Agoston, W. C. Bowman, R. D . Miller and J. Viby-Mogensen), Current Clinical Practice Series, 11, p. 3. Amsterdam: Excerpta Medica. Bowman, W. C , Gibb, A. J., and Marshall, I. G. (1983). Prejunctional and postjunctional effects of vecuronium; in Clinical Experiences with Norcuron (Org NC 45, vecuronium bromide) (eds S. Agoston, W. C. Bowman, R. D. Miller and J. Viby-Mogensen), Current Clinical Practice Series, 11, p. 26. Amsterdam: Excerpta Medica. Clarke, R. S. J. (1982). Intubation conditions and neuromuscular effects following administration of vecuronium bromide. Comparison with suxamethonium chloride and pancuronium bromide; in Clinical Experiences with Norcuron (Org NC 45, vecuronium bromide) (ed. S. Agoston) Current Clinical Practice Series, 6, p. 60. Amsterdam: Excerpta Medica. Fahey, M. R., Morris, R. B., Miller, R. D., Nguyen, T.-L., and Upton, R. A. (1981). Pharmacokinetics of Org NC 45 (Norcuron) in patients with and without renal failure. Br. J. Anaesth., 53, 1049. Feldman, S. A. (1963). Effect of changes in electrolytes, hydration and pH upon the reactions to muscle relaxants. Br. J. Anaesth., 35, 546. (1982). Peripheral nervous disease, neuromuscular disorders and the myopathies; in Medicine for Anaesthetists, 2nd edn (ed. M. D. Vickers). Oxford: Blackwell Scientific Publications. Hodes, R. (1948). Electromyographic study of defects of neuromuscular transmission in human poliomyelitis. Arch. Neurol. Psychiatr., 60, 457. d'Hollander, A., Barvais, L., Massaut, J., Duvaldestin, P., and Desmonts, J. M. (1983). Vecuronium in geriatric patients; in Clinical Experiences with Norcuron (Org NC 45, vecuronium bromide) (eds. S. Agoston, W. C. Bowman, R. D. Miller and J. Viby-Mogensen), Current Clinical Practice Series, 11, p. 171. Amsterdam: Excerpta Medica. Bomblet, J. P., and Esselen, M. (1982). Administration of vecuronium bromide by intravenous infusion during long-lasting operations. Effects of age, and interaction with suxamethonium chloride; in Clinical Experiences with Norcuron (Org NC 45, vecuronium bromide) (ed. S. Agoston), Current Clinical Practice Series, 6, p. 85. Amsterdam: Excerpta Medica. Krieg, N., Hendrickx, H. H. L., and Crul, J. F. (1981). Influence of suxamethonium on the potency of Org NC 45 in anaesthetized patients. Br. J. Anaesth., 53, 259.

BRITISH JOURNAL OF ANAESTHESIA Lee, C , Tran, D. K., and Nguyen, N. B. (1983). Influence of isoflurane on vecuronium neuromuscular block in the cat; in Clinical Experiences with Norcuron (Org NC 45, vecuronium bromide) (eds. S. Agoston, W. C. Bowman, R. D. Miller and J. Viby-Mogensen), Current Clinical Practice Series, 11, p. 39. Amsterdam: Excerpta Medica. Marshall, I. G., Agoston, S., Booij, L. H. D. J., Durant, N. N., and Foldes, F. F. (1980). Pharmacology of Org NC 45comparedwithothernon-depolarizingneuromuscular blocking drugs. Br. J. Anaesth., 52, U S . Miller, R. D., Sohn, Y. J., and Matteo, R. S. (1976). Enhancement of d-tubocurarine neuromuscular blockade by diuretics in man. Anesthesiology, 45, 442. Way, W. L., Dolan, W. M., Stevens, W. C , and Eger, E. I. II (1971). Comparative neuromuscular effects of pancuronium gnllaminr and succinylcholine during forane and halothane anesthesia in man. Anesthesiology, 35, 509. Rook, E. D., Moulder, D. W., Eaton, L. M., and Lambert, E. H. (1961). Studies of neuromuscular conduction in myasthenia gravis and related disorders; in My asthenia Grafts, p. 435. Springfield, Illinois: Charles C. Thomas. Rosenbaum, K. J., Neigh, J. L., and Strobel, G. E. (1971). Sensitivity to non depolarising muscle relaxants in amyotrophic lateral sclerosis—report of two cases. Anesthesiology, 35, 638. Rupp, S. M., Miller, R. D., and Gencarelli, P. J. (1982). The effects of enflurane, halothane and isoflurane on vecuronium neuromuscular blockade in humans. Anesthesiology, 57, A259. Telivuo, L., and Katz, R. L. (1970). The effects of modern intravenous local analgesics on respiration during partial neuromuscular block in man. Anaesthesia, 25, 30. Torda, T. A. (1983). Drug interactions with vecuronium and other competitive neuromuscular blockers; in Clinical Experiences with Norcuron (Org NC 45, vecuronium bromide) (eds S. Agoston, W. C. Bowman, R. D. Miller and J. VibyMogensen), Current Clinical Practice Series, 11, p. 72. Amsterdam: Excerpta Medica. Vickers, M. D., Schneiden, H., and Wood-Smith, F. G. (1984). Drugs in Anaesthetic Practice, 6th edn. London: Butterworths. Vitez, T. S., Miller, R. D., Eger, E. I. n, van Nyhuis, L. S., and Way, W. L. (1974). Comparison in vitro of isoflurane and halothane potentiation of d-tubocurarine and succinylcholine neuromuscular blockade. Anesthesiology, 41, 53.