British Journal of Anaesthesia 1995; 74: 26-30

Dose-response studies of the interaction between mivacurium andsuxamethonium

M. NAGUIB, M. ABDULATIF, M. SELIM AND A. AL-GHAMDI

Summary

We have determined the effect of pretreatment withmivacurium on the potency of suxamethonium andthe effect of prior administration of suxamethoniumon the potency of mivacurium. We studied 100ASA I or II patients during thiopentone-fentanyl-nitrous oxide-isoflurane anaesthesia. Neuro-muscular block was recorded as the evoked thenarmechanomyographic response to train-of-fourstimulation of the ulnar nerve (2 Hz at 12-s inter-vals). Single dose-response curves were determinedby probit analysis. Pretreatment with mivacuriumhad a marked antagonistic effect on the develop-ment of subsequent depolarizing block produced bysuxamethonium. The dose-response curves for sux-amethonium alone and after pretreatment withmivacurium did not deviate from parallelism, butthose constructed after mivacurium were shiftedsignificantly to the right {P < 0.0001). The cal-culated doses producing 50% depression of T1(EDBQ) were 86 (95% confidence intervals 83-88)and 217 (208-225) ug kg"1 for suxamethoniumalone and after mivacurium, respectively. This studyalso demonstrated that prior administration ofsuxamethonium did not appear to influence eitherthe slope of the regression lines or the potency ofmivacurium. Combining the results of this studywith a previous study (mivacurium EDso = 20.8(20.3-21.3) jig kg"1 during isoflurane-nitrousoxide anaesthesia), we suggest that the potency ofmivacurium did not differ from that observed aftersuxamethonium (17.4 (16.9-17.9) ug kg"1). (Br.J.Anaesth. 1995; 74: 26-30)

Key wordsNeuromuscular block, mivacurium. Neuromuscular block, suxa-methonium. Neuromuscular block, measurement of response.Pharmacology, dose-response.

Mivacurium chloride is a short-acting, non-depolarizing neuromuscular blocking agent that hasrecently been introduced into clinical practice [1,2].It is hydrolysed by plasma cholinesterase at a rate70% of that of suxamethonium [3]. The effects ofthe interaction between suxamethonium and non-depolarizing neuromuscular blocking agents dependupon the order of administration and doses used[4—16]. Previous studies of the effects of suxa-methonium on the neuromuscular effects of sub-sequently administered non-depolarizing neuro-muscular blocking drugs in patients have produced

conflicting results. Several investigators reportedpotentiation of the effects of tubocurarine [4],pancuronium [5], vecuronium and atracurium [6-8]by prior administration of suxamethonium. Incontrast, Walts and Dillon [9] noted the opposite fortubocurarine. Others found no significant influencefor suxamethonium on the subsequent administra-tion of pancuronium, doxacurium, pipecuronium orrocuronium [10-13]. On the other hand, prioradministration of small doses of different non-depolarizing neuromuscular blocking drugs had anantagonistic effect on the development of subsequentdepolarizing block produced by suxamethonium[14-16].

The detailed interactions of mivacurium andsuxamethonium have not been studied previously.Therefore, the purpose of this study was twofold: (a)to compare dose—response data for suxamethoniumalone and after pretreatment with mivacurium 21 ugkg"1, and (b) to compare the dose-response curvesfor mivacurium alone and after complete recoveryfrom a preceding bolus administration of suxa-methonium 1 mg kg"1.

Patients and methods

After obtaining institutional approval and informedconsent, we studied 100 ASA I or II patients of bothsexes, aged 16-55 (mean 31.9) yr and weight 45-88(mean 65.6 (SD 11.5)) kg. All patients were under-going elective procedures, had no neuromuscular,hepatic or renal disease, and were not receiving anydrug known or suspected to interfere with neuro-muscular function. All patients were premedicatedwith lorazepam 2 mg orally approximately 90 minbefore induction of anaesthesia. An i.v. infusion oflactated Ringer's solution was commenced beforeinduction of anaesthesia. ECG, pulse oximetry andarterial pressure were monitored. Temperature wasmonitored by a nasopharyngeal thermistor andmaintained at 36.5 ±0.5 °C.

Anaesthesia was induced with thiopentone 5 mgkg"1 and maintained with 60% nitrous oxide inoxygen supplemented with fentanyl 2 ug kg"1 and

MOHAMED NAGUIB, MB, BCH, MSC, FFARCSI, MD, MOHAMEDABDULATIF*, MB, BCH, MSC, MD, MAHDI SELIM*, MB, BCH, MSC,ABDULMOHSIN AL-GHAMDI*, MD, BS, DA, Department of An-aesthesia and ICU, King Saud University, Faculty of Medicine atKing Khalid University Hospital, PO Box 7805, Riyadh 11472,Saudi Arabia. Accepted for publication: July 28, 1994.

*Present address: Department of Anaesthesia, King FaisalUniversity, Saudi Arabia.

Suxamethonium—mivacurium interactions 27

isoflurane via a face mask. The trachea was sprayedwith 4 ml of 4 % lignocaine and intubated withoutthe use of neuromuscular blockers. After intubation,the end-tidal concentration of isoflurane was adjustedto 1.2% (1 MAC excluding nitrous oxide). Theconcentrations of isoflurane, nitrous oxide, oxygenand carbon dioxide were determined continuouslyby a multiple-gas analyser (Capnomac, Datex Instru-mentarium Corporation, Helsinki, Finland). Ven-tilation was adjusted to maintain normocapnia (end-tidal carbon dioxide partial pressure 4.8—5.3 kPa).

While end-tidal concentrations were stabilized for30 min, monitoring of neuromuscular block startedonly 10 min before administration of the neuro-muscular blocker. The ulnar nerve was stimulatedsupramaximally at the wrist with square pulses of0.2-ms duration, delivered in a train-of-four (TOF)sequence at 2 Hz every 12 s, using a Myotestperipheral nerve stimulator (Biometer International,Odense, Denmark). The resultant contraction of theadductor pollicis muscle was recorded using a forcedisplacement transducer and neuromuscular func-tion analyser (Myograph 2000, Biometer Inter-national, Odense, Denmark). Preload tension of thethumb was maintained at 300 g throughout theinvestigation.

Patients were allocated randomly to three groups.In group I, suxamethonium 50, 100 or 200 ug kg"1

was administered in a random order to threesubgroups of 10 patients each. Patients in group IIreceived mivacurium 21|igkg~' (lxED,,, duringthiopentone-fentanyl-nitrous oxide-isoflurane an-aesthesia [17]) as pretreatment. In group II, aftermaximum twitch depression of the pretreatment wasidentified, suxamethonium 100, 200, 300 or 450 ugkg"1 was administered in a random fashion to foursubgroups of 10 patients each. Patients in group IIIreceived suxamethonium 1 mg kg"1, and after com-plete recovery from depolarizing block, mivacurium10, 25 or 40 ug kg"1 was administered in a randomfashion to three subgroups of 10 patients each. In thelatter group, the dose-response data were compared

with the data previously obtained by Naguib and co-workers under identical experimental conditions,but in the absence of prior suxamethonium [17]. Alldrugs were given over 5 s into a rapidly flowing i.v.infusion. The neuromuscular response was recordedas maximum depression of T l , expressed as apercentage of the control value. When the maximumeffect of the selected dose was reached, the study wasterminated and anaesthesia continued as appropriatefor surgery. Onset of neuromuscular block was theinterval between administration of suxamethoniumin groups I and II, or mivacurium in group III, untilmaximum depression of twitch height.

Depression of Tl (expressed as a percentage of thecontrol value) in each group was transformed toprobits and plotted against the logarithm of the doseusing PCNONLIN version 4.2A (ClinTrials, Inc.,Lexington, KY, USA) [18]. Regression lines werecompared using analysis of covariance. First, wetested the lines to determine if they deviated fromparallelism. If they did not, an F test was applied todetermine if the elevations were different. If so, a ttest was applied to determine which line differed inelevation [19], using the BMDP statistical package,release 7.01 (University of California Press, Berkeley,CA, USA, 1994). The EDW, EDgo and EDW values(doses causing 50%, 80% and 95% depression oftwitch tension, respectively) were calculated fromthe log-probit regression lines for each group. Usinganalysis of variance, we compared age and bodyweight between the different groups. UnpairedStudent's t tests were used where appropriate.Results are expressed as mean (95% confidenceintervals) and were considered significant whenP < 0.05.

Results

POTENCY ESTIMATES OF SUXAMETHONIUM

The mean Tl and TOF ratio observed afterpretreatment with mivacurium 21 ug kg"1 (group II)were 71 (95% confidence intervals 62-81)% of

10 3 •

j. L

-.-.,, i

,»=.*•

10 s

i IFigure 1 Myographic recordings obtained after administration of suxamethonium (S) 200 ug kg"1 alone in apatient in group I (A) and suxamethonium 200 ug kg"1 after pretreatment with mivacurium 21 jig kg"1 in a patientin group II (B). A: Maximum block occurred after 52 s and Tl at maximum block was 20% (of control tension).Recovery from maximum depression to control twitch height occurred 197 s after administration ofsuxamethonium. B: T l height was 82% of control before administration of suxamethonium. After administrationof suxamethonium 200 ug kg"1, maximum block was observed after 42 s, at which time T l was 25 % (of controltension). Recovery to pre-suxamethonium T l height (82% of control) occurred 286 s after administration ofsuxamethonium (not shown). The fade observed in the TOF stimulation in recording A was because of the use ofisoflurane in dris study.

28 British Journal of Anaesthesia

Table 1 Mean (95 % confidence intervals) doses of suxamethonium (with and without mivacurium pretreatment)required for 50% (ED*,) and 80% (EDgo) depression of Tl . ***/> < 0.0001 compared with the correspondingvalue in patients who received mivacurium pretreatment

EDgo (ug kg"1)Slope of probit response vslogarithm of dose

Without mivacuriumpretreatment

After mivacuriumpretreatment

86 (83-88)***

217(208-225)

135(130-141)***

420 (389-̂ 150)

4.2 (3.9-̂ 1.4)

2.9 (2.6-3.2)

99

98

95-

90-

a of

con

s£co

9SSI

a.•D

80

70

60

50

40 -

3 0 -

2 0 -

50 100 200 300 400 500Suxamethonium (ug kg"1)

Figure 2 Log dose-probit plot for Tl depression afteradministration of suxamethonium alone ( • ) or aftermivacurium pretreatment (#) . Individual points represent themean value attained with each dose and bars represent 95 %confidence intervals.

control tension and 0.68 (0.57-0.77), respectively.These effects were observed after 366 (331-401) s. Arepresentative result of the effects of suxamethoniumadministered alone and after mivacurium pre-treatment is shown in figure 1.

The ED,,, and EDgo values for suxamethoniumalone and after mivacurium are presented in table 1.Pretreatment with mivacurium significantly (P <0.0001) increased all ED values for suxamethonium

9 8 -

95

90

8 0 -

tro

cou'oa?

non

i

aQ.<D

T3

H

70

60

50

40

30

20

10

5

2

10 20 30 40

Mivacurium (ug kg"1)

50 60

Figure 3 Log dose—probit plot for Tl depression formivacurium with (# ) and without ( • ) prior suxamethonium.The curve for the group without suxamethonium is taken fromNaguib and colleagues [17]. Individual points represent themean value attained with each dose and bars represent 95 %confidence intervals.

(table 1). Some of the calculated ED values were notreported because they were outside the range ofdoses tested. The slope of the line describing Tldepression after suxamethonium in group I was notsignificantly different from the corresponding line ingroup II who received mivacurium pretreatment(table 1, fig. 2). The lines constructed for group IIwere shifted significantly to the right (P < 0.0001).

Table 2 Mean (95 % confidence intervals) doses of mivacurium (with and without prior suxamethonium)required for 50% (ED*,), 80% (EDg,) and 95% (EDOT) depression of Tl

EDW Qtg kg-1) EDJO (ug kg"') ED<» (ug kg"1)Slope of probit responsevs logarithm of dose

Without priorsuxamethonium [17]

After suxamethonium

20.8(20.3-21.3)

17.4(16.9-17.9)

28 (27-29)

27(26-28)

37.4 (35.8-39)

38 (36-̂ K))

5.0 (4.6-5.4)

4.4 (4.05-4.7)

Suxamethonium-mivacurium interactions 29

INFLUENCE OF SUXAMETHONIUM ON THE POTENCY OFMIVACURIUM

Administration of suxamethonium 1 mg kg"1 togroup III resulted in 100% neuromuscular block inall patients. Twitch response ceased after 36 (32—40) sand returned to 100% of control tension after 707(649-764) s. The dose-response curve after ad-ministration of different doses of mivacurium afterprior suxamethonium is shown in figure 3. Thecalculated Tl ED50, EDgo and ED95 values are givenin table 2. Table 2 also shows, for comparison, dataobtained previously without prior administration ofsuxamethonium [17]. The regression lines did notdeviate from parallelism and the calculated ED,,,,EDgo and EDW values did not differ significantlybetween groups.

We did not observe any substantial haemodynamicchanges during the 30-min period of stabilization ofend-tidal anaesthetic concentrations.

Discussion

The results of this study demonstrated that prioradministration of mivacurium had a marked an-tagonistic effect on the development of subsequentdepolarizing block produced by suxamethonium,and the regression lines for suxamethonium blockwith and without mivacurium pretreatment wereparallel (fig. 2, table 1). The calculated ED50 andEDgo values were more than doubled after miva-curium pretreatment (table 1). We interpret thesefindings collectively as indicative of competitiveantagonism between the two drugs at the post-junctional receptors. We waited for the maximumeffect of mivacurium pretreatment to occur beforeadministration of suxamethonium. This was ob-served after 366 (331^01) s. As a result of themarked antagonistic effect of mivacurium, only theED50 and EDgo values were within the range of dosestested. Similar observations were noted by Szalados,Donati and Bevan after administration of tubo-curarine 50 ug kg"1, 3 min before suxamethonium[20]. They noted that the potency of suxamethoniumwas decreased by approximately 50% in patientswho were pretreated with tubocurarine and thecalculated ED,o and ED,, values after tubocurarinepretreatment were outside the range of doses tested.In clinical practice, however, a dose of mivacuriumas high as that used in this study would not normallybe used for pretreatment, so this effect of antagonismof suxamethonium may not be as intense with smallerdoses of mivacurium.

Our estimate obtained in this study for suxa-methonium Tl EDW (86 ug kg"1) was similar to thatreported by Miller and colleagues [21], who wereusing a different methodology, during 1.25 MAC ofisoflurane anaesthesia and single twitch stimuli.Their EDW value was 3.4 mg m2. This correspondsto 88 ug kg"1, assuming a surface area of 1.81 m2 andweight 70 kg. Caldwell and colleagues reported ahigher T l EDW value (mugkg" 1 ) during 1.25MAC of isoflurane anaesthesia [22]. This differencein results could be attributed to the difference intechniques used for generating the dose-response

data. In the current study we used the single-dosetechnique, but both Miller and colleagues [21] andCaldwell and co-workers [22] used the cumulativedose technique. They administered three [21] to five[22] different doses of suxamethonium, respectively,to each patient during the same anaesthetic afterallowing for suitable recovery from the effects of theprevious dose. With such a technique, each dose ofsuxamethonium probably has influenced the re-sponse to subsequent doses. In fact, Smith, Donatiand Bevan noted that the cumulative dose techniqueunderestimated the potency of suxamethonium [23].

The effect of prior administration of suxa-methonium on a subsequent block induced by non-depolarizing blocking drugs has produced conflictingresults. In the current study, we were not able to findany significant difference in the potency of miva-curium administered after recovery from suxa-methonium block compared with a previous studyusing the same methodology, with the exception ofprior administration of suxamethonium [17]. Thecalculated EDW ED^ and ED,5 values were similarwhether mivacurium was administered alone orpreceded by suxamethonium (table 2, fig. 3), indi-cating no potentiation of the effect of mivacurium byprior administration of suxamethonium. The lack ofan effect of suxamethonium on subsequentmivacurium-induced neuromuscular block, however,depends on our retrospective control data [17].Maddineni, Mirakhur and McCoy [24] reported thatprior administration of suxamethonium had nosignificant effect on the actions of mivacurium withrespect to recovery indices and time to recovery ofTOF to 0.70.

In conclusion, this study demonstrated that duringthiopentone-fentanyl-nitrous oxide-isoflurane an-aesthesia, prior administration of mivacurium had amarked antagonistic effect on the development ofsubsequent depolarizing block produced by suxa-methonium. In addition, we found that prioradministration of suxamethonium did not affect thepotency of mivacurium.

References1. Savarese JJ, Ali HH, Basta SJ, Embree PB, Scott RPF,

Sunder N, Weakly JN, Wajtila WB, El-Sayad HA. Theclinical neuromuscular pharmacology of mivacurium chloride(BW B1090U). A short-acting nondepolarizing ester neuro-muscular blocking drug. Anesthesiology 1988; 68: 723-732.

2. Ali HH, Savarese JJ, Embree PB, Basta SJ, Stout RG,Bottros LH, Weakly JN. Clinical pharmacology of miva-curium chloride (BW B1090U) infusion: comparison withvecuronium and atracurium. British Journal of Anaesthesia1988; 61: 541-546.

3. Cook DR, Stiller RL, Weakly JN, Chakravorti S, BrandomBW, Welch RM. In vitro metabolism of mivacurium chloride(BW B1090U) and succinylcholine. Anesthesia and Analgesia1989; 68: 452^156.

4. Katz RL, Norman J, Seed RF, Conrad L. A comparison ofthe effects of suxamethonium and tubocurarine in patients inLondon and New York. British Journal of Anaesthesia 1989;41: 1041-1047.

5. Katz RL. Modification of the action of pancuronium bysuccinylcholine and halothane. Anesthesiology 1971; 35:602-606.

6. Krieg N, Hendrickx HHL, Crul JF. Influence of suxa-methonium on the potency of ORG NC 45 in anaesthetizedpatients. British Journal of Anaesthesia 1981; 51: 259-262.

7. Ono K, Manabe N, Ohta Y, Morita K, Kosaka F. Influence

30 British Journal of Anaesthesia

of suxamethonium on the action of subsequently administeredvecuronium or pancuronium. British Journal of Anaesthesia1989; 62: 324-326.

8. Stirt JA, Katz RL, Murray AL, Schehl DL, Lee C. Modifi-cation of atracurium blockade by halothane and by suxa-methonium. A review of clinical experience. British Journal ofAnaesthesia 1983; SS: 71S-75S.

9. Walts LF, Dillon JB. Clinical studies of the interactionbetween d-tubocurarine and succinylcholine. Anesthesiology1969; 31: 39-44.

10. Walts LF, Rusin WD. The influence of succinylcholine onthe duration of pancuronium neuromuscular blockade. Anes-thesia and Analgesia 1977; 56: 22-25.

11. Katz JA, Fragen RJ, Shanks CA, Dunn K, McNulty B, RuddGD. The effects of succinylcholine on doxacurium-inducedneuromuscular blockade. Anesthesiology 1988; 69: 604-607.

12. Dubois MY, Fleming NW, Lea DE. Effects of succinyl-choline on the pharmacodynamics of pipecuronium andpancuronium. Anesthesia and Analgesia 1991; 72: 364-368.

13. Cooper R, Mirakhur RK, Clarke RSJ, Boules Z. Comparisonof intubating conditions after administration of ORG 9426(rocuronium) and suxamethonium. British Journal of An-aesthesia 1992; 69: 269-273.

14. Cullen DJ. The effect of pretreatment with nondepolarizingmuscle relaxants on the neuromuscular blocking action ofsuccinylcholine. Anesthesiology 1971; 35: 572-578.

15. Freund FG, Rubin AP. The need for additional succinyl-choline after d-tubocurarine. Anesthesiology 1972; 36,185-187.

16. Naguib M, Farag H, Magbagbeola JAO. Effect of pre-treatment with lysine acetyl salicylate on suxamethonium-

induced myalgia. British Journal of Anaesthesia 1987; 59:606-610.

17. Naguib M, Abdulatif M, Al-Ghamdi A, Selim M, Seraj M,EL-Sanbary M, Magboul MA. Interactions between miva-curium and atracurium. British Journal of Anaesthesia 1994;73: 484-̂ 189.

18. Statistical Consultants, Inc. PCNONLIN and NONLIN84.Software for the statistical analysis on nonlinear models.American Statistician 1986; 40: 52.

19. Finney DJ. Statistical Methods in Biological Assay, 2nd Edn.London: Griffin, 1971; 21-57.

20. Szalados JE, Donati F, Bevan DR. Effect of d-tubocurarinepretreatment on succinylcholine twitch augmentation andneuromuscular blockade. Anesthesia and Analgesia 1990; 71:55-59.

21. Miller RD, Way WL, Dolan WM, Stevens WC, Eger El II.Comparative neuromuscular effects of pancuronium,gallamine, and succinylcholine during forane and halothaneanesthesia in man. Anesthesiology 1971; 35: 509-514.

22. Caldwell JE, Laster MJ, Magorian T, Heier T, Yasuda N,Lynam DP, Eger El n, Weiskopf RB. The neuromusculareffects of desflurane, alone and combined with pancuroniumor succinylcholine in humans Anesthesiology 1991; 74:412-418.

23. Smith CE, Donati F, Bevan DR. Dose—response curves forsuccinylcholine: single versus cumulative techniques. Anes-thesiology 1988; 69: 338-342.

24. Maddineni VR, Mirakhur RK, McCoy EP. Intubatingconditions and neuromuscular effects after mivacurium withor without prior suxamethonium. British Journal of An-aesthesia 1993; 71: 312P.