Pipecuronium-Induced Neurornuscular Blockade During Nitrous Oxide-Fentanyl, Enflurane, Isoflurane, and Halothane Anesthesia in Surgical Patients Mohamed Naguib, Essam Abdulrazik,
MB, BCh, MSc, FFARCSI, MD, MB, BCh, MSC
Mohamed Seraj, MB, BCh, DA, FFARCSI, and
Department of Critical Care Medicine, Faculty of Medicine and Health Sciences, United Arab Emirates University, United Arab Emirates, and Department of Anaesthesia, King Khalid University Hospital, Saudi Arabia
This study was designed to determine the capacity of several anesthetics to augment pipecuronium neuromuscular blockade. The potency of pipecuronium was determined with single-bolus administration of 20-50 pglkg in 160 patients. Patients were anesthetized with N,O/O, (60:40) supplemented with fentanyl (4-5 pg/kg), halothane (0.8%), isoflurane (1.2%), or enflurane (1.7%). Neuromuscular blockade was measured by an acceleration-responsivetransducer (the Accelograph, Biometer International, Odense, Denmark). Responses were defined in terms of percent depression in first-twitch height and train-of-four response, and the dose-response curves were constructed after probit transformation of the responses. The dose-responsecurves were found to be parallel for both first twitch height and train-of-fourresponses. The
T
he relative potency of pipecuronium during administration of various anesthetics is not clear. The reported estimated doses producing 95% depression of twitch tension (ED,, doses) during nitrous oxide (N,O)-narcotic anesthesia have ranged from 48.7 pg/kg (1) to 59.4 pg/kg (2). In addition, discrepancies in dose-response results were reported for the effect of isoflurane on the potency of pipecuronium (1,2). Wierda et al. (1)reported that the ED,, for pipecuronium was 44.6 pg/kg in patients anesthetized with N 2 0 / 0 2and 3% isoflurane (inspired concentration). Pittet et al. (2) reported a similar value (42.3 pg/kg) in patients anesthetized with N20/0, and 0.9% isoflurane. Furthermore, there are no data The results of this study were presented in part at the 10th World Congress of Anaesthesiologists, The Hague, The Netherlands, June 1992. Accepted for publication March 31, 1992. Address correspondence to Dr. Naguib, Department of Critical Care Medicine, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, A1 Ain, United Arab Emirates. 01992 by the International Anesthesia Research Society 0003-2999/92/$5.00
dose-response lines for the enflurane and isoflurane groups were displaced significantly (P < 0.01) to the lett of the line for the fentanyl-N,O group. The calculated doses producing 50% depression of first twitch height were 21.9, 21.2, 18.9, and 17.8 p g k g for the N,Ofentanyl, halothane, isoflurane, and enflurane groups, respectively. Corresponding calculated doses for 50% depression of train-of-four response were significantly smaller (15.5, 14.4, 13.7, 11.9 @kg, respectively).The enhancing effects of the volatile anesthetics were reflected by significant prolongation of the clinical duration of neuromuscular blockade by pipecuronium. It is concluded that the potency of pipecuronium is enhanced more by enflurane and isoflurane than halothane or fentanyl-N,O anesthesia. (Anesth Analg 1992;75:19>7)
available for the effects of enflurane or quantitative comparisons of the effects of the four commonly used anesthetics on the neuromuscular block produced by pipecuronium. This study was designed to determine the doseresponse relation of pipecuronium during fentanylN20/02, enflurane-N20/02, isoflurane-N20/02, and halothane-N,0/02 anesthesia.
Methods After institutional approval, 160 ASA physical status group I and I1 adult patients (80 male, 80 female) were studied. All patients were undergoing elective procedures, had no neuromuscular, renal, or hepatic disease, and were not taking any drug known to interfere with neuromuscular function. Informed consent was obtained. A11 patients received 2 mg of oral lorazepam 90 min preoperatively. An intravenous infusion of lactated Ringer’s solution was established
Anesth Analg 1992;75:19>7
193
194
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NAGUIB ET AL. PII'ECURONIUM AND VOLATILE ANESTHETICS
Table 1. Demographic Data for 160 Patients Undergoing Elective Surgery Age (yr) Weight (kg) Gender (ME)
Enflurane
Isoflurane
Halothane
Fentanyl-N,O
32.1 (8.2) 65.3 (5.1) 20/20
33.3 (7.6) 63.6 (5.7) 20120
35.9 (6.5) 63.3 (4.5) 20120
33.9 (8.2) 62.4 (4.4) 20120
Age and body weight are presented as means (SD)
before induction of anesthesia. Routine monitoring was used. Temperature was monitored by a nasopharyngeal thermistor and maintained at 36.5 2 0.5"C. Patients were randomly assigned to one of the following anesthetic groups (n = 40 in each): N,Ofentanyl, N,O-enflurane, N20-isoflurane, or N,Ohalothane. Stratified sampling was used to obtain an even gender distribution. Anesthesia was induced with thiopental (5 mgkg) and was maintained with N,O and 0, (60:40) supplemented with fentanyl ( 4 5 pgkg IV),enflurane, isoflurane, or halothane via a face mask. The trachea was sprayed with 4 mL of 4% lidocaine and was intubated without the use of muscle relaxants. After intubation, the end-tidal concentration of the volatile anesthetics was adjusted to 1 MAC (excluding N20). The resulting end-tidal concentrations were 1.7% for enflurane, 1.2% for isoflurane, and 0.8% for halothane. The concentrations of the volatile anesthetics, N,O, O,, and CO, were determined continuously by a multiple-gas analyzer (Capnomac, Datex Instrumentarium Corporation, Helsinki, Finland). Ventilation was adjusted to maintain normocapnia (end-tidal CO, pressure [PETCOz] 3 5 4 0 mm Hg). The acceleration transducer, 5 x 10 mm in size and weighing 20 g, is a piezoelectric ceramic wafer with an electrode on each side (Biometer International, Odense, Denmark) that was fastened to the volar side of the interphalangeal joint of the thumb (3,4). When the wafer experiences acceleration, a voltage difference develops between the two electrodes, and this voltage can be measured and recorded directly. The ulnar nerve was stimulated at the wrist with squarewave supramaximal stimuli of 0.2-ms duration, delivered in a train-of-four (TOF) sequence at 2 Hz every 15 s. A free movement during evoked thumb adduction was allowed by fixation of the extended four ulnar fingers by an elastic band. On stimulating the ulnar nerve, the transducer was set in motion, and a voltage developed that was proportional to the acceleration. The resulting electrical signal was analyzed by the Accelograph (Biometer International). The TOF values were displayed and recorded. The first twitch (Tl) of the TOF was considered the twitch height. After end-tidaI anesthetic concentration was stable for 30 min, we administered at random one of the
selected doses of pipecuronium (20, 30, 40, or 50 p g k g ) intravenously as a free-flowing bolus dose. Ten patients were studied at each dose level in each of the four anesthetic groups. The neuromuscular response to pipecuronium was recorded as the maximum depression of T1 and TOF expressed as a percent of the control value. Once the maximum effect of the selected initial dose was reached (that is, when no further decrease in evoked response to three consecutive stimuli occurred), a supplementary dose was chosen so that together with the selected initial dose, a total of 50 p g k g was administered to all patients. Time to maximum effect (the time from injection of the selected dose to maximum effect) and time from injection of the full dose (50 pgikg) to 10% recovery of the twitch height (clinical duration) were recorded. The percent values for T1 and TOF depression were transformed to probits and plotted against the logarithm of the dose of pipecuronium with PCNONLIN (5). Regression lines were compared with analysis of covariance. First, we tested the l i e s to determine whether they deviated from parallelism; if they did not, an F-test was applied to determine whether the elevations were different. If so, a t-test was applied to determine which line differed in elevation (6) with a BMDP statistical package (1990). The ED, and ED, values (doses causing 50% and 95% depression of twitch tension and TOF ratio, respectively) were calculated from the log-probit regression lines for each anesthetic group. Using analysis of variance, we compared age, body weight, onset time, and clinical duration among anesthetic groups. For all statistical comparisons, differences were considered significant when P < 0.05.
Results Results are expressed as means (sD). There was no significant difference among the four groups with respect to age or weight (Table 1). Figures 1 and 2 show dose-response curves for the first-twitch height (Tl) and TOF response, respectively. For all groups, the regression lines did not deviate from parallelism but differed in position ( P < 0.0001). The dose-response regression lines of pipecuronium for the enflurane and isoflurane groups
ANESTH ANALG 1992;75:19>7
NAGUIB ET AL. PIPECURONIUM AND VOLATILE ANESTHETICS
Q)
99.5
=0
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195
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0 LL. 490
.-E9 E I-
80
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70
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.-c0 P
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60
o 40
30 c,
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20
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- 1
10
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I
I
20
30
40
I 50
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I 60
-
Pipecuronium ( pg.Kg‘ ) Figure 1. Dose-response relation for twitch height (Tl) for pipecuronium during fentanyl-N,O/O,, halothane-N,O/O,, isofluraneN,O/O,, and enflurane-N20/Oz anesthesia. The horizontal lines at the ED, and ED, levels indicate 95% confidence limits.
were shifted significantly (P < 0.01) to the left of that for the fentanyl-N,0/02 group. Calculated ED,, and ED, values are presented in Table 2. The calculated ED,, and ED,, values of pipecuronium for TOF response were significantly smaller than those for the T1 response (the 95% confidence limits did not overlap). The time to maximum effect for pipecuronium in patients receiving N,O and fentanyl, halothane, isoflurane, and enflurane was 6.3 (0.5), 4.2 (0.7), 3.8 (0.5), and 2.7 (0.4) min, respectively, and was statistically different (P < 0.01) among all groups. The clinical duration of the total 50-pgkg dose for these groups was 29.4 (4.5), 39.5 (4.7), 50.9 (4.5), and 62.9 (4.4) min, respectively, and was statistically different ( P < 0.01) among the four groups.
Discussion The results of the present study demonstrate that compared with fentanyl-N,O/O, anesthesia, enflurane and isoflurane but not halothane enhance the
n
o
10
20
30
50
40
Log
-
60
Pipecuronium ( pg.Kg’ ) Figure 2. Dose-response relation for train-of-four (TOF) response for pipecuronium during fentanyl-N,O/O,, halothane-N,O/O,, isoflurane-N20/02, and enflurane-N,O/O, anesthesia. The horizontal lines at the ED, and ED,, levels indicate 95% confidence limits.
neuromuscular blocking effect of pipecuronium. It also demonstrates that the potency of pipecuronium does not differ by >23% from the four anesthetic techniques used in this study. Our findings are consistent with those of Pittet et al. (2) who reported that isoflurane but not halothane enhanced the potency of pipecuronium. In contrast, Wierda et al. (1) found that the estimated ED,, doses for pipecuronium during N,O/O, and isoflurane, halothane, or droperidol/fentanyl were not different and were, respectively, 44.6, 46.9, and 48.7 p g k g . This apparent lack of significant difference among the ED9, doses has been attributed to the brevity of exposure of their patients to the anesthetic (10-15 min) before the administration of pipecuronium (1). The potency of nondepolarizing relaxants depends on the volatile anesthetic used, the method of monitoring neuromuscular function (7), and even geographic location (8). We found that TOF EDso and ED,, values were significantly less than that of the T1 response (Table 2). Recent investigations (9) indicated that the calculated ED, and ED,, values of ORG 9426
196
ANESTH ANALG 1992;7519>7
NAGUIB ET AL. PII'ECURONIUM AND VOLATILE ANESTHETICS
Table 2. Effective Doses of Pipecuronium for 50% (EDm) and 95% (ED,,) Depression of Twitch Height (Tl) and Train-of-Four (TOF) Response (and Their 95% Confidence Limits) During Enflurane, Isoflurane, Halothane, and
Fentanyl-N,O Anesthesia Depression of TOF response
Depression of T1 (% control value)
ED, (Ilg/kg) ED,, ( P g w
Enflurane
Isoflurane
Halothane
FentanylN*O
Enflurane
Isoflurane
Halothane
N2O
17.8 (17.1-18.5) 35 (33.8-36.3)
18.9 (18.3-19.5) 35.9 (34.7-37.2)
21.2 (20.7-21.7) 37.3 (36.138.5)
21.9 (21.4-22.4) 39 (37.8-40.3)
11.9 (10.7-13.2) 28.7 (27.5-30)
13.7 (12.7-14.8) 30.8 (29.6-32.1)
14.4 (13.5-15.4) 31.9 (30.6-33.2)
15.5 (14.7-16.4) 33.9 (32.5-35.3)
were significantly less with the TOF mode of stimulation compared with the single-twitch stimulation. Ali and Savarese (10) showed that the dose-response curve for d-tubocurarine shifted to the left as the frequency of stimulation was increased. This could be attributed to a stimulation-induced increase in the muscle blood flow that would increase delivery of the drug to the neuromuscular junction. Dose-response relations obtained after TOF stimulation may be of more importance than after single-twitch stimulation, because the former is a more sensitive indicator of neuromuscular blockade (11,12). In this study, the calculated first-twitch ED,, doses during fentanyl-N,O/O,, halothane, and isoflurane anesthesia were 21.9, 21.2, and 18.9 pgkg, respectively. Similar values (27.3, 22.7, and 20.6 p g k g , respectively) were reported by Wierda et al. (1) who used a single-twitch mode of stimulation and mechanomyography and by Pittet et al. (2) (31.7, 25, and 18 pgkg, respectively) who used electromyography and cumulative technique to construct the doseresponse curve. The range of values reported for the ED,, has been greater than for the ED, (1,2). This variability can be attributed to the difficulty of accurately defining the extreme ranges of the dose-response curve and to the differences in the anesthetic techniques and stimulation frequency used by various investigators. We found that at 1 MAC value, enflurane and isoflurane were similar in enhancing the neuromuscular blockade induced by pipecuronium (Table 2). The first-twitch ED,, of pipecuronium was approximately 19% less during enflurane (17.8 p g k g ) and 14% less during isoflurane (18.9 p g k g ) than that during fentanyl-N,O anesthesia (21.9 pgkg). This is consistent with the effect of these volatile anesthetics on other nondepolarizing muscle relaxants (11-14) despite the differences in end-tidal concentration of volatile agents used in these various studies. Several investigators demonstrated that enflurane and isoflurane equally augmented a neuromuscular blockade induced by pancuronium or d-tubocurarine and that both anesthetics were approximately twice
Fentanyl-
as potent as halothane (14-16). On the other hand, Rupp et al. (17) found that the volatile anesthetics interact differently with vecuronium than with other nondepolarizing muscle relaxants. At 1.2 and 2.2 MAC levels of anesthesia (which included the MAC contribution from 70% N,O), enflurane was more potent than either isoflurane or halothane in augmenting a vecuronium-induced neuromuscular blockade, but the effects of isoflurane and halothane were similar (17). Several studies have compared the potency of atracurium during various anesthetic conditions (18-20). Rupp et al. (18) concluded that the potency of atracurium was not different during halothane-N,O and enflurane-N20 anesthesia. In contrast, Sokoll et al. (20) found that the ED, of atracurium was 40% less during isoflurane anesthesia than during N,O-fentanyl anesthesia. Isoflurane (21) and enflurane (22) were shown to have a potentiating effect on the dose-response relation of mivacurium. This is also consistent with the known effect of these volatile anesthetics on d-tubocurarine, pancuronium, pipecuronium, and possibly atracurium. In vitro, halothane and isoflurane potentiate the effects of neuromuscular blocking agents to the same extent (23). In contrast, in vivo, isoflurane produces more potentiation than does halothane (16). This was attributed to an increased muscle blood flow produced by isoflurane. Possible mechanisms by which inhaled anesthetics may exert their effect include depression of the central nervous system, presynaptic inhibition of acetylcholine mobilization and release, postsynaptic receptor desensitization, and an action on the muscle at some point distal to the cholinergic receptor (24,25). Stanec and Baker (26) noted that volatile anesthetics and nondepolarizing muscle relaxants may have synergistic prejunctional actions at the neuromuscular junction. The time to development of maximal block and the clinical duration of the total dose of 50 p g k g were dependent on the type of anesthetic used. In this respect, the potentiation of the neuromuscular effects of pipecuronium may be ranked as follows: enflurane > isoflurane > halothane > fentanyl.
ANESTH ANALG 1992;75:19S7
We used the Accelograph to monitor the neuromuscular effects of pipecuronium. The Accelograph is based on a new measuring principle: measurement of force is replaced by measurement of acceleration. The principle behind the use of the accelerometer for measuring neuromuscular transmission is Newton's second law: Force = Mass X Acceleration. Because the mass involved is constant, the acceIeration is proportional to the force. Therefore, a TOF ratio, for example, measured by means of the acceleration transducer, should in theory correspond to a TOF ratio determined by a measurement of force (4). Viby-Mogensen et al. (3) noted that the relation between force displacement transducer-derived TOF responses and acceleration transducer-derived TOF responses is better than that between force displacement transducer-derived TOF responses and electromyography-derived TOF. Similarly, May and colleagues (27,28) reported that the acceleration transducer is equal to the force displacement transducer with regard to precision and accuracy in clinical recordings. In conclusion, we have demonstrated that the potency of pipecuronium is enhanced by enflurane and isoflurane but not halothane when compared with fentanyl-N,O/O, anesthesia. The duration of neuromuscular blockade induced by pipecuronium was significantly influenced by the anesthetic technique in the following decreasing order: enflurane > isoflurane > halothane > fentanyl. We thank Lorraine Ritchie for expert secretarial assistance. Pipecuronium was supplied by Organon Teknika, Belgium.
References 1. Wierda JMKH, Richardson FJ, Agoston S. Dose-response relation and time course of action of pipecuronium bromide in humans anesthetized with nitrous oxide and isoflurane, halothane, or droperidol and fentanyl. Anesth Analg 1989;68: 208-13. 2. Pittet J-F, Tassonyi E, Morel DR, Gemperle G, Richter M, Rouge J-C. Pipecuronium-induced neuromuscular blockade during nitrous oxide-fentanyl, isoflurane, and halothane anesthesia in adults and children. Anesthesiology 1989;71:2103. 3. Viby-Mogensen J, Hensen E, Wemer M, Nielsen K. Measurement of acceleration: a new method of monitoring neuromuscular function. Acta Anaesthesiol Scand 1988;32:45-8. 4. Jensen E, Viby-Mogensen J, Bang U. The Accelograph: a new neuromuscular transmission monitor. Acta Anaesthesiol Scand 1988;32:49-52. 5. Statistical Consultants, Inc. PCNONLIN and NONLINM software for the statistical analysis on nonlinear models. American Statistician 1986;40:52. 6. Armitage P. Statistical methods in medical research. 1st ed. London: Blackwell, 1971:269-301. 7. Blackman JG. Stimulus frequency and neuromuscular block. Br J Pharmacol1963;205-16.
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8. Fiset P, Donati F, BaIendran P, Meistelman C , Lira E, Bevan DR. Vecuronium is more potent in Montreal than in Paris. Can
J Anaesth 1991;38:717-21. 9. Cooper RA, Mirakhur RK, Elliott P, McCarthy G. Estimation of the potency of ORG 9426 using two different modes of nerve stimulation. Can J Anaesth 1992;39:139-42. 10. Ali HH, Savarese JJ. Stimulus frequency and dose-response curve to d-tubocurarine in man. Anesthesiology 1980;52:3&9. 11. Ali HH, Utting JE, Gray C. Stimulus frequency in the detection of neuromuscular blockade in humans. Br J Anaesth 1970;42: 967-78. 12. Waud BE, Waud DR. The relation between the response to "train-of-four" stimulation and receptor occlusion during competitive neuromuscular block. Anesthesiology 1972;3731&22. 13. Gencarelli PJ, Miller RD, Eger EI 11, Newfield P. Decreasing enflurane concentrations and d-tubocurarine neuromuscular blockade. Anesthesiology 1982;561924. 14. Fogdall RP, Miller RD. Neuromuscular effects of enflurane, alone and combined with d-tubocurarine, pancuronium and sucanylcholine in man. Anesthesiology 1975;42:173-8. 15. Miller RD, Eger EI 11, Way WL, Stevens WC, Dolan WM. Comparative neuromuscular effects of Forane and halothane alone and in combination with d-tubocurarine in man. Anesthesiology 1971;35:38-42. 16. Miller RD, Way WL, Dolan WM, Stevens WC, Eger EI 11. Comparative neuromuscular effects of pancuronium, gallamine, and succinylcholine during Forane and halothane anaesthesia in man. Anesthesiology 1980;35:509-14. 17. Rupp SM, Miller RD, Gencarelli P. Vecuronium-induced neuromuscular blockade during enflurane, isoflurane and halothane anesthesia in humans. Anesthesiology 1984;60:102-5. Miller RD. Neuromuscular effects of 18. Rupp SM, McChristian JW, atracurium during halothane-nitrous oxide and enflurane-nitrous oxide anesthesia in humans. Anesthesiology 1985;63.16-9. 19. Payne JP, Hughes R. Evaluation of atracurium in anaesthetized man. Br J Anaesth 1981;53:45-54. 20. Sokoll MD, Gergis SD, Mehta M, Ali NM, Lineberry C. Safety and efficacy of atracurium (BW33A) in surgical patients receiving balanced or isoflurane anesthesia. Anesthesiology 1983;58:45&5. 21. 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;67495-9. 22. Caldwell JE, Kitts JB, Heier T, Fahey MR, Lynam DP, Miller RD. The dose-response relationship of mivacurium chloride in humans during nitrous oxide-fentanyl or nitrous oxideenflurane anesthesia. Anesthesiology 1989;70:31-5. 23. Vitez TS, Miller RD, Eger EI 11, Way WL. An in-vitro comparison of halothane and isoflurane potentiation of neuromuscular blockade. Anesthesiology 1974;41:534. 24. Waud BE, Waud DR. The effects of diethyl ether, enflurane, and isoflurane at the neuromuscular junction. Anesthesiology 1975;42:275430. 25. Waud BE, Waud DR. Comparison of the effects of general anesthetics on the end-plate of skeletal muscle. Anesthesiology 1975;43:54&7. 26. Stanec A, Baker MS. Prejunctional effects of potent inhalation anesthetics in man and cat (abstract). Anesthesiology 1987;67 A336. 27. May 0, Nielsen HK, Werner MU. The acceleration transducer-an assessment of the precision in comparison with a force displacement transducer. Acta Anaesthesiol Scand 1988;32 23943. 28. Wemer MU, Nielsen HK, May 0, Hemes M. Assessment of neuromuscular transmission by the evoked acceleration response. An evaluation of the accuracy of the acceleration transducer in comparison with a force displacement transducer. Acta Anaesthesiol Scand 1988;32:395400.
MB, BCh, MSc, FFARCSI, MD, MB, BCh, MSC
Mohamed Seraj, MB, BCh, DA, FFARCSI, and
Department of Critical Care Medicine, Faculty of Medicine and Health Sciences, United Arab Emirates University, United Arab Emirates, and Department of Anaesthesia, King Khalid University Hospital, Saudi Arabia
This study was designed to determine the capacity of several anesthetics to augment pipecuronium neuromuscular blockade. The potency of pipecuronium was determined with single-bolus administration of 20-50 pglkg in 160 patients. Patients were anesthetized with N,O/O, (60:40) supplemented with fentanyl (4-5 pg/kg), halothane (0.8%), isoflurane (1.2%), or enflurane (1.7%). Neuromuscular blockade was measured by an acceleration-responsivetransducer (the Accelograph, Biometer International, Odense, Denmark). Responses were defined in terms of percent depression in first-twitch height and train-of-four response, and the dose-response curves were constructed after probit transformation of the responses. The dose-responsecurves were found to be parallel for both first twitch height and train-of-fourresponses. The
T
he relative potency of pipecuronium during administration of various anesthetics is not clear. The reported estimated doses producing 95% depression of twitch tension (ED,, doses) during nitrous oxide (N,O)-narcotic anesthesia have ranged from 48.7 pg/kg (1) to 59.4 pg/kg (2). In addition, discrepancies in dose-response results were reported for the effect of isoflurane on the potency of pipecuronium (1,2). Wierda et al. (1)reported that the ED,, for pipecuronium was 44.6 pg/kg in patients anesthetized with N 2 0 / 0 2and 3% isoflurane (inspired concentration). Pittet et al. (2) reported a similar value (42.3 pg/kg) in patients anesthetized with N20/0, and 0.9% isoflurane. Furthermore, there are no data The results of this study were presented in part at the 10th World Congress of Anaesthesiologists, The Hague, The Netherlands, June 1992. Accepted for publication March 31, 1992. Address correspondence to Dr. Naguib, Department of Critical Care Medicine, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, A1 Ain, United Arab Emirates. 01992 by the International Anesthesia Research Society 0003-2999/92/$5.00
dose-response lines for the enflurane and isoflurane groups were displaced significantly (P < 0.01) to the lett of the line for the fentanyl-N,O group. The calculated doses producing 50% depression of first twitch height were 21.9, 21.2, 18.9, and 17.8 p g k g for the N,Ofentanyl, halothane, isoflurane, and enflurane groups, respectively. Corresponding calculated doses for 50% depression of train-of-four response were significantly smaller (15.5, 14.4, 13.7, 11.9 @kg, respectively).The enhancing effects of the volatile anesthetics were reflected by significant prolongation of the clinical duration of neuromuscular blockade by pipecuronium. It is concluded that the potency of pipecuronium is enhanced more by enflurane and isoflurane than halothane or fentanyl-N,O anesthesia. (Anesth Analg 1992;75:19>7)
available for the effects of enflurane or quantitative comparisons of the effects of the four commonly used anesthetics on the neuromuscular block produced by pipecuronium. This study was designed to determine the doseresponse relation of pipecuronium during fentanylN20/02, enflurane-N20/02, isoflurane-N20/02, and halothane-N,0/02 anesthesia.
Methods After institutional approval, 160 ASA physical status group I and I1 adult patients (80 male, 80 female) were studied. All patients were undergoing elective procedures, had no neuromuscular, renal, or hepatic disease, and were not taking any drug known to interfere with neuromuscular function. Informed consent was obtained. A11 patients received 2 mg of oral lorazepam 90 min preoperatively. An intravenous infusion of lactated Ringer’s solution was established
Anesth Analg 1992;75:19>7
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194
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Table 1. Demographic Data for 160 Patients Undergoing Elective Surgery Age (yr) Weight (kg) Gender (ME)
Enflurane
Isoflurane
Halothane
Fentanyl-N,O
32.1 (8.2) 65.3 (5.1) 20/20
33.3 (7.6) 63.6 (5.7) 20120
35.9 (6.5) 63.3 (4.5) 20120
33.9 (8.2) 62.4 (4.4) 20120
Age and body weight are presented as means (SD)
before induction of anesthesia. Routine monitoring was used. Temperature was monitored by a nasopharyngeal thermistor and maintained at 36.5 2 0.5"C. Patients were randomly assigned to one of the following anesthetic groups (n = 40 in each): N,Ofentanyl, N,O-enflurane, N20-isoflurane, or N,Ohalothane. Stratified sampling was used to obtain an even gender distribution. Anesthesia was induced with thiopental (5 mgkg) and was maintained with N,O and 0, (60:40) supplemented with fentanyl ( 4 5 pgkg IV),enflurane, isoflurane, or halothane via a face mask. The trachea was sprayed with 4 mL of 4% lidocaine and was intubated without the use of muscle relaxants. After intubation, the end-tidal concentration of the volatile anesthetics was adjusted to 1 MAC (excluding N20). The resulting end-tidal concentrations were 1.7% for enflurane, 1.2% for isoflurane, and 0.8% for halothane. The concentrations of the volatile anesthetics, N,O, O,, and CO, were determined continuously by a multiple-gas analyzer (Capnomac, Datex Instrumentarium Corporation, Helsinki, Finland). Ventilation was adjusted to maintain normocapnia (end-tidal CO, pressure [PETCOz] 3 5 4 0 mm Hg). The acceleration transducer, 5 x 10 mm in size and weighing 20 g, is a piezoelectric ceramic wafer with an electrode on each side (Biometer International, Odense, Denmark) that was fastened to the volar side of the interphalangeal joint of the thumb (3,4). When the wafer experiences acceleration, a voltage difference develops between the two electrodes, and this voltage can be measured and recorded directly. The ulnar nerve was stimulated at the wrist with squarewave supramaximal stimuli of 0.2-ms duration, delivered in a train-of-four (TOF) sequence at 2 Hz every 15 s. A free movement during evoked thumb adduction was allowed by fixation of the extended four ulnar fingers by an elastic band. On stimulating the ulnar nerve, the transducer was set in motion, and a voltage developed that was proportional to the acceleration. The resulting electrical signal was analyzed by the Accelograph (Biometer International). The TOF values were displayed and recorded. The first twitch (Tl) of the TOF was considered the twitch height. After end-tidaI anesthetic concentration was stable for 30 min, we administered at random one of the
selected doses of pipecuronium (20, 30, 40, or 50 p g k g ) intravenously as a free-flowing bolus dose. Ten patients were studied at each dose level in each of the four anesthetic groups. The neuromuscular response to pipecuronium was recorded as the maximum depression of T1 and TOF expressed as a percent of the control value. Once the maximum effect of the selected initial dose was reached (that is, when no further decrease in evoked response to three consecutive stimuli occurred), a supplementary dose was chosen so that together with the selected initial dose, a total of 50 p g k g was administered to all patients. Time to maximum effect (the time from injection of the selected dose to maximum effect) and time from injection of the full dose (50 pgikg) to 10% recovery of the twitch height (clinical duration) were recorded. The percent values for T1 and TOF depression were transformed to probits and plotted against the logarithm of the dose of pipecuronium with PCNONLIN (5). Regression lines were compared with analysis of covariance. First, we tested the l i e s to determine whether they deviated from parallelism; if they did not, an F-test was applied to determine whether the elevations were different. If so, a t-test was applied to determine which line differed in elevation (6) with a BMDP statistical package (1990). The ED, and ED, values (doses causing 50% and 95% depression of twitch tension and TOF ratio, respectively) were calculated from the log-probit regression lines for each anesthetic group. Using analysis of variance, we compared age, body weight, onset time, and clinical duration among anesthetic groups. For all statistical comparisons, differences were considered significant when P < 0.05.
Results Results are expressed as means (sD). There was no significant difference among the four groups with respect to age or weight (Table 1). Figures 1 and 2 show dose-response curves for the first-twitch height (Tl) and TOF response, respectively. For all groups, the regression lines did not deviate from parallelism but differed in position ( P < 0.0001). The dose-response regression lines of pipecuronium for the enflurane and isoflurane groups
ANESTH ANALG 1992;75:19>7
NAGUIB ET AL. PIPECURONIUM AND VOLATILE ANESTHETICS
Q)
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Pipecuronium ( pg.Kg‘ ) Figure 1. Dose-response relation for twitch height (Tl) for pipecuronium during fentanyl-N,O/O,, halothane-N,O/O,, isofluraneN,O/O,, and enflurane-N20/Oz anesthesia. The horizontal lines at the ED, and ED, levels indicate 95% confidence limits.
were shifted significantly (P < 0.01) to the left of that for the fentanyl-N,0/02 group. Calculated ED,, and ED, values are presented in Table 2. The calculated ED,, and ED,, values of pipecuronium for TOF response were significantly smaller than those for the T1 response (the 95% confidence limits did not overlap). The time to maximum effect for pipecuronium in patients receiving N,O and fentanyl, halothane, isoflurane, and enflurane was 6.3 (0.5), 4.2 (0.7), 3.8 (0.5), and 2.7 (0.4) min, respectively, and was statistically different (P < 0.01) among all groups. The clinical duration of the total 50-pgkg dose for these groups was 29.4 (4.5), 39.5 (4.7), 50.9 (4.5), and 62.9 (4.4) min, respectively, and was statistically different ( P < 0.01) among the four groups.
Discussion The results of the present study demonstrate that compared with fentanyl-N,O/O, anesthesia, enflurane and isoflurane but not halothane enhance the
n
o
10
20
30
50
40
Log
-
60
Pipecuronium ( pg.Kg’ ) Figure 2. Dose-response relation for train-of-four (TOF) response for pipecuronium during fentanyl-N,O/O,, halothane-N,O/O,, isoflurane-N20/02, and enflurane-N,O/O, anesthesia. The horizontal lines at the ED, and ED,, levels indicate 95% confidence limits.
neuromuscular blocking effect of pipecuronium. It also demonstrates that the potency of pipecuronium does not differ by >23% from the four anesthetic techniques used in this study. Our findings are consistent with those of Pittet et al. (2) who reported that isoflurane but not halothane enhanced the potency of pipecuronium. In contrast, Wierda et al. (1) found that the estimated ED,, doses for pipecuronium during N,O/O, and isoflurane, halothane, or droperidol/fentanyl were not different and were, respectively, 44.6, 46.9, and 48.7 p g k g . This apparent lack of significant difference among the ED9, doses has been attributed to the brevity of exposure of their patients to the anesthetic (10-15 min) before the administration of pipecuronium (1). The potency of nondepolarizing relaxants depends on the volatile anesthetic used, the method of monitoring neuromuscular function (7), and even geographic location (8). We found that TOF EDso and ED,, values were significantly less than that of the T1 response (Table 2). Recent investigations (9) indicated that the calculated ED, and ED,, values of ORG 9426
196
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Table 2. Effective Doses of Pipecuronium for 50% (EDm) and 95% (ED,,) Depression of Twitch Height (Tl) and Train-of-Four (TOF) Response (and Their 95% Confidence Limits) During Enflurane, Isoflurane, Halothane, and
Fentanyl-N,O Anesthesia Depression of TOF response
Depression of T1 (% control value)
ED, (Ilg/kg) ED,, ( P g w
Enflurane
Isoflurane
Halothane
FentanylN*O
Enflurane
Isoflurane
Halothane
N2O
17.8 (17.1-18.5) 35 (33.8-36.3)
18.9 (18.3-19.5) 35.9 (34.7-37.2)
21.2 (20.7-21.7) 37.3 (36.138.5)
21.9 (21.4-22.4) 39 (37.8-40.3)
11.9 (10.7-13.2) 28.7 (27.5-30)
13.7 (12.7-14.8) 30.8 (29.6-32.1)
14.4 (13.5-15.4) 31.9 (30.6-33.2)
15.5 (14.7-16.4) 33.9 (32.5-35.3)
were significantly less with the TOF mode of stimulation compared with the single-twitch stimulation. Ali and Savarese (10) showed that the dose-response curve for d-tubocurarine shifted to the left as the frequency of stimulation was increased. This could be attributed to a stimulation-induced increase in the muscle blood flow that would increase delivery of the drug to the neuromuscular junction. Dose-response relations obtained after TOF stimulation may be of more importance than after single-twitch stimulation, because the former is a more sensitive indicator of neuromuscular blockade (11,12). In this study, the calculated first-twitch ED,, doses during fentanyl-N,O/O,, halothane, and isoflurane anesthesia were 21.9, 21.2, and 18.9 pgkg, respectively. Similar values (27.3, 22.7, and 20.6 p g k g , respectively) were reported by Wierda et al. (1) who used a single-twitch mode of stimulation and mechanomyography and by Pittet et al. (2) (31.7, 25, and 18 pgkg, respectively) who used electromyography and cumulative technique to construct the doseresponse curve. The range of values reported for the ED,, has been greater than for the ED, (1,2). This variability can be attributed to the difficulty of accurately defining the extreme ranges of the dose-response curve and to the differences in the anesthetic techniques and stimulation frequency used by various investigators. We found that at 1 MAC value, enflurane and isoflurane were similar in enhancing the neuromuscular blockade induced by pipecuronium (Table 2). The first-twitch ED,, of pipecuronium was approximately 19% less during enflurane (17.8 p g k g ) and 14% less during isoflurane (18.9 p g k g ) than that during fentanyl-N,O anesthesia (21.9 pgkg). This is consistent with the effect of these volatile anesthetics on other nondepolarizing muscle relaxants (11-14) despite the differences in end-tidal concentration of volatile agents used in these various studies. Several investigators demonstrated that enflurane and isoflurane equally augmented a neuromuscular blockade induced by pancuronium or d-tubocurarine and that both anesthetics were approximately twice
Fentanyl-
as potent as halothane (14-16). On the other hand, Rupp et al. (17) found that the volatile anesthetics interact differently with vecuronium than with other nondepolarizing muscle relaxants. At 1.2 and 2.2 MAC levels of anesthesia (which included the MAC contribution from 70% N,O), enflurane was more potent than either isoflurane or halothane in augmenting a vecuronium-induced neuromuscular blockade, but the effects of isoflurane and halothane were similar (17). Several studies have compared the potency of atracurium during various anesthetic conditions (18-20). Rupp et al. (18) concluded that the potency of atracurium was not different during halothane-N,O and enflurane-N20 anesthesia. In contrast, Sokoll et al. (20) found that the ED, of atracurium was 40% less during isoflurane anesthesia than during N,O-fentanyl anesthesia. Isoflurane (21) and enflurane (22) were shown to have a potentiating effect on the dose-response relation of mivacurium. This is also consistent with the known effect of these volatile anesthetics on d-tubocurarine, pancuronium, pipecuronium, and possibly atracurium. In vitro, halothane and isoflurane potentiate the effects of neuromuscular blocking agents to the same extent (23). In contrast, in vivo, isoflurane produces more potentiation than does halothane (16). This was attributed to an increased muscle blood flow produced by isoflurane. Possible mechanisms by which inhaled anesthetics may exert their effect include depression of the central nervous system, presynaptic inhibition of acetylcholine mobilization and release, postsynaptic receptor desensitization, and an action on the muscle at some point distal to the cholinergic receptor (24,25). Stanec and Baker (26) noted that volatile anesthetics and nondepolarizing muscle relaxants may have synergistic prejunctional actions at the neuromuscular junction. The time to development of maximal block and the clinical duration of the total dose of 50 p g k g were dependent on the type of anesthetic used. In this respect, the potentiation of the neuromuscular effects of pipecuronium may be ranked as follows: enflurane > isoflurane > halothane > fentanyl.
ANESTH ANALG 1992;75:19S7
We used the Accelograph to monitor the neuromuscular effects of pipecuronium. The Accelograph is based on a new measuring principle: measurement of force is replaced by measurement of acceleration. The principle behind the use of the accelerometer for measuring neuromuscular transmission is Newton's second law: Force = Mass X Acceleration. Because the mass involved is constant, the acceIeration is proportional to the force. Therefore, a TOF ratio, for example, measured by means of the acceleration transducer, should in theory correspond to a TOF ratio determined by a measurement of force (4). Viby-Mogensen et al. (3) noted that the relation between force displacement transducer-derived TOF responses and acceleration transducer-derived TOF responses is better than that between force displacement transducer-derived TOF responses and electromyography-derived TOF. Similarly, May and colleagues (27,28) reported that the acceleration transducer is equal to the force displacement transducer with regard to precision and accuracy in clinical recordings. In conclusion, we have demonstrated that the potency of pipecuronium is enhanced by enflurane and isoflurane but not halothane when compared with fentanyl-N,O/O, anesthesia. The duration of neuromuscular blockade induced by pipecuronium was significantly influenced by the anesthetic technique in the following decreasing order: enflurane > isoflurane > halothane > fentanyl. We thank Lorraine Ritchie for expert secretarial assistance. Pipecuronium was supplied by Organon Teknika, Belgium.
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