Mivacurium Infusion during Nitrous Oxide-Isoflurane Anesthesia: A Comparison with Nitrous Oxide-Opioid Anesthesia Danae M. Powers, MD,* Barbara W. Brandom, MD,? D. Ryan Cook, MD,+ Robert Byers, MD,$ Joel B. Sarner, MD,* Kathy Simpson, BS,]] Stanley Weber, MD,* Susan K. Woelfel, MD,* Vicki J. Foster, MSPH# Department of Anesthesiology and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA; Division of Anesthesiology, Allegheny General Hospital, Pittsburgh, PA, and the Medical College of Pennsylvania; DeBurroughs Wellcome Company, Research partment of Clinical Neurosciences, Triangle Park, NC.

*Assistant University

Professor of of Pittsburgh

Anesthesiology,

tAssociate University

Professor of of Pittsburgh

Anesthesiology,

SProfessor Pittsburgh

of Anesthesiology,

University

§Resident, Division of Anesthesiology, legheny General Hospital

of

Al-

[IResearch Assistant, Division of Anesthesiology, Allegheny General Hospital #Research Associate, Department ical Neurosciences, Burroughs Company

of ClinWellcome

Address reprint requests to Dr. Brandom at the Department of Anesthesiology, Children’s dren’s

Hospital of Pittsburgh, One ChilPlace, Pittsburgh, PA 15232, USA.

Received for publication August 8, 1991; revised manuscript accepted for publication November 2 1, 199 1.

Study Objective: To determine thepotentiation of the neuromuscular blockade induced by a titrated infusion of mivacurium in the presence of isojlurane versus a nitrous oxide (N,O)-opioid anesthesia. Design: An open-label, controlled study. Setting: The inpatient anesthesia service of two university medical centers. Patients: Thirty adults divided into two groups. Intervention: An intravenous infusion of mivacurium during anesthesia with N,Oopioid or N,O-isoflurane. Measurements and Main Results: A neuromuscular blockade was monitored by recording the electromyographic activity of the adductor pollicti muscle resulting from supramaximal stimulation at the ulnar nerve at 2 Hz for 2 seconds at 1 O-second intervals. The mivacurium infusion rate was significantly less in the presence of isoflurane [4.0 -+ 0.8 pglkglmin (mean +- SEM)] than during N,O-opioid anesthesia (6.4 2 0.6 kglkglmin). The recovery rates did not differ between anesthetic groups. After the termination of the infwion, spontaneous recovery to TJT, of at least 0.75 occurred in an average of 17.9 t 1.5 minutes, with a mean recovery index (T2& of 6.0 f 0.7 minutes. Conclusion: Isojlurane anesthesia reduces the infusion rate of mivacurium required to produce about 95% depression of neuromuscular function. Keywords: Neuromuscular relaxants, mivacurium infusion), opioids; isoflurane; electromyography.

(administered

by

Introduction

0 1992 Butterworth-Heinemann 1. Clin. Anesth. 4:123-126.

1992.

Mivacurium (Mivacron), a new short-acting blocking drug with minimal cardiovascular

J. Clin.

nondepolarizing neuromuscular effects, is metabolized by human

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plasma cholinesterase.l-ll In prior studies, the dose-response relations for mivacurium in adults were higher during nitrous oxide (N,O)-opioid anesthesia than with N,O-isoflurane (0.5% to 0.7% end-tidal concentration) anesthesia.3 We were interested in determining the infusion rate of mivacurium required to maintain approximately 95% neuromuscular blockade in adults during these two anesthetic conditions. Materials and Methods Thirty patients of either sex, ages 18 to 68 years and ASA physical status I or II, were divided into two groups (Table I). All patients were undergoing low- to moderaterisk elective surgical procedures requiring administration of a neuromuscular blocking drug. The study was approved by the Institutional Review Boards of the University of Pittsburgh and Allegheny General Hospital. Informed consent was obtained from all patients. No patient received aminoglycoside antibiotics or antihistamines within 48 hours of the study. Patients were premeditated with morphine 0.06 to 0.19 mg/kg intramuscularly (IM) and/or midazolam 0.03 to 0.1 mg/kg IM or intravenously (IV). Blood was obtained for measurement of plasma cholinesterase activity and dibucaine inhibition with acetylthiocholine as the substrate. Anesthesia was induced with thiopental sodium 2 to 13 mg/kg and fentanyl 1 to 10 pg/kg IV. Tracheal intubation was facilitated with 4 ml of intratracheal lidoCaine spray (4%). In 12 patients (Group I), anesthesia was maintained with 70% N,O in 30% oxygen (0,) and isoflurane (0.5% to 0.7% end-tidal concentration). When changes in heart rate and blood pressure suggested that more anesthetic could be beneficial, these patients were given supplemental fentanyl and/or thiopental sodium rather than a higher concentration of isoflurane. The largest doses of thiopental sodium and fentanyl administered to a patient in Group I were 3 mg/kg/hr and 7 pg/kg/hr, respectively. In the other 18 patients, anesthesia was maintained with 70% N,O in 30% 02, fentanyl 1 to 13 kg/kg/hr, and thiopental sodium (0 to 7 mg/kgl hr (Group 0). Ventilation was controlled to maintain end-tidal carbon dioxide tension at 35 to 40 mmHg. The patients’ body temperature was maintained in the normal range. The ulnar nerve was stimulated supramaximally with repetitive train-of-four (TOF) stimuli (2 Hz for 2 seconds at lo-second intervals) using surface electrodes on the Table

1.

Demographic Characteristics

Weight Group

forearm. The compound electromyogram of thumb adduction (adductor pollicis) was recorded using a PuritanBennett/Datex Monitor (Datex Instrumentarium, Helsinki, Finland). The degree of neuromuscular blockade was described as percent of control; the heights of the first TOF response (T,) before and after mivacurium administration were compared. The degree of neuromuscular blockade during recovery from infusion was referenced to the final baseline at the end of the study when T, equaled T,. Anesthetic administration was continued unchanged until T, equaled T,. Each patient in both groups received two to three small boluses of mivacurium to produce about 95% blockade, followed by an infusion of mivacurium 500 +g/ml in 5% dextrose and water. The rate of infusion was titrated with an adjustable infusion pump (IVAC, San Diego, CA), to maintain the neuromuscular blockade from 89% to 99%. The mivacurium infusion was continued for as long as required by the surgical procedure (range 30 to 330 minutes). For each patient, the mivacurium infusion rate and percent of neuromuscular blockade present were recorded at the beginning of each J-minute period. The infusion rate of mivacurium (kg/kg/min) required to maintain approximately 95% neuromuscular blockade during the first 15 minutes of infusion was calculated and compared with the rate calculated after 15 minutes of infusion for each patient. After the first 15 minutes of infusion, all patients had at least five 3minute periods during which infusion of mivacurium maintained neuromuscular blockade from 89% to 99%. Data from periods during which neuromuscular blockade was outside this range were excluded from the analysis. An average effective infusion rate was calculated for each patient in both groups. The first 15 minutes of infusion, during which the rate was of-ten adjusted, were excluded from these calculations. Within each anesthetic group, the individual time-weighted average infusion rates were averaged to obtain a mean. Group mean values were not weighted by duration of infusion. Neostigmine 0.04 to 0.06 mg/kg with atropine 0.01 to 0.03 mg/kg was administered to 16 patients at levels of spontaneous recovery ranging from 11% to 5 1% (89% to 49% blockade). Neuromuscular function was monitored until the TOF ratio was at least 0.75. Standard errors are shown for all mean values. Student’s t-tests and chi-square analysis were used appropriately to assess demographic differences between the

Number 12 18

I 0

Body Surface (m?

(kg) 62 + 4* 76 t 4

Area

1.67 1.92

t 0.06” k 0.06

*Statistically significant difference between Groups I and 0. Note: Data are means ? SEM. Group I received isoflurane; Group 0 received opioid.

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Sex (M/P) 3/9* 1215

Plasma Choline&erase (U/L) 3,446 3,461

+ 221 ? 134

Mivacurium

groups. Repeated measures analysis of variance (ANOVA) was used to assess changes in infusion rate with time and recovery time after repeated bolus administration; Student’s t-test was used when appropriate. Correlation coefficients were calculated to examine potential associations between independent variables and infusion rate. Differences were considered to be statistically significant at p < 0.05.

Results Twenty-nine patients who contributed to the final data analysis had plasma cholinesterase activity and dibucaine inhibition in the normal range. One patient in Group 0 was excluded because of an abnormally low plasma cholinesterase activity of I,3 10 U/L (normal range is 2,436 to 4,872 U/L) with a 77% inhibition by dibucaine. No further attempt to characterize the phenotype of this patient was made. The average infusion rate of this patient was 1.8 pg/kg/min, and the T,,_,, recovery index after termination of infusion was 12.7 minutes. Mean plasma cholinesterase activity did not differ between the rest of Group 0 and Group I. The mean mivacurium infusion rates for Groups 1 and 0 differed significantly, and the infusion rates within each group varied over a threefold range (Table 2). The mean mivacurium infusion rate was approximately onethird less in the presence of isoflurane. During the first 15 minutes of mivacurium infusion, the infusion rates in each group tended to be higher by 35% to 50% and more variable than rates thereafter. There was no significant correlation between infusion rate and plasma cholinesterase activity. Following termination of the infusion, the Tpj_,j recovery index and the time to recovery of a TOF ratio of at least 0.75 were similar in both groups (n = 14). The recovery index was 6.0 + 0.7 minutes, and the time for the TOF ratio to reach at least 0.75 occurred in 17.9 * 1.5 minutes. There was no correlation between duration of infusion and the recovery index. In the 11 patients in Group 0 who received neostigmine at spontaneous recovery levels ranging from 11% to 51%, recovery to a

infusion in a.duh:

Powers el al.

TOF ratio of at least 0.75 occurred in 2.7 to 11.7 minutes. In the 5 patients in Group I who received neostigmine at spontaneous recovery levels of 14% to 25%, recovery to a TOF ratio of at least 0.75 occurred in 3.0 to 16.2 minutes.

Discussion Previous studies have determined the infusion rate of mivacurium required to maintain 95% neuromuscular blockade in adults during N,O-opioid anesthesia.5-g The average effective infusion rate of mivacurium in these studies ranged from 5.2 to 8.3 p.g/kg/min. The average effective mivacurium infusion rate reported in our study, 6.4 pg/kg/min, is consistent with these previous observations, No previous study has documented the effective infusion rate of mivacurium in the presence of isoflurane. We demonstrated that isoflurane (in the presence of N,O and fentanyl) potentiates neuromuscular blockade induced by mivacurium. The average effective infusion rate during isoflurane (0.5% to 0.75% end-tidal concentration) anesthesia was approximately one-third less than that during N,O-opioid anesthesia. This degree of potentiation is similar to that previously observed for bolus doses of mivacurium with isofluraneS-4 and for an infusion of mivacurium with enflurane.g Plasma cholinesterase activity could be one of several factors that influence the infusion rate for mivacurium.jJ’ However, the correlation between the mivacurium infusion rate and plasma cholinesterase activity was not significant in this study. Although women may have lower plasma cholinesterase activity than men,‘* and although Group I included more women than Group 0, the plasma cholinesterase values did not differ between the groups. We found no evidence of a prolonged recovery rate or recovery index with prolonged infusions of mivacurium. The duration of infusion did not correlate with the recovery index. This absence of accumulation is presumably related to mivacurium’s short half-life, a result of its metabolism by normal plasma cholinesterase. In conclusion, mivacurium can be administered for

Table 2. Steady-State Infusion Rate and Recovery Data after Mivacurium Infusion Was Stopped

Recovery Index Group I

Infusion Rate (pg/kg/min) 4.0 + 0.8*

(1.4 to 8.6) 0

6.4 5 0.6 (2.7 to 10.4)

(TwA (min) 6.5 ? 1.0 (3.5 to 9.4) 5.7 t 0.9 (2.8 to 11.0)

Train-of-Four T,/T, 2 0.75 (min)

17.6 t 3.1 (10.3 to 26.2) 18.1 +z 1.8

(11.0 to 26.0)

*Statistically significant difference compared with Group I. Note: Data are means (range) ir SEM. Group I received isoflurane; Group 0 received opioid. No statistically significant difference between Groups I and 0 in recovery.

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several hours with no evidence of time-related change in the effective infusion rate. The effective infusion rate may be expected to be about one-third less in the presence of isoflurane than during opioid-barbiturate anesthesia. Interpatient variability is more than threefold, and a slightly greater infusion rate may be necessary in the first 15 minutes of infusion than is required thereafter. Therefore, the rate of infusion should be titrated with appropriate neuromuscular monitoring. After termination of a titrated infusion, relatively rapid spontaneous recovery of neuromuscular function occurs in normal adults. Alternatively, mivacurium-induced neuromuscular blockade may be readily antagonized with standard doses of neostigmine.

References Cook DR, Stiller RL, Weakly JN, Chakravorti S, Brandom BW, Welch RM: In vitro metabolism of mivacurium chloride (BW B1090U) and succinylcholine. Anesth Analg 1989;68:452-6. Savarese JJ, Ali HH, Basta SJ, et al: The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U). Anesthesiology 1988;68:723-32. Weber S, Brandom BW, Powers DM, et al: Mivacurium chloride (BW B1090U)-induced neuromuscular blockade during nitrous oxide-isoflurane and nitrous oxide-narcotic anesthesia in adult surgical patients. Anesth Analg 1988;67:495-9. Choi WW, Mehta MP, Murray DJ, et al: Neuromuscular and cardiovascular effects of mivacurium chloride in surgical patients receiving nitrous oxide-narcotic or nitrous oxide-isoflurane anaesthesia. CanJ Am&h 1989;36:641-50.

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5. Ah HH, Savarese JJ, Embree PB, et al: Clinical pharmacology of mivacurium chloride (BW B1090U) infusion: comparison with vecuronium and atracurium. Br / Anaesth 1988;61: 541-6. 6. Brandom BW, Woelfel SK, Cook DR, Weber S, Powers DM, Weakly JN: Comparison of mivacurium and suxamethonium administered by bolus and infusion. Br J Anaesth 1989;62: 488-93. 7. Caldwell JE, Heier T, Kitts JB, Lynam P, Fahey MR, Miller RD: Comparison of the neuromuscular block induced by mivacurium, suxamethonium or atracurium during nitrous oxidefentanyl anaesthesia. BrJ Anaesth 1989;63:393-9. ME, Larijani GE, Azad SS, et al: Comparison of 8. Goldberg tracheal intubating conditions and neuromuscular blocking profiles after intubating doses of mivacurium chloride or succinylcholine in surgical outpatients. Anesth Analg 1989;69: 959-65. 9. Shanks CA, Fragen RJ, Pemberton D, Katz JA, Risner ME: Mivacurium-induced neuromuscular blockade following single bolus doses and with continuous infusion during either balanced or enflurane anesthesia. Anesthesiology 1989;71:362-6. BW, Sarner JB, Woelfel SK, et al: Mivacurium in10. Brandom fusion requirements in pediatric surgical patients during nitrous oxide-halothane and during nitrous oxide-narcotic anesthesia. Anesth Analg 1990;71:16-22. NG: Continuous infusion of miv11. Alifimoff JK, Goudsouzian acurium in children. BrJ Anaesth 1989;63:520-4. CJ: The relation of sex, age, smok12. Propert DN, Brackenridge ing status, birth rank, and parental ages to pseudocholinesterase activity and phenotypes in a sample of Australian Caucasian adults. Hum Genet 1976;32:181-8.

Mivacurium infusion during nitrous oxide-isoflurane anesthesia: a comparison with nitrous oxide-opioid anesthesia.

To determine the potentiation of the neuromuscular blockade induced by a titrated infusion of mivacurium in the presence of isoflurane versus a nitrou...
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