ISOBOLOGRAPHIC AND DOSE-RESPONSE ANALYSIS OF THE INTERACTION BETWEEN PIPECURONIUM AND VECURONIUM

We have studied the neuromuscular effects of pipecuronium, vecuroniumand their combination in 130 ASA group I or II patients. Patientswere anaesthetized with 0.8% halothane and 60% nitrous oxidein oxygen. Neuromuscular block was recorded as the evoked thenarmechanomyographic response to train-of-four stimulation of theulnar nerve (2Hz at 10-s intervals). The dose-response curveswere determined by probit analysis. The calculated doses producing50% depression of the first twitch height were 15.6, 16.9 and15.0 µg kg^–1 for the pipecuronium, vecuronium andpipecuronium-vecuronium combination groups, respectively. Isobolographic and algebraic (fractional) analyses were used to assessquantitatively the combined neuromuscular effect of pipecuroniumand vecuronium and to define the type of interaction betweenthese drugs. The interaction between pipecuronium and vecuroniumwas found to be additive. (Br. J. Anaesth. 1993; 71: 556–560)      

COMPARATIVE EFFECTS OF PIPECURONIUM AND TUBOCURARINE ON PLASMA CONCENTRATIONS OF HISTAMINE IN HUMANS

We have examined the effects of a rapid bolus dose of pipecuronium0.1 mg kg^–1 or tubo-curarine 0.5mg kg^–1 on plasmahistamine concentration, heart rate and arterial pressure in20 patients (n = 10 in each group). Anaesthesia was inducedwith thiopentone 6 mg kg^–1 i.v. and maintained with 70%nitrous oxide and halo-thane in oxygen. Neuromuscular blockingdrugs were administered 4 min after administration of thiopentone.Venous blood samples were obtained before induction, 1 min afterthiopentone and 1, 3 and 5 min after the administration of theneuromuscular blocking drugs. Tubocurarine caused 240% and 210%increases in plasma concentration of histamine at 1 and 3 min,respectively. These changes were significant (P < 0.05) at1 min and associated with a decrease in mean arterial pressureand an increase in heart rate. None of the 10 patients receivingpipecuronium had a significant change in plasma concentrationof histamine or in haemo-dynami variables. ^*Present addresses: Department of Anaesthesia, Al-Kasr El-AniHospital, Cairo University, Cairo, Egypt. Present addresses: Department of Pharmacology, Lund University,Lund, Sweden.     

Recovery characteristics after early administration of anticholinesterases during intense mivacurium-induced neuromuscular block

The time course of recovery after early administration of anticholinesterasesduring intense mivacurium-induced block was evaluated by recordingthe mechanomyographic response of the adductor pollicis to post-tetaniccount (PTC) and train-of-four (TOF) ulnar nerve stimulation.Seventy-two adult patients receiving thiopentone, fentanyl,nitrous oxide, isoflurane anaesthesia and mivacurium 0.15 mgkg^–1 were allocated randomly to one of six equal groupsaccording to the type of anticholinesterase and intensity ofblock at which antagonism was attempted. Groups 1, 3 and 5 receivedneostigmine 0.07 mg kg^–1, while groups 2, 4 and 6 receivededrophonium 1 mg kg^–1. At the time of administration ofantagonist there was no response to PTC in groups 1 and 2, aPTC of 1 or more was detectable in groups 3 and 4 and the firsttwitch of the TOF (T1) had recovered to 10% in the conventionalantagonism groups (5 and 6). The longest clinical duration (CD)values (time from administration of mivacurium to T1 25%) wereencountered in groups 1, 5 and 6 and were 17.4 (7.9), 19.7 (3.4)and 21.4 (4.8) min, respectively. CD was reduced significantlyin groups 2, 3 and 4 and values were 13.9 (3.5), 13.7 (3.5)and 13.8 (3.3) min, respectively. Recovery indices (Rl) (timeinterval between T1 25% and 75%) were 13.8 (7.3), 6.3 (1.4),4.6 (1.8), 6.0 (2.1), 3.7 (2.2) and 4.8 (3.1) min in groups1–6, respectively and was prolonged with neostigmine antagonismat PTC 0 (group 1). Reversal time (RT) (time between administrationof antagonist and TOF 0.70) was 34.9 (16.6) min in group 1 whoreceived neostigmine at PTC 0 and was prolonged markedly comparedwith all other groups. Antagonism with edrophonium at PTC 0(group 2) was associated with an RT of 16.7 (5.1) min and wassignificantly longer compared with the conventional antagonismgroups only. Reversal times were similar in groups 3–6.Total recovery times (TRT) (time between administration of mivacuriumand TOF 0.70) were 41.5 (16.6), 23.2 (5.2), 23.2 (5.3), 24.1(4.5), 26.8 (4.8) and 28.5 (9.1) min in groups 1–6, respectively,and was markedly prolonged in group 1 only. In summary, administrationof neostigmine during intense mivacurium block, not responsiveto TOF and PTC stimulation was associated with marked delayin recovery, possibly because of inhibition of plasma cholinesterase.At this intensity of block, edrophonium was preferable. It isadvisable to wait for a detectable PTC before attempting antagonismof an intense mivacurium block. After detection of PTC, neostigmineor edrophonium antagonism reduced the clinical duration butnot the total recovery time compared with conventional reversaladministered at T1 10%.     

Thenar muscle blood flow and neuromuscular effects of vecuronium in patients receiving balanced or isoflurane anaesthesia

We have tested the hypothesis that isoflurane potentiates non-depolarizingneuromuscular block via an increase in muscle blood flow. Anaesthesiawas induced with thiopentone 4–5 mg kg^–1 in 30 adultmale patients of ASA physical status I or II and was maintainedwith 70% nitrous oxide in oxygen supplemented with either abolus dose of fentanyl 4µg kg^–1 followed by an infusionof 1 7µg kg^–1 h^–1 (balanced anaesthesia group,n=15) or 1.1% end-tidal isoflurane (isoflurane group, n=15).Vecuronium 0.1 mg kg^–1 was given for neuromuscular block.The force of contraction of the adductor pollicis of the thumbin response to ulnar nerve stimulation was recorded. Thenarmuscle blood flow was measured continuously with a laser Dopplerflowmeter. Times required for the first twitch in the train-of-four(T1) to recover to 25%, 75% and 90% of its control value weremean 26.3 (SD 5), 35.3 (10), 43.5 (7) min and 39.2 (15), 53(12.5), 61.2 (10) min in the balanced anaesthesia and isofluranegroups, respectively (P<0.01). Recovery index (time betweenT1 25% and 75%) was prolonged significantly in the isofluranegroup. Administration of thiopentone significantly increasedthenar muscle blood flow from 2.6 (1.9) and 2.2 (1.5) ml min^–1/100g to 19.2 (14) and 21.7 (16) ml min^–11100 g in the balancedanaesthesia and isoflurane groups, respectively (P<0.001).The addition of fentanyl (balanced) or isoflurane to the anaestheticmixture produced further increases in thenar muscle blood flowto reach, respectively, 26.2 (16) and 26.8 (13.6) ml min^–1/1100g during steady state anaesthesia. Thenar muscle blood flowwas comparable in the two groups throughout the study. We concludethat isoflurane prolonged vecuronium-induced neuromuscular block.This prolongation was not related primarily to increase in muscleblood flow.     

DOSE-RESPONSE RELATIONSHIPS FOR EDROPHONIUM AND NEOSTIGMINE ANTAGONISM OF MIVACURIUM-INDUCED NEUROMUSCULAR BLOCK

We have studied the dose-response relationships for neostigmineand edrophonium during antagonism of neuromuscular block inducedby mivacurium chloride. Sixty-four ASA group I or II adultswere given mivacurium 0.15 mg kg^–1 during fentanyl-thiopentone-nitrousoxide-iso flurane anaesthesia. Train-of-four stimulation (TOF)was applied to the ulnar nerve every 10 s, and the force ofcontraction of the adductor pollicis muscle was recorded. Whenspontaneous recovery of first twitch height reached 10% of itsinitial control value, edrophonium 0.1, 0.2, 0.4, or 1 mg kg^–1or neostigmine 0.005, 0.01, 0.02, or 0.05 mg kg^–1 wasadministered by random allocation. Neuromuscular function inanother 16 subjects was allowed to recover spontaneously. Spontaneousrecovery from 90% mivacurium block to 95% twitch height andTOF ratio 0.75 occurred within 15 min. This study demonstratedthat the dose-response curves for these two drugs for antagonismof neuromuscular block (first twitch and train-of-four ratio)were parallel. The doses of neostigmine required to achieve50% (ED₅₀) and 70% (ED₇₀) recovery of the first twitch after10 min were 2 (1.5– 2.5) µg kg^–1 and 4.7 (4.1–5.4)µg kg^–1 (mean (95% confidence intervals)), respectively.Corresponding ED₅₀ and ED₇₀ values for edrophonium were 2.8(0.75–10.2) pg kg^–1 and 9.2 (3.6–23.6) µgkg^–1, respectively. These values corresponded to neostigmine:edrophonium potency ratios of 1.4 (0.4–2.4) and 1.95(0.9–2.9) for first twitch ED₅₀ and ED₇₀ height, respectively.The calculated doses producing 50% (ED₅₀ recovery of the TOFratio at 10 min were neostigmine 2.57 (1.8–3.6) µgkg^–1 and edrophonium 26.9 (14.6–49.6) pg kg^–1.These values corresponded to a potency ratio of 10.4 (0.7–20).(Br. J. Anaesth. 1993; 71: 709–714)     

Interactions between mivacurium and atracurium

We have studied the interaction between atracurium and mivacurium.The dose—response relationships of atracurium, mivacuriumand their combination were studied in 96 ASA I or II patientsduring thiopentone—fentanyl—nitrous oxide—isoflurane(1.2% end-tidal) anaesthesia. Neuromuscular block was recordedas the evoked thenar mechanomyographic response to train-of-fourstimulation of the ulnar nerve (2 Hz at 12-s intervals). Thedose—response curves were determined by probit analysis.Isobolographic and algebraic (fractional) analyses were usedto assess quantitatively the combined effect of equipotent dosesof atracurium and mivacurium and to define the type of interactionbetween these drugs. Isobolograms were constructed by plottingsingle drug ED₅₀ points on the dose co-ordinates and a combinedED₅₀ point in the dose field. The calculated doses producing50% depression (ED₅₀) of the first twitch height were 50.5 (95%confidence intervals 48.9–52.1) and 20.8 (20.3–21.3) µg kg^–1 for the atracurium and mivacurium groups,respectively. Isobolographic and fractional analyses of theatracurium-mivacurium combination demonstrated zero interaction(additivism). An additional 26 patients anaesthetized with thiopentone-fentanyl-nitrousoxide—isoflurane were allocated randomly to receive eitheratracurium 0.5 mg kg^–1 (n = 13) or mivacurium 0.15 mgkg^–1 (n = 13). Additional maintenance doses of mivacurium0.1 mg kg^–1 were administered to patients in both groups,whenever the first twitch recovered to 10% of control. The durationof the first maintenance dose of mivacurium to 10% recoveryof the first twitch was greater (P < 0.0005) after atracurium(25 (21.8–28.5) min) than after mivacurium (14.2 (11.9–16.6)min). However, the duration of the second maintenance dose ofmivacurium after atracurium (18.3 (12.6–24) min) was similarto that of mivacurium after mivacurium (14.6 (10.6–18.6)min). We conclude that the combination of atracurium and mivacuriumis additive and that the use of mivacurium after atracurium-inducedneuromuscular block results in increased duration of the first(but not the subsequent) maintenance dose of mivacurium.     

Dose-response studies of the interaction between mivacurium and suxamethonium

We have determined the effect of pretreatment with mivacuriumon the potency of suxamethonium and the effect of prior administrationof suxamethonium on the potency of mivacurium. We studied 100ASA I or II patients during thiopentone-fentanyl-nitrous oxide-isofluraneanaesthesia. Neuro-muscular block was recorded as the evokedthenar mechanomyographic response to train-of-four stimulationof the ulnar nerve (2 Hz at 12-s intervals). Single dose-responsecurves were determined by probit analysis. Pretreatment withmivacurium had a marked antagonistic effect on the developmentof subsequent depolarizing block produced by suxamethonium.The dose-response curves for suxamethonium alone and after pretreatmentwith mivacurium did not deviate from parallelism, but thoseconstructed after mivacurium were shifted significantly to theright (P < 0.0001). The calculated doses producing 50% depressionof T1 (ED₅₀) were 86 (95% confidence intervals 83–88)and 217 (208–225) µg kg^–1 for suxamethoniumalone and after mivacurium, respectively. This study also demonstratedthat prior administration of suxamethonium did not appear toinfluence either the slope of the regression lines or the potencyof mivacurium. Combining the results of this study with a previousstudy (mivacurium ED₅₀ = 20.8 (20.3–21.3) µg kg^–1during isoflurane-nitrous oxide anaesthesia), we suggest thatthe potency of mivacurium did not differ from that observedafter suxamethonium (17.4 (16.9–17.9) µg kg^–1).(Br.J. Anaesth. 1995; 74: 26–30) ^*Present address: Department of Anaesthesia, King Faisal University,Saudi Arabia