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USE OF CONTINUOUS PROLONGED ADMINISTRATION OF ATRACURIUM IN THE ITU TO A PATIENT WITH MYASTHENIA GRAVIS
Br. J. Anaesth. (1989), 62, 95-97
USE OF CONTINUOUS PROLONGED ADMINISTRATION OF ATRACURIUM IN THE ITU TO A PATIENT WITH MYASTHENIA GRAVIS B. J. POLLARD, N. J. N. HARPER AND B. R. H. DORAN
CASE REPORT
A 16-yr-old girl with known myasthenia gravis was admitted to hospital complaining of difficulty in swallowing and weak phonation. Myasthenia gravis had been diagnosed approximately 6 months earlier; the weakness affected mainly her bulbar muscles. She had been well controlled with neostigmine and pyridostigmine. On examination she was pyrexial (38 °C), had coarse crepitations in both lung fields and was expectorating purulent sputum. She was improved transiently by 10 mg of edrophonium and was therefore treated with increasing doses of neostigmine. A course of ampicillin was begun, together with chest physiotherapy. Her weakness did not improve and she began to have difficulty in coughing; progressive respiratory failure necessitated her admission to the Intensive Therapy
B. J. POLLARD,* B. PHARM., M.B., CH.B., F.F.A.R.C.S.; N. J. N. HARPER, M.B., CH.B., F.F.A.R.C.S. ; B. R. H. DORAN, M.B., B.S.,
F.F.A.R.C.S.; Adult Intensive Care Unit, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL. Accepted for Publication: May 31, 1988. •Address for correspondence: University Department of Anaesthesia, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL.
SUMMARY The case is described of a patient with myasthenia gravis who required prolonged controlled ventilation for respiratory failure. Muscular relaxation was obtained with a continuous infusion of atracurium 5 mg h'1 for 45 h. Following cessation of the infusion, paralysis disappeared rapidly.
Unit. On arrival in the ITU she was tachypnoeic (30 b.p.m.), distressed, very weak, and could not cough. Her arterial Po2 was 10.5 kPa with an FiO2 of 0.8 by facemask. Etomidate 16 mg and suxamethonium 50 mg were given, cricoid pressure applied and the trachea was intubated. Controlled ventilation and tracheobronchial toilet were begun, with rapid improvement in oxygenation. Sedation was continued with a loading bolus dose of midazolam followed by a continuous infusion; anticholinesterase therapy was discontinued. Surface electrodes were placed over the ulnar nerve on one wrist and over the ipsilateral adductor pollicis muscle. These were connected to a Relaxograph (Datex). When recovery from the suxamethonium had reached a constant level in the uncalibrated mode (approx. 20 min) the Relaxograph was calibrated. Supramaximal stimulus current was 45 mA, stimulus artefact 2 %, and train-of-four (TOF) ratio 0.84. Bolus doses of atracurium 2 mg were given at 2-min intervals until 100% neuromuscular blockade resulted (total 8 mg). A dilute solution of atracurium was prepared as 1 mg ml"1 in 5 % dextrose and a continuous infusion begun. As neuromuscular function began to return, the infusion rate was adjusted to give a Tl reading of approximately 10-15% of control on the Relaxograph. This
Downloaded from http://bja.oxfordjournals.org/ at University of Sydney on May 2, 2015
The use of a neuromuscular blocking drug is avoided frequently in patients with myasthenia gravis because of increased sensitivity to these agents. Occasionally, these patients require admission to an intensive care unit when neuromuscular blockade is necessary to allow controlled ventilation. A patient with myasthenia gravis is described who required a period of controlled ventilation, neuromuscular blockade for which was obtained using a continuous infusion of atracurium.
BRITISH JOURNAL OF ANAESTHESIA
96
TABLE I. (T1/T0), atracurium Simmonds
Time
Height of first twitch compared with control train-of-four ratio and plasma concentrations of and laudanosine (assayed using the method of [ 17]) measured at various times during the study T1/T0 (%)
After infusion Oh 100 5h 15 10 h 12.5 7.5 20 h 30 h 7.5 40h 16 15 45 h
Trainof-four ratio
Plasma concn (ug ml"1) Atracurium Laudanosine
0.84 0.25 0.20 0.17 0.17 0.28 0.25
— 0.11 — — 0.21 — 0.27
— 0.10 — — 0.18 — 0.29
After infusion discontinued 17 5 min 0.25 23 10 min 0.28 30 20 min 0.25 50 min 65 0.54 — 2h 4h 24 h — —
0.16 0.09 0.09 0.00 0.00 0.00 0.00
0.25 0.22 0.21 0.17 0.12 0.03 0.00
DISCUSSION
Myasthenia gravis is an autoimmune neuromuscular disorder affecting the acetylcholine receptors on the postjunctional membrane [1]. Myasthenic patients therefore show an unusual response to neuromuscular blocking drugs [2, 3]. The value of atracurium for intraoperative muscular relaxation in myasthenia gravis is accepted [4-9], and it is probably the agent of choice. The use of atracurium by prolonged continuous infusion in the intensive care management of a myasthenic patient has not been described previously. In the intensive therapy management of myasthenic patients requiring controlled ventilation, a neuromuscular blocking agent is not often required because the muscles are already weak, and may be made more so by simply reducing the anticholinesterase therapy. It was felt clinically appropriate in this patient, however, to provide relaxation so that aggressive tracheobronchial toilet could be carried out more easily. The dose requirement of atracurium for use during operation in myasthenia is variable (0.05-0.33 mg kg"1) [4-9]. This is an individual feature of each patient, and appears to be unrelated to anticholinesterase therapy. We found that a dose of atracurium 8 mg (0.22 mg kg"1) was needed for 100% neuromuscular blockade, which compares closely with the dose requirement for a normal individual [10-12]. Maintenance of blockade was effected with a rate of only 5 mg h"1 (0.14 mgkg"1 h"1) which, from our own experience, is approximately 20 % of the requirement of a normal adult in a similar situation, and of a normal adult undergoing continuous infusion for surgery [13]. For ease and accuracy of administration, the atracurium was prepared as a dilute solution in 5 % dextrose, spontaneous breakdown being negligible in this diluent [14]. The Relaxograph was found to be satisfactory for the estimation of neuromuscular blockade over this 45-h period. However, we have observed that the response does drift over a prolonged period of time, often not returning to the preblockade control of 100% on discontinuing administration of the blocking agent. Therefore, it is likely that, after the first few hours, the recorded percent depression was not a true measure of neuromuscular function, although it proved a useful guide and did correlate well with
Downloaded from http://bja.oxfordjournals.org/ at University of Sydney on May 2, 2015
infusion rate was 5 mg h"1, and was kept constant throughout. Sedation and neuromuscular blockade were continued in this way for a period of 45 h. After approximately 20 h, the electrodes were removed, the skin washed and dried, and new electrodes applied over the same sites. This was repeated after approximately 40 h. The Relaxograph was kept on standby mode with periods of stimulation at convenient intervals. After 45 h, the patient was apyrexial and sputum production was greatly reduced. The decision was made to wean her from controlled ventilation. Pyridostigmine was instilled down the nasogastric tube and the atracurium and midazolam infusions discontinued. Neuromuscular function slowly returned, such that she was able to breathe unaided after 2.5 h. Monitoring was continued, using the Relaxograph, until neuromuscular recovery had reached a steady level. Subsequent recovery was uneventful. At intervals during the course of the infusion of atracurium and following its cessation, blood samples were taken for measurement of plasma concentrations of atracurium and laudanosine. Atracurium disappeared completely from the plasma within 50 min of discontinuation of the infusion. The amount of laudanosine was also so small that it had been cleared completely within 24 h (table I).
ATRACURIUM INFUSION IN MYASTHENIA GRAVIS
1. 2. 3. 4. 5.
6. Ramsey FM, Smith GD. Clinical use of atracurium in myasthenia gravis: a case report. Canadian Anaesthetists Society Journal 1985; 32: 642-645. 7. Bell GF, Florence AM, Hunter JM, Jones RS, Utting JE. Atracurium in the myasthenic patient. Anaesthesia 1984; 39: 961-968. 8. Ward S, Wright DJ. Neuromuscular blockade in myasthenia gravis with atracurium besylate. Anaesthesia 1984; 39: 51-53. 9. MacDonald AM, Keen RI, Pugh ND. Myasthenia gravis and atracurium. British Journal of Anaesthesia 1984; 56: 651-653. 10. Ali HH, Basta SJ, Savarase JJ, Gargarian M, Scott RFP, Sunder N, Gionfriddo M. Single twitch and train-of-four responses for atracurium and vecuronium. Anesthesia and Analgesia 1985; 64: 185. 11. Katz RL, Stirt J, Murray AL, Lee C. Neuromuscular effects of atracurium in man. Anesthesia and Analgesia 1982; 61: 730-734. 12. Black TE, Healy TEJ, Pugh ND, Kay B, Harper NJN, Pens HV, Sivalingham T. Neuromuscular block: atracurium and vecuronium compared and combined. European Journal of Anaesthesiology 1985; 2: 29-37. 13. Eagar BM, Flynn PJ, Hughes R. Infusion of atracurium for long surgical procedures. British Journal of Anaesthesia 1984; 56:447^151. REFERENCES 14. Harper NJN, Pollard BJ, Edwards D, Wilson A. Stability Fambrough DM, Drachman DB, Satyo S. Neuroof atracurium in dilute solutions. British Journal of muscular junction in myasthenia gravis: decreased acetylAnaesthesia 1988; 60: 344P-345P. choline receptors. Science 1973; 182: 293-295. 15. Weatherley BC, Williams SG, Neill EAM. PharmacoFoldes FF, McNall PG. Myasthenia gravis: a guide for kinetics, pharmacodynamics and dose—response relationanesthesiologists. Anesthesiology 1962; 23: 837-872. ships of atracurium administered i.v. British Journal of Hunter JM. Use of atracurium in patients with myasthenia Anaesthesia 1983; 55: 39S-45S. gravis. British Journal of Anaesthesia 1986; 58: 89S. 16. Ward S, Wright D. Combined pharmacokinetic and Baraka A, Dejani A. Atracurium in myasthenics underpharmacodynamic study of a single bolus dose of atragoing thymectomy. Anesthesia and Analgesia 1984; 63: curium. British Journal of Anaesthesia 1983; 55: 35S-38S. 1127-1130. 17. Simmonds RJ. Determination of atracurium, laudanosine Vacanti CA, AH HH, Schweiss JF, Scott RP. The response and related compounds in plasma by high performance of myasthenia gravis to atracurium. Anesthesiology 1985; liquid chromatography. Journal of Chromatography 1985; 62: 692-694. 343: 431^437.
Downloaded from http://bja.oxfordjournals.org/ at University of Sydney on May 2, 2015
clinical observations. There was some train-offour fade recorded before administration of the atracurium and it is not possible to ascertain if this resulted from the myasthenia, the suxamethonium or a combination of factors. Recovery was uneventful, and plasma atracurium concentrations taken during the course of the infusion are compatible with such a low rate of infusion. It is interesting to note that the plasma concentrations which corresponded to approximately 85% neuromuscular blockade in this myasthenic patient were of an order of magnitude similar to those found in other studies at a similar degree of neuromuscular blockade in normal patients [15,16]. These previous studies, however, examined bolus doses of atracurium, and the recorded measurement of neuromuscular blockade is more likely to have been an absolute value than those we obtained.
97
USE OF CONTINUOUS PROLONGED ADMINISTRATION OF ATRACURIUM IN THE ITU TO A PATIENT WITH MYASTHENIA GRAVIS B. J. POLLARD, N. J. N. HARPER AND B. R. H. DORAN
CASE REPORT
A 16-yr-old girl with known myasthenia gravis was admitted to hospital complaining of difficulty in swallowing and weak phonation. Myasthenia gravis had been diagnosed approximately 6 months earlier; the weakness affected mainly her bulbar muscles. She had been well controlled with neostigmine and pyridostigmine. On examination she was pyrexial (38 °C), had coarse crepitations in both lung fields and was expectorating purulent sputum. She was improved transiently by 10 mg of edrophonium and was therefore treated with increasing doses of neostigmine. A course of ampicillin was begun, together with chest physiotherapy. Her weakness did not improve and she began to have difficulty in coughing; progressive respiratory failure necessitated her admission to the Intensive Therapy
B. J. POLLARD,* B. PHARM., M.B., CH.B., F.F.A.R.C.S.; N. J. N. HARPER, M.B., CH.B., F.F.A.R.C.S. ; B. R. H. DORAN, M.B., B.S.,
F.F.A.R.C.S.; Adult Intensive Care Unit, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL. Accepted for Publication: May 31, 1988. •Address for correspondence: University Department of Anaesthesia, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL.
SUMMARY The case is described of a patient with myasthenia gravis who required prolonged controlled ventilation for respiratory failure. Muscular relaxation was obtained with a continuous infusion of atracurium 5 mg h'1 for 45 h. Following cessation of the infusion, paralysis disappeared rapidly.
Unit. On arrival in the ITU she was tachypnoeic (30 b.p.m.), distressed, very weak, and could not cough. Her arterial Po2 was 10.5 kPa with an FiO2 of 0.8 by facemask. Etomidate 16 mg and suxamethonium 50 mg were given, cricoid pressure applied and the trachea was intubated. Controlled ventilation and tracheobronchial toilet were begun, with rapid improvement in oxygenation. Sedation was continued with a loading bolus dose of midazolam followed by a continuous infusion; anticholinesterase therapy was discontinued. Surface electrodes were placed over the ulnar nerve on one wrist and over the ipsilateral adductor pollicis muscle. These were connected to a Relaxograph (Datex). When recovery from the suxamethonium had reached a constant level in the uncalibrated mode (approx. 20 min) the Relaxograph was calibrated. Supramaximal stimulus current was 45 mA, stimulus artefact 2 %, and train-of-four (TOF) ratio 0.84. Bolus doses of atracurium 2 mg were given at 2-min intervals until 100% neuromuscular blockade resulted (total 8 mg). A dilute solution of atracurium was prepared as 1 mg ml"1 in 5 % dextrose and a continuous infusion begun. As neuromuscular function began to return, the infusion rate was adjusted to give a Tl reading of approximately 10-15% of control on the Relaxograph. This
Downloaded from http://bja.oxfordjournals.org/ at University of Sydney on May 2, 2015
The use of a neuromuscular blocking drug is avoided frequently in patients with myasthenia gravis because of increased sensitivity to these agents. Occasionally, these patients require admission to an intensive care unit when neuromuscular blockade is necessary to allow controlled ventilation. A patient with myasthenia gravis is described who required a period of controlled ventilation, neuromuscular blockade for which was obtained using a continuous infusion of atracurium.
BRITISH JOURNAL OF ANAESTHESIA
96
TABLE I. (T1/T0), atracurium Simmonds
Time
Height of first twitch compared with control train-of-four ratio and plasma concentrations of and laudanosine (assayed using the method of [ 17]) measured at various times during the study T1/T0 (%)
After infusion Oh 100 5h 15 10 h 12.5 7.5 20 h 30 h 7.5 40h 16 15 45 h
Trainof-four ratio
Plasma concn (ug ml"1) Atracurium Laudanosine
0.84 0.25 0.20 0.17 0.17 0.28 0.25
— 0.11 — — 0.21 — 0.27
— 0.10 — — 0.18 — 0.29
After infusion discontinued 17 5 min 0.25 23 10 min 0.28 30 20 min 0.25 50 min 65 0.54 — 2h 4h 24 h — —
0.16 0.09 0.09 0.00 0.00 0.00 0.00
0.25 0.22 0.21 0.17 0.12 0.03 0.00
DISCUSSION
Myasthenia gravis is an autoimmune neuromuscular disorder affecting the acetylcholine receptors on the postjunctional membrane [1]. Myasthenic patients therefore show an unusual response to neuromuscular blocking drugs [2, 3]. The value of atracurium for intraoperative muscular relaxation in myasthenia gravis is accepted [4-9], and it is probably the agent of choice. The use of atracurium by prolonged continuous infusion in the intensive care management of a myasthenic patient has not been described previously. In the intensive therapy management of myasthenic patients requiring controlled ventilation, a neuromuscular blocking agent is not often required because the muscles are already weak, and may be made more so by simply reducing the anticholinesterase therapy. It was felt clinically appropriate in this patient, however, to provide relaxation so that aggressive tracheobronchial toilet could be carried out more easily. The dose requirement of atracurium for use during operation in myasthenia is variable (0.05-0.33 mg kg"1) [4-9]. This is an individual feature of each patient, and appears to be unrelated to anticholinesterase therapy. We found that a dose of atracurium 8 mg (0.22 mg kg"1) was needed for 100% neuromuscular blockade, which compares closely with the dose requirement for a normal individual [10-12]. Maintenance of blockade was effected with a rate of only 5 mg h"1 (0.14 mgkg"1 h"1) which, from our own experience, is approximately 20 % of the requirement of a normal adult in a similar situation, and of a normal adult undergoing continuous infusion for surgery [13]. For ease and accuracy of administration, the atracurium was prepared as a dilute solution in 5 % dextrose, spontaneous breakdown being negligible in this diluent [14]. The Relaxograph was found to be satisfactory for the estimation of neuromuscular blockade over this 45-h period. However, we have observed that the response does drift over a prolonged period of time, often not returning to the preblockade control of 100% on discontinuing administration of the blocking agent. Therefore, it is likely that, after the first few hours, the recorded percent depression was not a true measure of neuromuscular function, although it proved a useful guide and did correlate well with
Downloaded from http://bja.oxfordjournals.org/ at University of Sydney on May 2, 2015
infusion rate was 5 mg h"1, and was kept constant throughout. Sedation and neuromuscular blockade were continued in this way for a period of 45 h. After approximately 20 h, the electrodes were removed, the skin washed and dried, and new electrodes applied over the same sites. This was repeated after approximately 40 h. The Relaxograph was kept on standby mode with periods of stimulation at convenient intervals. After 45 h, the patient was apyrexial and sputum production was greatly reduced. The decision was made to wean her from controlled ventilation. Pyridostigmine was instilled down the nasogastric tube and the atracurium and midazolam infusions discontinued. Neuromuscular function slowly returned, such that she was able to breathe unaided after 2.5 h. Monitoring was continued, using the Relaxograph, until neuromuscular recovery had reached a steady level. Subsequent recovery was uneventful. At intervals during the course of the infusion of atracurium and following its cessation, blood samples were taken for measurement of plasma concentrations of atracurium and laudanosine. Atracurium disappeared completely from the plasma within 50 min of discontinuation of the infusion. The amount of laudanosine was also so small that it had been cleared completely within 24 h (table I).
ATRACURIUM INFUSION IN MYASTHENIA GRAVIS
1. 2. 3. 4. 5.
6. Ramsey FM, Smith GD. Clinical use of atracurium in myasthenia gravis: a case report. Canadian Anaesthetists Society Journal 1985; 32: 642-645. 7. Bell GF, Florence AM, Hunter JM, Jones RS, Utting JE. Atracurium in the myasthenic patient. Anaesthesia 1984; 39: 961-968. 8. Ward S, Wright DJ. Neuromuscular blockade in myasthenia gravis with atracurium besylate. Anaesthesia 1984; 39: 51-53. 9. MacDonald AM, Keen RI, Pugh ND. Myasthenia gravis and atracurium. British Journal of Anaesthesia 1984; 56: 651-653. 10. Ali HH, Basta SJ, Savarase JJ, Gargarian M, Scott RFP, Sunder N, Gionfriddo M. Single twitch and train-of-four responses for atracurium and vecuronium. Anesthesia and Analgesia 1985; 64: 185. 11. Katz RL, Stirt J, Murray AL, Lee C. Neuromuscular effects of atracurium in man. Anesthesia and Analgesia 1982; 61: 730-734. 12. Black TE, Healy TEJ, Pugh ND, Kay B, Harper NJN, Pens HV, Sivalingham T. Neuromuscular block: atracurium and vecuronium compared and combined. European Journal of Anaesthesiology 1985; 2: 29-37. 13. Eagar BM, Flynn PJ, Hughes R. Infusion of atracurium for long surgical procedures. British Journal of Anaesthesia 1984; 56:447^151. REFERENCES 14. Harper NJN, Pollard BJ, Edwards D, Wilson A. Stability Fambrough DM, Drachman DB, Satyo S. Neuroof atracurium in dilute solutions. British Journal of muscular junction in myasthenia gravis: decreased acetylAnaesthesia 1988; 60: 344P-345P. choline receptors. Science 1973; 182: 293-295. 15. Weatherley BC, Williams SG, Neill EAM. PharmacoFoldes FF, McNall PG. Myasthenia gravis: a guide for kinetics, pharmacodynamics and dose—response relationanesthesiologists. Anesthesiology 1962; 23: 837-872. ships of atracurium administered i.v. British Journal of Hunter JM. Use of atracurium in patients with myasthenia Anaesthesia 1983; 55: 39S-45S. gravis. British Journal of Anaesthesia 1986; 58: 89S. 16. Ward S, Wright D. Combined pharmacokinetic and Baraka A, Dejani A. Atracurium in myasthenics underpharmacodynamic study of a single bolus dose of atragoing thymectomy. Anesthesia and Analgesia 1984; 63: curium. British Journal of Anaesthesia 1983; 55: 35S-38S. 1127-1130. 17. Simmonds RJ. Determination of atracurium, laudanosine Vacanti CA, AH HH, Schweiss JF, Scott RP. The response and related compounds in plasma by high performance of myasthenia gravis to atracurium. Anesthesiology 1985; liquid chromatography. Journal of Chromatography 1985; 62: 692-694. 343: 431^437.
Downloaded from http://bja.oxfordjournals.org/ at University of Sydney on May 2, 2015
clinical observations. There was some train-offour fade recorded before administration of the atracurium and it is not possible to ascertain if this resulted from the myasthenia, the suxamethonium or a combination of factors. Recovery was uneventful, and plasma atracurium concentrations taken during the course of the infusion are compatible with such a low rate of infusion. It is interesting to note that the plasma concentrations which corresponded to approximately 85% neuromuscular blockade in this myasthenic patient were of an order of magnitude similar to those found in other studies at a similar degree of neuromuscular blockade in normal patients [15,16]. These previous studies, however, examined bolus doses of atracurium, and the recorded measurement of neuromuscular blockade is more likely to have been an absolute value than those we obtained.
97