Prolonged Neuromuscular Blockade Following Vecuronium Infusion
Robert S. Lagasse, MD,* Robert I. Katz, MD,? Michael Petersen, MD,* Myron J. Jacobson, MD,5 Paul J. Poppers, MD11 Departments of Anesthesiology and Surgery, Northport Veteran’s Administration Hospital and State University of New York at Stony Brook, Stony Brook, NY.
Administration of vecuronium by infusion is an increasingly common technique, both in the operating room and in the intensive care unit (ICU), for patients requiring prolonged neuromuscular blockade and mechanical ventilation. The major advantage
of vecuronium
ration of action. Prior to the current case report, the longest reported continuous paralysis after the cessation of a uecuinfusion
of neuromuscularfunction
is recommended
whenever muscle
relaxants are administered by continuous infwion.
over older neuromuscular
blocking agents is its rapid excretion and intermediate du-
ronium
of the liver, who remained paralyzed for 13 days following a vecuronium infusion, is described. Intensive monitoring
Keywords: Anesthetic blockade, vecuronium prolonged paralysis.
techniques, neuromuscular infusion; complications,
was 90 hours. A case of an 81 -year-old
patient with renal failure
and subclinical chronic cirrhosis
*Clinical Assistant Professor,
Department
of Anesthesiology
TClinical Associate Professor, Department
of Anesthesiology
Introduction
#Resident, Department
of Surgery
OClinical Associate Professor, [JProfessor and Chairman,
Department
Department
of Surgery
of Anesthesiology
Address reprint requests to Dr. Lagasse at the Department of Anesthesiology, Health Sciences Center, State University of New York at Stony Brook, NY 11794-8480, USA. Received for publication November 1, 1989; revised manuscript accepted for publication February 12, 1990. 0 1990 Butterworth-Heinemann
Patients in the ICU setting who are receiving intermittent positive pressure ventilation often require muscle paralysis to increase chest wall compliance. Long-acting nondepolarizing muscle relaxants such as pancuronium have been used in bolus doses to accomplish this goal. With the development of shorteracting nondepolarizing muscle relaxants such as vecuronium bromide, the safety of this technique was felt to be improved because the rate of recovery seemed independent of the total dose administered.’ The safety of administering vecuronium by infusion was later demonstrated.2 Prior to the current case, the longest continuous paralysis reported after cessation of a vecuronium infusion was 90 hours.3 In the current case, an 8 l-year-old patient with renal failure and subclinical cirrhosis of the liver experienced neuroJ. Clin. Anesth.,
vol. 2, July/August
1990
269
muscular infusion
paralysis for 13 davs was discontinued.
after
a vecuroniuni
Case Report An 81-year-old, 76 kg male with a hist.ory of hypertension, atria1 fibrillation, and chronic renal insufficiency secondary to insulin-dependent diabetes mellitus underwent a right upper lobectomy for adenocarcinoma of the lung. Preoperative medications included quinidine, nifedipine, digoxin, and atenolol. In the course of his uneventful surgery and general anesthesia, it was noted that the patient had a normal recovery from bolus doses of vecuronium (0.05 mg/ kg/h), as demonstrated by response of the adductor pollicis muscle to “train-of-four” and tetanic (100 Hz) stimulation of the ulnar nerve. The postoperative course in the surgical ICU was complicated by progressive renal failure, which required hemodialysis, and by a staphylococcal pneumonia, necessitating intubation of the trachea for mechanical support of ventilation. Due to poor pulmonary compliance and high peak airway pressures, muscular paralysis became desirable. Vecuronium was chosen for its lack of cardiac effects and minimal dependence on renal function for adequate clearance. It was administered by continuous infusion at an arbitrary rate of 0.13 mgikglh, which was maintained for 3 days. Recovery of neuromuscular blockade was profoundly prolonged. Four days after the infusion had been discontinued, the patient still made no respiratory efforts. No twitch of the adductor pollicis muscle could be elicited on train-of-four stimulation of the ulnar nerve. An attempt was made at this time to reverse the neuromuscular blockade with neostigmine, but only three twitches could be obtained by train-of-four stimulation. Eighteen hours later, the patient was again completely paralyzed. No further attempts were made to antagonize the neuromuscular block. Only on the 13th day after the vecuronium infusion had been discontinued did the patient’s neuromuscular function improve, although the response to a tetanic stimulus was still unsustained and a minimal fade persisted on train-of-four stimulation. Fifteen days after the vecuronium infusion was stopped, the patient expired. Postmortem examination confirmed a myocardial infarction, unrelated to the prolonged paralysis, as the cause of death. It also showed cirrhosis of the liver, despite normal liver function indicated by serum transaminase, albumin, bilirubin, prothrombin time, and partial thromboplastin time.
270
.J. Clin. Anesth., vol. 2, July/August
1990
Discussion Vecuroniimi appears to be excreted principally in fee-c\ \-ia the biliary tract. It should be administered with c.aution in patients with hepatic tlysfunction,‘, >inc.c reco\‘er\’ from nt’llroIIiIisc11lar blockade may be slog in patients with cholestasis or liver dysfunction. It i\ not known, however, to what degree the liver 111ust he damaged befijre llelirol~liisculaIblockade is profoundly prolonged. Although liver cirrhosis was diagnosed in this patient at the postmortem examination, there had been no clinical or laboratory eGdence of hepatic injury or cholestasis either prior to or during his hospitalization. One cannot assume. however, that the subclinical degree of‘ liver cirrhosis did not cooltribute to the prolonged neuromuscular blockade. ‘I‘he kidney plays a secondary role in the clearance of vecuronium. The half-life during the distribution phase (I‘,!, a) and the half-life during the elimination are not substantially aphase (l‘,#- p) o f vecuronium tered in patients with renal failure, and neuromuscular blockade is not significantly prolonged.‘~~ ‘I‘otal body clearance of vecuronium averages 3.0 to 6.3 ml/ kg/min when renal function is normal: it I-anges from 2.5 to 4.5 mllkgimin in patients with renal dysfunction.h Although the tissue distribution of’ vecuronium is not clearly determined, it may be increased in renal failure. 3’his finding, in combination with an excessive dose that may saturate peripheral stores, could partially account for the prolonged recovery of neuromuscular function observed in this case. Other factors also must have played a part. ‘I‘he effect of age on I1euromuscular blockade induced bv vecuronium remains controversial. Some studies have shown that maintenance dose requirements and rate of recover!’ are decreased in the elderly. Whether this finding is a pharmacokinetic or pharmacodynamic effect is unknown. Other studies suggest that pharmacodynamic requirements and rate of recovery are similar in all age groups.” Clearly, age alone cannot account for the prolonged neuromuscular blockade in this case. ‘I‘hroughout the postoperative course, the patient’s arterial pH varied between 7.29 and 7.45. In animals, metabolic or respiratory acidosis enhances the neuromuscular blockade produced by vecuronium, but it is not known by which mechamsm this occurs. .41though the effect of acidosis on neuromuscular blockade in humans is not clear, the metabolic acidosis secondary to renal failure and the respiratory acidosis secondary to pneumonia may have contributed to the delayed recovery. No other known factors could account for this degree of prolonged paralysis. Despite the patient’s renal
Prolonged blockadefollowing vecuronium infmion: Lagasse et al.
failure, laboratory values for electrolytes were within normal limits, including those for calcium and magnesium. Although the patient was receiving antibiotics, these were cephalosporins, which have not been reported to prolong neuromuscular blockage. The patient was not receiving local anesthetics or antiarrhythmics, which have been reported to potentiate neuromuscular blockers. While low body temperature has been associated with prolonged paralysis, the temperature of the patient remained between 36.3% and 37.8%. Since none of the factors that could cause a prolonged neuromuscular blockade are reversible, the question arises as to the correct patient management. Antagonism of profound neuromuscular blockade with an anticholinesterase proved to be incomplete and temporary. Hemodialysis did not appear to clinically affect the degree of neuromuscular blockade, and, unfortunately, serum assays for vecuronium are unreliable. The addition of a charcoal filter to the dialysis circuit has an unproven benefit and increases the risk of thrombocytopenia. A more conservative approach-that of continued mechanical ventilation until spontaneous recovery occurs-can be associated with increased morbidity such as deep venous thrombosis and subsequent pulmonary embolization. Vigilant nursing care, including frequent repositioning, is required to prevent pressure sores. Although not reported with vecuronium, prolonged paralysis following pancuronium administration has been associated with severe tetroparesia and diffuse muscle atrophy persisting for weeks to months after discontinuation of the drug.‘O In summary, this case raises a warning that, counter to prior claims, vecuronium infusions can be followed by prolonged neuromuscular blockade. Its cause is most likely multifactorial and includes excessive dose, advanced age, acidosis, renal failure, and hepatic cirrhosis. The latter may play a role even in the absence of clinical or laboratory evidence of hepatic dysfunction. Since the management of these patients remains controversial, the only sensible recommendation to
prevent prolonged paralysis should be the use of intensive monitoring of neuromuscular function whenever muscle relaxants, even supposedly noncumulative ones with short duration of action, are administered by continuous infusion.
References of pan1. Buzello W, Noldge G: Repetitive administration curonium and vecuronium (Or-g NC45, Norcuron) in patients undergoing long lasting operations. BrJ Anaesth 1982;54: 1151-7. 2. Mirakhur RK, Furres CJ, Panoit SK: Muscle relaxation with an infusion of vecuronium [Abstract]. Anesthesiology 1984;6l:A293. neuro3. Slater RM, Pollard BJ, Doran BR: Prolonged muscular blockade with vecuronium in renal failure [Letter]. Anaesthesia 1988;43:250-1. 4. Bencini AF, Scaf AH, Sohn YJ, Kerston-Kleef UW, Agoston S: Hepatobiliary disposition of vecuronium bromide in man. BrJ Anaesth 1986;58:988-95. 5. Arcen JR, Lynam DP, Castragnoli KP, Cafnell PC, Cannon JC, Miller, RD: Vecuronium in alcoholic liver disease: a pharmacokinetic and pharmacodynamic analysis. Anesthesiology 1988;68:771-6. 6. Smith CL, Hunter JM, Ross RS: Vecuronium infusions in patients with renal failure in an ITU. Anaesthesia 1987;42:387-93. 7. Bencini AF, Scaf AH, Sohn YJ, et al: Disposition and urinary excretion of vecuronium bromide in anesthetized patients with normal renal function or renal failure. Anesth Analg 1988;65:245-5 1. 8. McEvoy GK, ed: American Society of Hospital Pharmacists, Inc. American Hospital Formulary Service Drug Information 88. 1988;12:693-4. 9. Rupp SM, Castagnoli KP, Fisher DM, Miller RD: Pancuronium and vecuronium pharmacokinetics and pharmacodynamics in younger and elderly adults. Anesthesiology 1987;67:45-9. 10. Op de Coul AAW, Lambregts PCLA, Koeman J, Van Puyenbroek MJE, Ter Laak HJ, Gabreels-festen AAWM: Neuromuscular complications in patients give Pavulon@ (pancuronium bromide) during artificial ventilation. Clin Neural Neurosurg 1985;87: 1.
J. Clin. Anesth.,
vol. 2, July/August
1990
271
Robert S. Lagasse, MD,* Robert I. Katz, MD,? Michael Petersen, MD,* Myron J. Jacobson, MD,5 Paul J. Poppers, MD11 Departments of Anesthesiology and Surgery, Northport Veteran’s Administration Hospital and State University of New York at Stony Brook, Stony Brook, NY.
Administration of vecuronium by infusion is an increasingly common technique, both in the operating room and in the intensive care unit (ICU), for patients requiring prolonged neuromuscular blockade and mechanical ventilation. The major advantage
of vecuronium
ration of action. Prior to the current case report, the longest reported continuous paralysis after the cessation of a uecuinfusion
of neuromuscularfunction
is recommended
whenever muscle
relaxants are administered by continuous infwion.
over older neuromuscular
blocking agents is its rapid excretion and intermediate du-
ronium
of the liver, who remained paralyzed for 13 days following a vecuronium infusion, is described. Intensive monitoring
Keywords: Anesthetic blockade, vecuronium prolonged paralysis.
techniques, neuromuscular infusion; complications,
was 90 hours. A case of an 81 -year-old
patient with renal failure
and subclinical chronic cirrhosis
*Clinical Assistant Professor,
Department
of Anesthesiology
TClinical Associate Professor, Department
of Anesthesiology
Introduction
#Resident, Department
of Surgery
OClinical Associate Professor, [JProfessor and Chairman,
Department
Department
of Surgery
of Anesthesiology
Address reprint requests to Dr. Lagasse at the Department of Anesthesiology, Health Sciences Center, State University of New York at Stony Brook, NY 11794-8480, USA. Received for publication November 1, 1989; revised manuscript accepted for publication February 12, 1990. 0 1990 Butterworth-Heinemann
Patients in the ICU setting who are receiving intermittent positive pressure ventilation often require muscle paralysis to increase chest wall compliance. Long-acting nondepolarizing muscle relaxants such as pancuronium have been used in bolus doses to accomplish this goal. With the development of shorteracting nondepolarizing muscle relaxants such as vecuronium bromide, the safety of this technique was felt to be improved because the rate of recovery seemed independent of the total dose administered.’ The safety of administering vecuronium by infusion was later demonstrated.2 Prior to the current case, the longest continuous paralysis reported after cessation of a vecuronium infusion was 90 hours.3 In the current case, an 8 l-year-old patient with renal failure and subclinical cirrhosis of the liver experienced neuroJ. Clin. Anesth.,
vol. 2, July/August
1990
269
muscular infusion
paralysis for 13 davs was discontinued.
after
a vecuroniuni
Case Report An 81-year-old, 76 kg male with a hist.ory of hypertension, atria1 fibrillation, and chronic renal insufficiency secondary to insulin-dependent diabetes mellitus underwent a right upper lobectomy for adenocarcinoma of the lung. Preoperative medications included quinidine, nifedipine, digoxin, and atenolol. In the course of his uneventful surgery and general anesthesia, it was noted that the patient had a normal recovery from bolus doses of vecuronium (0.05 mg/ kg/h), as demonstrated by response of the adductor pollicis muscle to “train-of-four” and tetanic (100 Hz) stimulation of the ulnar nerve. The postoperative course in the surgical ICU was complicated by progressive renal failure, which required hemodialysis, and by a staphylococcal pneumonia, necessitating intubation of the trachea for mechanical support of ventilation. Due to poor pulmonary compliance and high peak airway pressures, muscular paralysis became desirable. Vecuronium was chosen for its lack of cardiac effects and minimal dependence on renal function for adequate clearance. It was administered by continuous infusion at an arbitrary rate of 0.13 mgikglh, which was maintained for 3 days. Recovery of neuromuscular blockade was profoundly prolonged. Four days after the infusion had been discontinued, the patient still made no respiratory efforts. No twitch of the adductor pollicis muscle could be elicited on train-of-four stimulation of the ulnar nerve. An attempt was made at this time to reverse the neuromuscular blockade with neostigmine, but only three twitches could be obtained by train-of-four stimulation. Eighteen hours later, the patient was again completely paralyzed. No further attempts were made to antagonize the neuromuscular block. Only on the 13th day after the vecuronium infusion had been discontinued did the patient’s neuromuscular function improve, although the response to a tetanic stimulus was still unsustained and a minimal fade persisted on train-of-four stimulation. Fifteen days after the vecuronium infusion was stopped, the patient expired. Postmortem examination confirmed a myocardial infarction, unrelated to the prolonged paralysis, as the cause of death. It also showed cirrhosis of the liver, despite normal liver function indicated by serum transaminase, albumin, bilirubin, prothrombin time, and partial thromboplastin time.
270
.J. Clin. Anesth., vol. 2, July/August
1990
Discussion Vecuroniimi appears to be excreted principally in fee-c\ \-ia the biliary tract. It should be administered with c.aution in patients with hepatic tlysfunction,‘, >inc.c reco\‘er\’ from nt’llroIIiIisc11lar blockade may be slog in patients with cholestasis or liver dysfunction. It i\ not known, however, to what degree the liver 111ust he damaged befijre llelirol~liisculaIblockade is profoundly prolonged. Although liver cirrhosis was diagnosed in this patient at the postmortem examination, there had been no clinical or laboratory eGdence of hepatic injury or cholestasis either prior to or during his hospitalization. One cannot assume. however, that the subclinical degree of‘ liver cirrhosis did not cooltribute to the prolonged neuromuscular blockade. ‘I‘he kidney plays a secondary role in the clearance of vecuronium. The half-life during the distribution phase (I‘,!, a) and the half-life during the elimination are not substantially aphase (l‘,#- p) o f vecuronium tered in patients with renal failure, and neuromuscular blockade is not significantly prolonged.‘~~ ‘I‘otal body clearance of vecuronium averages 3.0 to 6.3 ml/ kg/min when renal function is normal: it I-anges from 2.5 to 4.5 mllkgimin in patients with renal dysfunction.h Although the tissue distribution of’ vecuronium is not clearly determined, it may be increased in renal failure. 3’his finding, in combination with an excessive dose that may saturate peripheral stores, could partially account for the prolonged recovery of neuromuscular function observed in this case. Other factors also must have played a part. ‘I‘he effect of age on I1euromuscular blockade induced bv vecuronium remains controversial. Some studies have shown that maintenance dose requirements and rate of recover!’ are decreased in the elderly. Whether this finding is a pharmacokinetic or pharmacodynamic effect is unknown. Other studies suggest that pharmacodynamic requirements and rate of recovery are similar in all age groups.” Clearly, age alone cannot account for the prolonged neuromuscular blockade in this case. ‘I‘hroughout the postoperative course, the patient’s arterial pH varied between 7.29 and 7.45. In animals, metabolic or respiratory acidosis enhances the neuromuscular blockade produced by vecuronium, but it is not known by which mechamsm this occurs. .41though the effect of acidosis on neuromuscular blockade in humans is not clear, the metabolic acidosis secondary to renal failure and the respiratory acidosis secondary to pneumonia may have contributed to the delayed recovery. No other known factors could account for this degree of prolonged paralysis. Despite the patient’s renal
Prolonged blockadefollowing vecuronium infmion: Lagasse et al.
failure, laboratory values for electrolytes were within normal limits, including those for calcium and magnesium. Although the patient was receiving antibiotics, these were cephalosporins, which have not been reported to prolong neuromuscular blockage. The patient was not receiving local anesthetics or antiarrhythmics, which have been reported to potentiate neuromuscular blockers. While low body temperature has been associated with prolonged paralysis, the temperature of the patient remained between 36.3% and 37.8%. Since none of the factors that could cause a prolonged neuromuscular blockade are reversible, the question arises as to the correct patient management. Antagonism of profound neuromuscular blockade with an anticholinesterase proved to be incomplete and temporary. Hemodialysis did not appear to clinically affect the degree of neuromuscular blockade, and, unfortunately, serum assays for vecuronium are unreliable. The addition of a charcoal filter to the dialysis circuit has an unproven benefit and increases the risk of thrombocytopenia. A more conservative approach-that of continued mechanical ventilation until spontaneous recovery occurs-can be associated with increased morbidity such as deep venous thrombosis and subsequent pulmonary embolization. Vigilant nursing care, including frequent repositioning, is required to prevent pressure sores. Although not reported with vecuronium, prolonged paralysis following pancuronium administration has been associated with severe tetroparesia and diffuse muscle atrophy persisting for weeks to months after discontinuation of the drug.‘O In summary, this case raises a warning that, counter to prior claims, vecuronium infusions can be followed by prolonged neuromuscular blockade. Its cause is most likely multifactorial and includes excessive dose, advanced age, acidosis, renal failure, and hepatic cirrhosis. The latter may play a role even in the absence of clinical or laboratory evidence of hepatic dysfunction. Since the management of these patients remains controversial, the only sensible recommendation to
prevent prolonged paralysis should be the use of intensive monitoring of neuromuscular function whenever muscle relaxants, even supposedly noncumulative ones with short duration of action, are administered by continuous infusion.
References of pan1. Buzello W, Noldge G: Repetitive administration curonium and vecuronium (Or-g NC45, Norcuron) in patients undergoing long lasting operations. BrJ Anaesth 1982;54: 1151-7. 2. Mirakhur RK, Furres CJ, Panoit SK: Muscle relaxation with an infusion of vecuronium [Abstract]. Anesthesiology 1984;6l:A293. neuro3. Slater RM, Pollard BJ, Doran BR: Prolonged muscular blockade with vecuronium in renal failure [Letter]. Anaesthesia 1988;43:250-1. 4. Bencini AF, Scaf AH, Sohn YJ, Kerston-Kleef UW, Agoston S: Hepatobiliary disposition of vecuronium bromide in man. BrJ Anaesth 1986;58:988-95. 5. Arcen JR, Lynam DP, Castragnoli KP, Cafnell PC, Cannon JC, Miller, RD: Vecuronium in alcoholic liver disease: a pharmacokinetic and pharmacodynamic analysis. Anesthesiology 1988;68:771-6. 6. Smith CL, Hunter JM, Ross RS: Vecuronium infusions in patients with renal failure in an ITU. Anaesthesia 1987;42:387-93. 7. Bencini AF, Scaf AH, Sohn YJ, et al: Disposition and urinary excretion of vecuronium bromide in anesthetized patients with normal renal function or renal failure. Anesth Analg 1988;65:245-5 1. 8. McEvoy GK, ed: American Society of Hospital Pharmacists, Inc. American Hospital Formulary Service Drug Information 88. 1988;12:693-4. 9. Rupp SM, Castagnoli KP, Fisher DM, Miller RD: Pancuronium and vecuronium pharmacokinetics and pharmacodynamics in younger and elderly adults. Anesthesiology 1987;67:45-9. 10. Op de Coul AAW, Lambregts PCLA, Koeman J, Van Puyenbroek MJE, Ter Laak HJ, Gabreels-festen AAWM: Neuromuscular complications in patients give Pavulon@ (pancuronium bromide) during artificial ventilation. Clin Neural Neurosurg 1985;87: 1.
J. Clin. Anesth.,
vol. 2, July/August
1990
271
