194
ANESTH ANALG 1990;71:1946
Vancomycin Enhances the Neuromuscular Blockade of Vecuronium Kou Chu Huang, MD, Andrew Heise, Kentaro Tsueda, MD
DMD,
Anna K. Shrader, MD, and
Key Words: ANTIBIOTICS, VANCOMYCIN. Vancomycin is frequently used as the antibiotic of choice for methicillin-resistant staphylococcal infections and Streptococcus viridans endocarditis, and as a prophylactic antibiotic in patients with prosthetic heart valves or ventriculoperitoneal shunts (14). Adverse reactions to vancomycin include renal toxicity, ototoxicity, cardiovascular depression, histamine release, anaphylactoid reactions, and rare cases of cardiac arrest (5-16). Currently, renal toxicity is considered to be of little clinical significance in patients with normal renal function, but the other side effects of vancomycin are serious. We report a depression of neuromuscular function that developed after intravenously administered vancomycin, something that has not been described previously in the literature.
Case Report A 21-yr-old woman, 152 cm tall and weighing 34 kg, with recurrent pelvic inflammatory disease and a persistent right adnexal mass was anesthetized for exploratory laparoscopy. This patient had undergone surgery for a posterior fossa neuroblastoma at the age of 2 yr. A ventriculoperitoneal shunt was inserted at that time; it was revised at age 17 yr. The patient had been taking phenytoin for the control of seizures. She had done well since that time except for mild ataxia and mild mental retardation. The patient denied use of tobacco, alcohol, or drugs. There were no known allergies. At the time of surgery, physical examination was normal except for an old scar from ventriculoperitoneal shunt surgery; blood pressure was 100/ From the Department of Anesthesiology, Medical College of Virginia, Richmond, Virginia, and the Department of Anesthesiology, University of Louisville, Louisville, Kentucky. Accepted for publication April 9, 1990. Address correspondence to Dr. Kou Chu Huang, Department of Anesthesiology, Medical College of Virginia, Richmond, VA 23298. 01990 by the International Anesthesia Research Society
60 mm Hg and heart rate was 80 beats/min; the patient was afebrile; chest roentgenogram was normal; hemoglobin was 14.5 g% and plasma electrolyte levels were normal; serum phenytoin level was 9.0 mg%. Anesthesia was induced with 350 mg thiopental and 50 pg fentanyl. Tracheal intubation was facilitated with 4 mg vecuronium. Anesthesia was maintained with 50% nitrous oxide and 0.4%-1% isoflurane. Blood pressure, electrocardiogram, inspired oxygen concentration, oxygen saturation, end-tidal CO,, and esophageal temperature were monitored. Electromyographic (EMG) response to electrical stimulation of ulnar nerve (train-of-four) was monitored by NMT-221 (Puritan Bennett Corporation, Kansas City, Mo.). A program written in Quick Basic 4.5 (Microsoft, Inc., Redmond, Wash.) received the data from the NMT monitor and displayed the EMG response to the first stimulus (Tl) and the response to the fourth stimulus (T4) as two separate bar graphs on an IBM enhanced graphics display. All data were saved as a text file. Twenty minutes after induction of anesthesia, T1 had returned to 35% of the preinduction level, but T4 was barely perceptible. An infusion of vancomycin (1g diluted in 250 mL of normal saline) was started at the request of the surgeon. The 11 decreased immediately after the start of the infusion to less than 10% of the preinduction level. T4 was totally absent. The infusion lasted 35 min. Twenty-five minutes after the infusion was started, a blood sample was drawn to determine the level of vancomycin; it was 70 pg/mL. A decrease in blood pressure or heart rate was not observed. Within 3 min of cessation of vancomycin, the EMG began to recover steadily. Twenty minutes later the operation was completed and vecuronium was reversed with 0.6 mg atropine and 35 mg edrophonium intravenously. Initially, the EMG response demonstrated the recovery of the neuromuscular function to near preinduction levels, but the responses decreased approximately 5 min later to the same level they were before the edrophonium was given. The patient was
CLINICAL REPORTS
ANESTH ANALG 1990;71: 194-6
195
recuronium
120
110
8
g-%
loo
-
-
-
3%
90-
d -
80-
’z w
vancomycin infusion
70-
50 -
60
40
30
J
-
10 -
20
Time (15 min. increments)
awake and breathing spontaneously but was not able to sustain headlift. The plot of T1 through T4 for the entire period is shown in Figure 1. Twenty minutes after injection of edrophonium the patient’s muscle tone was judged to be adequate by both clinical assessment and EMG. The endotracheal tube was removed. The patient’s vital signs were stable, and no other side effects were noted.
Discussion A number of antibiotics, particularly the aminoglycosides, have been shown to produce skeletal muscle paralysis. The available literature suggests that antibiotics have multiple sites of action, i.e., prejunctional structures, postjunctional cholinergic receptors, and muscle membranes (17-20). The response to anticholinesterase and Ca2+ of the neuromuscular blockade produced by these antibiotics is variable. Vancomycin, a complex tricyclic glycopeptide, previously has not been considered to affect neuromuscular function (21). In our patient, the integrated EMG response to electrical stimulation of the ulnar nerve recovered to 35% of the control level approximately 25 min after an intubating dose of vecuronium. The duration of muscle relaxation was that expected in subjects with normal
Figure 1. Integrated EMG response to eIectrical stimulation of ulnar nerve (train-of-four)during vancomycin infusion. T1, top line; T4, bottom line.
hepatic function. The prompt reduction in the EMG response and the beginning of its recovery coincided with the start and cessation of vancomycin infusion, suggesting that the enhancement of muscle relaxation was caused by vancomycin. The ineffective antagonism by anticholinesterase observed in this patient was also consistent with that which characterizes neuromuscular depression secondary to antibiotics. A substantial depression before and a recovery of T3 and T4 after the administration of edrophonium appear to suggest that vancomycin had an effect on the neuromuscular junction as well as on skeletal muscles. The effect of antibiotics on neuromuscular function is more likely to become evident during anesthesia than in the absence of anesthesia because depression of neuromuscular function secondary to anesthetic and muscle relaxant drugs is already present. However, there have been no reports of vancomycin-induced neuromuscular depression with the exception of a communication by Glicklich and Figura (22) describing transient apnea and hypotension after an inadvertent rapid infusion of vancomycin, 1 g over 2 min, during peritoneal dialysis. Muscle weakness produced by vancomycin was thought to be the cause of the apnea in
196
ANESTH ANALG
CLINICAL REPORTS
1990;71:19&6
this patient. Lack of clinical reports may be partly due to our current practice to infuse vancomycin slowly and to control ventilation during anesthesia. The trachea was intubated in nine of 13 patients previously reported in whom hypotension andlor cardiac arrest developed after the administration of vancomycin (6-10,13-15). However, in a few of these patients in whom the trachea was not intubated, neuromuscular blockade in addition to cardiovascular depression cannot be excluded as an etiologic factor (12,14). The recommended usual daily intravenous dose of vancomycin in adults is 2 g, 500 mg every 6 h or 1 g every 12 h, with each dose infused over a period of 30 min or, more recently, over 60 min. The safe and effective serum levels have been considered arbitrarily to be 40-10 pg/mL (23)or 50-20 pg/mL (24).The highest concentration of vancomycin is expected to occur at the end of the infusion (25). Thus, the peak concentration in our patient would have been in excess of 70 pg/mL, presumably due to the small size of our patient. The neuromuscular depression in ow patient may have been due to the high serum concentration of vancomycin, but this level of concentration can occur during treatment of patients with vancomycin (26). The experience with this patient suggests that vancomycin in clinically encountered serum concentrations may depress neuromuscular function, especially during anesthesia in which muscle relaxants are used. The recommended dosage and method of administration should be adhered to, with appropriate adjustments for body size and renal function. In addition, patients must be observed carefully throughout anesthesia for signs of neuromuscular as well as cardiovascular depression because adverse effects, although usually associated with large doses or rapid infusion, have also been reported to occur during slow infusion (6,8,9,15).
References McDonald M, Hurse A, Sim KN. Methicillin-resistant Staphylococcus uureus bacteraemia. Med J Aust 1981;2:1914. Cook FV, Coddington CC, Wadland WC, Farrar WE Jr. Treatment of bacterial endocarditis with vancomycin. Am J Med Sci 1978;276:153-8. Masur H, Johnson WD Jr. Prosthetic valve endocarditis. J Thorac Cardiovasc Surg 1980;80:31-7.
4. Visconti EB, Peter G. Vancomycin treatment of cerebrospinal fluid shunt infections. Report of two cases. J Neurosurg 1979;51:245-6. Traber PG, Levine DP. Vancomycin ototoxicity in a patient 5. with normal renal function. Ann Intern Med 1981;95:458-60. 6. Miller R, Tausk HC. Anaphylactoid reaction to vancomycin during anesthesia: a case report. Anesth Analg 1977;56:870-2. 7. Newfield PA, Roizen MF. Hazards of rapid administration of vancomycin. Ann Intern Med 1979;91:581. 8. Waters BG, Rosenberg M. Vancomycin-induced hypotension. Oral Surg 1981;52:23940. 9. Odio C, Mohs E, Sklar FH, Nelson JD, McCracken GH. Adverse reactions to vancomycin used as prophylaxis for CSF shunt procedures. Am J Dis Child 1984;138:17-9. 10. Dajee H, Laks H, Miller J, Oren R. Profound hypotension from rapid vancomycin administration during cardiac operation. J Thorac Cardiovasc Surg 1984;87:145-6. 11. Hill LM. Fetal distress secondary to vancomycin-induced maternal hypotension. Am J Obstet Gynecol 1985;153:7&5. 12. Mayhew JF, Deutsch S. Cardiac arrest following administration of vancomycin. Can Anaesth SOCJ 1985;32:65-6. 13. Levy JH, Kettlekamp N, Goertz P, Hermens J, Hirshman CA. Histamine release by vancomycin: a mechanism for hypotension in man. Anesthesiology 1987;67:122-5. 14. Best CJ, Ewart M, Sumner E. Perioperative complications following the use of vancomycin in children: a report of two cases. Br J Anaesth 1989;67576-7. 15. Roelofse JA, Joubert J DeV. Anaphylactoid reaction to vancomycin: report of a case. J Oral Maxillofac Surg 1989;4769-71. 16. Cohen LS, Wechsler AS, Mitchell JH, Glick G. Depression of cardiac function by streptomycin and other antimicrobial agents. Am J Cardiol 1970;26:505-11. 17. Singh YN, Harvey AL, Marshall IG. Antibiotic-induced paralysis of the mouse phrenic nerve-hemidiaphragm preparation, and reversibility by calcium and by neostigmine. Anesthesiology 1978;48:418-24. 18. Singh YN, Marshall IG, Harvey AL. Depression of transmitter release and postjunctional sensitivity during neuromuscular block produced by antibiotics. Br J Anaesth 1979;51:1027-33. 19. Lee C, deSilva AJC. Acute and subchronic neuromuscular blocking characteristics of streptomycin: a comparison with neomycin. Br J Anaesth 1979;51:431-4. 20. Sokoll MD, Gergis SD. Antibiotics and neuromuscular function. Anesthesiology 1981;55:148-59. 21. Orkin FK, Cooperman LH. Complications in anesthesiology. Philadelphia: JB Lippincott, 1983:33. 22. Glicklich D, Figura I. Vancomycin and cardiac arrest. Ann Intern Med 1984;101:880. 23. Geraci JE. Vancomycin. Mayo Clin Proc 1977;52:6314. 24. Fakety R. Vancomycin. Med Clin North Am 1982;66:175-81. 25. Schaad UB, McCracken GH, Nelson JD. Clinical pharmacology and efficacy of vancomycin in pediatric patients. J Pediatr 1980;96:119-26. 26. Alpert G, Campos JM, Harris MC, Preblud SR, Plotkin SA. Vancomycin dosage in pediatrics reconsidered. Am J Dis Child 1984;138:2&2.
ANESTH ANALG 1990;71:1946
Vancomycin Enhances the Neuromuscular Blockade of Vecuronium Kou Chu Huang, MD, Andrew Heise, Kentaro Tsueda, MD
DMD,
Anna K. Shrader, MD, and
Key Words: ANTIBIOTICS, VANCOMYCIN. Vancomycin is frequently used as the antibiotic of choice for methicillin-resistant staphylococcal infections and Streptococcus viridans endocarditis, and as a prophylactic antibiotic in patients with prosthetic heart valves or ventriculoperitoneal shunts (14). Adverse reactions to vancomycin include renal toxicity, ototoxicity, cardiovascular depression, histamine release, anaphylactoid reactions, and rare cases of cardiac arrest (5-16). Currently, renal toxicity is considered to be of little clinical significance in patients with normal renal function, but the other side effects of vancomycin are serious. We report a depression of neuromuscular function that developed after intravenously administered vancomycin, something that has not been described previously in the literature.
Case Report A 21-yr-old woman, 152 cm tall and weighing 34 kg, with recurrent pelvic inflammatory disease and a persistent right adnexal mass was anesthetized for exploratory laparoscopy. This patient had undergone surgery for a posterior fossa neuroblastoma at the age of 2 yr. A ventriculoperitoneal shunt was inserted at that time; it was revised at age 17 yr. The patient had been taking phenytoin for the control of seizures. She had done well since that time except for mild ataxia and mild mental retardation. The patient denied use of tobacco, alcohol, or drugs. There were no known allergies. At the time of surgery, physical examination was normal except for an old scar from ventriculoperitoneal shunt surgery; blood pressure was 100/ From the Department of Anesthesiology, Medical College of Virginia, Richmond, Virginia, and the Department of Anesthesiology, University of Louisville, Louisville, Kentucky. Accepted for publication April 9, 1990. Address correspondence to Dr. Kou Chu Huang, Department of Anesthesiology, Medical College of Virginia, Richmond, VA 23298. 01990 by the International Anesthesia Research Society
60 mm Hg and heart rate was 80 beats/min; the patient was afebrile; chest roentgenogram was normal; hemoglobin was 14.5 g% and plasma electrolyte levels were normal; serum phenytoin level was 9.0 mg%. Anesthesia was induced with 350 mg thiopental and 50 pg fentanyl. Tracheal intubation was facilitated with 4 mg vecuronium. Anesthesia was maintained with 50% nitrous oxide and 0.4%-1% isoflurane. Blood pressure, electrocardiogram, inspired oxygen concentration, oxygen saturation, end-tidal CO,, and esophageal temperature were monitored. Electromyographic (EMG) response to electrical stimulation of ulnar nerve (train-of-four) was monitored by NMT-221 (Puritan Bennett Corporation, Kansas City, Mo.). A program written in Quick Basic 4.5 (Microsoft, Inc., Redmond, Wash.) received the data from the NMT monitor and displayed the EMG response to the first stimulus (Tl) and the response to the fourth stimulus (T4) as two separate bar graphs on an IBM enhanced graphics display. All data were saved as a text file. Twenty minutes after induction of anesthesia, T1 had returned to 35% of the preinduction level, but T4 was barely perceptible. An infusion of vancomycin (1g diluted in 250 mL of normal saline) was started at the request of the surgeon. The 11 decreased immediately after the start of the infusion to less than 10% of the preinduction level. T4 was totally absent. The infusion lasted 35 min. Twenty-five minutes after the infusion was started, a blood sample was drawn to determine the level of vancomycin; it was 70 pg/mL. A decrease in blood pressure or heart rate was not observed. Within 3 min of cessation of vancomycin, the EMG began to recover steadily. Twenty minutes later the operation was completed and vecuronium was reversed with 0.6 mg atropine and 35 mg edrophonium intravenously. Initially, the EMG response demonstrated the recovery of the neuromuscular function to near preinduction levels, but the responses decreased approximately 5 min later to the same level they were before the edrophonium was given. The patient was
CLINICAL REPORTS
ANESTH ANALG 1990;71: 194-6
195
recuronium
120
110
8
g-%
loo
-
-
-
3%
90-
d -
80-
’z w
vancomycin infusion
70-
50 -
60
40
30
J
-
10 -
20
Time (15 min. increments)
awake and breathing spontaneously but was not able to sustain headlift. The plot of T1 through T4 for the entire period is shown in Figure 1. Twenty minutes after injection of edrophonium the patient’s muscle tone was judged to be adequate by both clinical assessment and EMG. The endotracheal tube was removed. The patient’s vital signs were stable, and no other side effects were noted.
Discussion A number of antibiotics, particularly the aminoglycosides, have been shown to produce skeletal muscle paralysis. The available literature suggests that antibiotics have multiple sites of action, i.e., prejunctional structures, postjunctional cholinergic receptors, and muscle membranes (17-20). The response to anticholinesterase and Ca2+ of the neuromuscular blockade produced by these antibiotics is variable. Vancomycin, a complex tricyclic glycopeptide, previously has not been considered to affect neuromuscular function (21). In our patient, the integrated EMG response to electrical stimulation of the ulnar nerve recovered to 35% of the control level approximately 25 min after an intubating dose of vecuronium. The duration of muscle relaxation was that expected in subjects with normal
Figure 1. Integrated EMG response to eIectrical stimulation of ulnar nerve (train-of-four)during vancomycin infusion. T1, top line; T4, bottom line.
hepatic function. The prompt reduction in the EMG response and the beginning of its recovery coincided with the start and cessation of vancomycin infusion, suggesting that the enhancement of muscle relaxation was caused by vancomycin. The ineffective antagonism by anticholinesterase observed in this patient was also consistent with that which characterizes neuromuscular depression secondary to antibiotics. A substantial depression before and a recovery of T3 and T4 after the administration of edrophonium appear to suggest that vancomycin had an effect on the neuromuscular junction as well as on skeletal muscles. The effect of antibiotics on neuromuscular function is more likely to become evident during anesthesia than in the absence of anesthesia because depression of neuromuscular function secondary to anesthetic and muscle relaxant drugs is already present. However, there have been no reports of vancomycin-induced neuromuscular depression with the exception of a communication by Glicklich and Figura (22) describing transient apnea and hypotension after an inadvertent rapid infusion of vancomycin, 1 g over 2 min, during peritoneal dialysis. Muscle weakness produced by vancomycin was thought to be the cause of the apnea in
196
ANESTH ANALG
CLINICAL REPORTS
1990;71:19&6
this patient. Lack of clinical reports may be partly due to our current practice to infuse vancomycin slowly and to control ventilation during anesthesia. The trachea was intubated in nine of 13 patients previously reported in whom hypotension andlor cardiac arrest developed after the administration of vancomycin (6-10,13-15). However, in a few of these patients in whom the trachea was not intubated, neuromuscular blockade in addition to cardiovascular depression cannot be excluded as an etiologic factor (12,14). The recommended usual daily intravenous dose of vancomycin in adults is 2 g, 500 mg every 6 h or 1 g every 12 h, with each dose infused over a period of 30 min or, more recently, over 60 min. The safe and effective serum levels have been considered arbitrarily to be 40-10 pg/mL (23)or 50-20 pg/mL (24).The highest concentration of vancomycin is expected to occur at the end of the infusion (25). Thus, the peak concentration in our patient would have been in excess of 70 pg/mL, presumably due to the small size of our patient. The neuromuscular depression in ow patient may have been due to the high serum concentration of vancomycin, but this level of concentration can occur during treatment of patients with vancomycin (26). The experience with this patient suggests that vancomycin in clinically encountered serum concentrations may depress neuromuscular function, especially during anesthesia in which muscle relaxants are used. The recommended dosage and method of administration should be adhered to, with appropriate adjustments for body size and renal function. In addition, patients must be observed carefully throughout anesthesia for signs of neuromuscular as well as cardiovascular depression because adverse effects, although usually associated with large doses or rapid infusion, have also been reported to occur during slow infusion (6,8,9,15).
References McDonald M, Hurse A, Sim KN. Methicillin-resistant Staphylococcus uureus bacteraemia. Med J Aust 1981;2:1914. Cook FV, Coddington CC, Wadland WC, Farrar WE Jr. Treatment of bacterial endocarditis with vancomycin. Am J Med Sci 1978;276:153-8. Masur H, Johnson WD Jr. Prosthetic valve endocarditis. J Thorac Cardiovasc Surg 1980;80:31-7.
4. Visconti EB, Peter G. Vancomycin treatment of cerebrospinal fluid shunt infections. Report of two cases. J Neurosurg 1979;51:245-6. Traber PG, Levine DP. Vancomycin ototoxicity in a patient 5. with normal renal function. Ann Intern Med 1981;95:458-60. 6. Miller R, Tausk HC. Anaphylactoid reaction to vancomycin during anesthesia: a case report. Anesth Analg 1977;56:870-2. 7. Newfield PA, Roizen MF. Hazards of rapid administration of vancomycin. Ann Intern Med 1979;91:581. 8. Waters BG, Rosenberg M. Vancomycin-induced hypotension. Oral Surg 1981;52:23940. 9. Odio C, Mohs E, Sklar FH, Nelson JD, McCracken GH. Adverse reactions to vancomycin used as prophylaxis for CSF shunt procedures. Am J Dis Child 1984;138:17-9. 10. Dajee H, Laks H, Miller J, Oren R. Profound hypotension from rapid vancomycin administration during cardiac operation. J Thorac Cardiovasc Surg 1984;87:145-6. 11. Hill LM. Fetal distress secondary to vancomycin-induced maternal hypotension. Am J Obstet Gynecol 1985;153:7&5. 12. Mayhew JF, Deutsch S. Cardiac arrest following administration of vancomycin. Can Anaesth SOCJ 1985;32:65-6. 13. Levy JH, Kettlekamp N, Goertz P, Hermens J, Hirshman CA. Histamine release by vancomycin: a mechanism for hypotension in man. Anesthesiology 1987;67:122-5. 14. Best CJ, Ewart M, Sumner E. Perioperative complications following the use of vancomycin in children: a report of two cases. Br J Anaesth 1989;67576-7. 15. Roelofse JA, Joubert J DeV. Anaphylactoid reaction to vancomycin: report of a case. J Oral Maxillofac Surg 1989;4769-71. 16. Cohen LS, Wechsler AS, Mitchell JH, Glick G. Depression of cardiac function by streptomycin and other antimicrobial agents. Am J Cardiol 1970;26:505-11. 17. Singh YN, Harvey AL, Marshall IG. Antibiotic-induced paralysis of the mouse phrenic nerve-hemidiaphragm preparation, and reversibility by calcium and by neostigmine. Anesthesiology 1978;48:418-24. 18. Singh YN, Marshall IG, Harvey AL. Depression of transmitter release and postjunctional sensitivity during neuromuscular block produced by antibiotics. Br J Anaesth 1979;51:1027-33. 19. Lee C, deSilva AJC. Acute and subchronic neuromuscular blocking characteristics of streptomycin: a comparison with neomycin. Br J Anaesth 1979;51:431-4. 20. Sokoll MD, Gergis SD. Antibiotics and neuromuscular function. Anesthesiology 1981;55:148-59. 21. Orkin FK, Cooperman LH. Complications in anesthesiology. Philadelphia: JB Lippincott, 1983:33. 22. Glicklich D, Figura I. Vancomycin and cardiac arrest. Ann Intern Med 1984;101:880. 23. Geraci JE. Vancomycin. Mayo Clin Proc 1977;52:6314. 24. Fakety R. Vancomycin. Med Clin North Am 1982;66:175-81. 25. Schaad UB, McCracken GH, Nelson JD. Clinical pharmacology and efficacy of vancomycin in pediatric patients. J Pediatr 1980;96:119-26. 26. Alpert G, Campos JM, Harris MC, Preblud SR, Plotkin SA. Vancomycin dosage in pediatrics reconsidered. Am J Dis Child 1984;138:2&2.
