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PRIMING WITH ALCURONIUM AND TUBOCURARINE ACCELERATES THE ONSET OF NEUROMUSCULAR BLOCK†
Br. J. Anaesth. (1989), 63, 7-11
PRIMING WITH ALCURONIUM AND TUBOCURARINE ACCELERATES THE ONSET OF NEUROMUSCULAR BLOCKf B. J. POLLARD Downloaded from http://bja.oxfordjournals.org/ at Indiana University Library on July 22, 2015
The ideal neuromuscular blocking agent should have a rapid onset of action and a non-depolar- SUMMARY izing character [1]. In order to accelerate the rate The individual rate of onset of action of tuboof onset of action, several techniques have been curarine and alcuronium has been examined with described, including the administration of a large and without a priming dose of the same agent or bolus dose several times that required to achieve the other agent, by measurement of changes in full neuromuscular block [2], and preliminary the evoked compound e/ectromyogram of the priming with a small subparalytic dose of the drug adductor pol/icis muscle. Priming was associated [3]. For optimum effect using the technique of with acceleration of the onset of neuromuscular priming, the first dose should be approximately block. 15-20% of the intubating dose [4], which may cause symptoms of partial neuromuscular block in a significant proportion of the population [5]. It has been suggested also that the priming dose of choice would include neuromuscular block. should be given 6-8 min before the main Ethics Committee approval was granted for the intubating dose for the greatest effect [4]. study. Patients with a known history of renal, Combination of some pairs of non-depolarizing hepatic, neurological or neuromuscular disorder neuromuscular blocking agents exhibits syner- and those taking drugs known to affect neurogism of action [6-8]. It is possible that priming muscular transmission were excluded. Each one blocking drug with a different synergistic patient was premedicated with diazepam by mouth agent may also accelerate the rate of onset. This 1 h before operation. In the anaesthetic room, has been tested with combinations of pancuro- surface electrodes were placed over the ulnar nium, tubocurarine and atracurium and the onset nerve at the wrist and over the ipsilateral adductor of neuromuscular block was increased, but to only pollicis muscle, after the skin was cleaned with a limited extent [9,10]. It was decided, therefore, acetone. The electrodes were connected to a to examine further this technique of synergistic Medelec MS6 system and the evoked compound priming, with a pair of non-depolarizing neuro- electromyogram (EMG) from the adductor polmuscular blocking agents which exhibit strong licis muscle was displayed and recorded. synergy of action—tubocurarine and alcuronium Anaesthesia was induced with a sleep dose of [6]. thiopentone and the nerve stimulated with trains of four stimuli (0.2 ms duration, supramaximal PATIENTS AND METHODS voltage) at 12-s intervals. The preliminary (primInformed consent was obtained from patients ing) dose of blocker was given, and the main (ASA I or II) in whom the anaesthetic technique intubating dose 3 min later. During this time, anaesthesia was maintained with increments of thiopentone as required and ventilation assisted This article is accompanied by Editorial I. B. J. POLLARD, B.PHARM., M.B., CH.B., F.F.A.R.C.S. ; Department with 67% nitrous oxide in oxygen, maintaining of Anaesthesia, Manchester Royal Infirmary, Oxford Road, normocapnia. Manchester M13 19WL. Accepted for Publication: January The intubating doses of tubocurarine and 20, 1989. 1 t An abstract of this work was presented to the Anaesthetic alcuronium were 0.5 mg kg" and 0.25 mg kg"', Research Society, November 1987. respectively; priming doses were 10% of the
BRITISH JOURNAL OF ANAESTHESIA TABLE I. Allocation and doses of neuromuscular blocking agents
Group 1 2 3 4 5 6 7 8
Preliminary agent
Intubating agent
Saline Tubocurarine 0.05 mg kg"1 Alcuronium 0.025 mg kg"1 Saline Alcuronium 0.025 mg kg"1 Tubocurarine 0.05 mg kg"1 Saline Saline
Tubocurarine 0.5 mg kg"1 Tubocurarine 0.5 mg kg"1 Tubocurarine 0.5 mg kg"1 1 Alcuronium 0 .25 mg kg"1 Alcuronium 0.25 mg kg"1 Alcuronium 0.25 mg kg" Tubocurarine 0.55 mg kg"1 Alcuronium 0.275 mg kg"
RESULTS
There were no significant differences between the groups with respect to mean age, weight and sex ratio (table II). There was no detectable change in neuromuscular transmission resulting from administration of the priming dose. There was no difference between the mean maximum neuromuscular block reached in each group (table II). A neuromuscular block of 100% was exceeded only in four patients, two each in groups 3 and 6. There was no significant difference between the two control groups at any time for the change in
TABLE II. Demographic patient data and maximum block reached (means (SEM))
Group
Age (yr)
Weight (kg)
37.1(3.4) 44.1(6.2) 36.4(4.7) 39.0(4.7) 34.5(3.5) 38.0(6.5) 32.0(3.7) 37.2(7.3)
70.1(5.3) 62.1(3.2) 65.6(4.9) 72.9(7.1) 64.2(3.8) 61.0(1.8) 69.6(3.1) 55.8(2.6)
Maximum block Sex(F:M) (%) 6:2 7:1 7:1 6:2 7:1 7:1 6:2 7:1
90.6(1.9) 91.6(2.7) 96.2(1.3) 91.9(1.7) 93.1(2.0) 97.0(0.9) 92.5(1.7) 93.5(2.8)
1OCH
80-
60-
o 3 40-
20-
Time (min)
FIG. 1. Percent reduction in EMG amplitude of first response of train-of-four (Tl) with time for tubocurarine as the intubating relaxant. • = Saline—tubocurarine 0.5 mg kg"1; O = saline-tubocurarine 0.55 mg kg"1; • = tubocurarine—tubocurarine; A = alcuronium-tubocurarine. Significant differences from saline groups (no priming): *P < 0.05; **P < 0.01; iP < 0.025; ft/ 5 < 0.005.
Downloaded from http://bja.oxfordjournals.org/ at Indiana University Library on July 22, 2015
intubating doses. Thus six groups were created: an intubating dose of each relaxant preceded by a priming dose of the same drug, the second agent, or normal saline (table I). Two further groups (7 and 8) were included also, using normal saline as the priming agent and an intubating dose equivalent to the sum of the first and second doses in the previous groups; that is, 110% of the intubating dose. The patients were allocated randomly to the respective groups. The degree of neuromuscular block was calculated as the percentage change in EMG amplitude of the first response of the train-of-four (Tl) from that before administration of any relaxant (TO) and also the train-of-four ratio (amplitude of fourth response/amplitude of first response: T4/T1). Data from the pairs of control groups (1 and 7; 4 and 8) were analysed using one-way analysis of variance at each time point. The aggregated data from groups 1 and 7 together were compared with those from groups 4 and 8 together. Two-way analysis of variance was carried out at each time point to see if there was any difference between the three agents given first, between the two agents given second, and to determine if the magnitude of any difference between the means was dependent on which drug was given first.
ALCURONIUM AND TUBOCURARINE PRIMING 100-i
-tt#** *
.
* J. *
t ! * *
10
80-
^ 6 0
40-
20-
50 Tl inhibition (%)
100
FIG. 3. Change in train-of-four ratio with change in Tl amplitude for tubocurarine and alcuronium without priming. V = Saline-tubocurarine; A = saline-alcuronium. Time (min)
FIG. 2. Percent reduction in EMG amplitude of first response of train-of-four (Tl) with time for alcuronium as the intubating relaxant. • = Saline-alcuronium 0.25 mg kg"1; O = saline-alcuronium 0.275 mg kg"1; T = alcuronium-alcuronium; A = tubocurarine-alcuronium. Significant differences from saline group (no priming): *P<0.05; **P<0.01; | P < 0.025; + t ^ < 0.005.
1.0
T l : T 0 ratio for those groups in which tuboi 0.5curarine was used to facilitate intubation (fig. 1). o Both of the lines for the two groups in which priming was used (groups 2 and 3) were significantly different from the control lines at the points indicated (fig. 1). Although the line for group 3 (alcuronium before tubocurarine) lies to the left of that for group 2 (tubocurarine before tubocurarine) there was no significant difference between these two groups. 100 50 Figure 2 illustrates data for those patients in Tl inhibition (%) whom alcuronium facilitated intubation; it reFIG. 4. Change in train-of-four ratio with change in Tl amsembles figure 1. There was no significant differ- plitude for tubocurarine and alcuronium when each primed ence between the two control lines at any time. with the other. V = Alcuronium-tubocurarine; A = tubocurarine—alcuronium. The lines for the two groups in which priming was used (groups 5 and 6) are significantly different from the control lines as indicated on the groups 1 and 7 together and groups 4 and 8 figure. Although the line for group 6 (tubo- together revealed no significant difference at any curarine before alcuronium) lies markedly to the time between the rates of onset of tubocurarine left of that for group 5 (alcuronium before and alcuronium when given alone. The changes in mean train-of-four ratio with alcuronium), there was no significant difference. Comparison of the tubocurarine and alcuro- changes in Tl :T0 are shown in figure 3 (control nium control groups using the aggregated data of groups 1 and 4: tubocurarine alone and alcuro-
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BRITISH JOURNAL OF ANAESTHESIA
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nium alone) and figure 4 (groups 3 and 6, in which acetylcholine receptors, other acetylcholine reeach agent was primed with the second one). ceptor systems exist on the prejunctional region Tubocurarine demonstrated slightly more fade [22] and different neuromuscular blocking drugs than alcuronium, a difference which was not are thought to possess a unique spectrum of significant and not present when priming with the actions on the whole receptor system. It is likely that synergism between some pairs of nonsecond agent had been used. depolarizing neuromuscular blocking agents appears when two agents with dissimilar activity DISCUSSION spectra are combined. The acceleration of neuroTubocurarine and alcuronium were chosen be- muscular block resulting from the priming dose of cause they are known to exhibit synergism of the second agent in this study was slightly greater action which is stronger than tubocurarine and than when the relaxant was primed with itself. If pancuronium in vitro [6]. In order to compare a pharmacokinetic effect alone is proposed for equipotent doses, the ED95 of each was selected as priming, one might expect priming with a differthe intubating dose with a priming dose of 10 % of ent agent to be no more effective, or even less effective than priming with itself. This was not the ED95. Savarese [11] suggested a dose of 0.51 mg kg"1 observed in the present study. It is interesting to as the ED 95 for tubocurarine and Shanks [12] an note that the rate of onset of alcuronium was overall mean for all published data of 0.48 mg accelerated to a greater extent by tubocurarine kg"1. A value of 0.50 mg kg"1 was therefore chosen than was tubocurarine by alcuronium. for ease of calculation. There are fewer data for Although no detectable block was found to alcuronium than for tubocurarine. Shanks [12] result from the priming dose in this study, suggested an ED95 of 0.22 mg kg"1 and Lund and administration of a small dose of a non-depolarStovner [13] suggested a relative potency of izing neuromuscular blocking agent has been alcuronium and tubocurarine as 1.8:1. A value of shown to cause unpleasant partial paralysis in 0.25 mg kg"1 was chosen, therefore, as an ED95 for some patients [5, 23]. Under some circumstances, this study. It is clear from inspection of the mean this might be hazardous [24]. maximum neuromuscular block reached (table II) The increase in rate of onset when alcuronium that these two doses were near to equivalence. and tubocurarine are primed with each other is There is a large margin of safety in neuro- marked, 80 % neuromuscular block being reached muscular transmission such that approximately in just over 60 s. With suxamethonium 1 mg kg"1 75 % of receptors have to be occupied by 100% block is reached in approximately 70 s [25]. antagonist molecules before failure of trans- The time response curve with suxamethonium is mission begins [14]. After a single bolus dose, steeper, however, and suxamethonium causes a receptor occupancy has to increase from zero to more profound block. more than 75 % before depression of Tl is seen. If a small priming dose is administered, sufficient to ACKNOWLEDGEMENT produce receptor occupancy of just less than 75 %, the addition of a second intubating dose has The author is grateful to Miss Linda Hunt, Lecturer in to increase receptor occupancy just above this Medical Statistics, University of Manchester, for her figure. An additional pharmacokinetic mechanism assistance in the analysis of these data. has been proposed also [15]. Because the concentration of blocking drug at the neuromuscular REFERENCES junction determines neuromuscular block, pre1. Savarese JJ, Kitz RJ. The quest for a short acting nondosing allows that drug to reach an effective depolarising neuromuscular blocking agent. Acta Anaesthesiologica Scandinavica 1973; 53 (Suppl.): 43-48. concentration sooner, thereby accelerating the 2. Casson WR, Jones RM. Vecuronium induced neuroonset of block. Whichever mechanism is operamuscular blockade. The effect of increasing dose on speed ting, onset would be expected to be more rapid, as of onset. Anaesthesia 1986; 41: 354-357. observed in this study and in previous studies 3. Doherty WG, Breen PJ, Donati F, Bevan DR. Accelerated with tubocurarine [4, 16], alcuronium [4, 17], onset of pancuronium with divided doses. Canadian Anaesthetists Society Journal 1985; 32: 1—4. vecuronium [18], atracurium [19, 20] and 4. Foldes F. Rapid tracheal intubation with non-depolarizing pancuronium [3, 21]. neuromuscular blocking drugs: The priming principle. British Journal of Anaesthesia 1984; 56: 663. In addition to the classical postjunctional
ALCURONIUM AND TUBOCURARINE PRIMING
14. Paton WDM, Waud DR. The margin of safety of neuromuscular transmission. Journal of Physiology (London) 1967; 191: 59-90. 15. Hull CJ, Van Beem HBH, McLeod K, Sibbald A, Watson MJ. A pharmacodynamic model for pancuronium. British Journal of Anaesthesia 1978; 50: 1113-1123. 16. Baxter M, Bevan JC, Donati F, Bevan DR. D-tubocurarine priming in children. Canadian Anaesthetists Society Journal 1986; 33: S86-S87. 17. Hutton P, Morgan G, El-Hassan K, Black AMS. Speeding the onset of neuromuscular block by alcuronium. British Journal of Anaesthesia 1983; 55: 918P. 18. Schwartz S, Ilias W, Lackner F, Mayrhofer O, Foldes FF. Rapid tracheal intubation with vecuronium: the priming principle. Anesthesiology 1985; 62: 388-391. 19. Nagashima H, Nguyen HD, Lee S, Kaplan R, Duncalf D, Foldes FF. Facilitation of rapid endotracheal intubation with atracurium. Anesthesiology 1984; 61: A289. 20. Sosis M, Larijani GE, Marr AT. Priming with atracurium. Anesthesia and Analgesia 1987; 66: 320-332. 21. Bevan JC, Donati F, Bevan DR. Attempted acceleration of the onset of action of pancuronium. British Journal of Anaesthesia 1985; 57: 1204-1208. 22. Bowman WC. Prejunctional and postjunctional cholinoceptors at the neuromuscular junction. Anesthesia and Analgesia 1980; 59: 935-943. 23. Mirakhur RK, Lavery GG, Gibson FM, Clarke RSJ. Intubating condition after vecuronium and atracurium given in divided doses (the priming technique). Acta Anaesthesiologica Scandinavica 1986; 30: 347-350. 24. Musich J, Walts LF. Pulmonary aspiration after a priming dose of vecuronium. Anesthesiology 1986; 64: 517-519. 25. Scott RPF, Goat VA. Atracurium: Its speed of onset. A comparison with suxamethonium. British Journal of Anaesthesia 1982; 54: 909-911.
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5. Engbouk J, Howardy-Hansen P, Ording H, Viby Mogenson J. Precurarization with vecuronium and pancuronium in awake healthy volunteers: the influence on neuromuscular transmission and pulmonary function. Acta Anaesthesiologica Scandinavica 1985; 29: 117-120. 6. Pollard BJ, Jones RM. Interactions between tubocurarine, pancuronium and alcuronium demonstrated in the rat phrenic nerve-hemidiaphragm preparation. British Journal of Anaesthesia 1983; 55: 1127-1131. 7. Lebowitz PW, Ramsey FM, Savarese JJ, AH HH. Potentiation of neuromuscular blockade in man produced by combinations of pancuronium and metocurine or pancuronium and d-tubocurarine. Anesthesia and Analgesia 1980; 59: 604-609. 8. Black TE, Healy TEJ, Pugh ND, Kay B, Harper NJN, Petts HV, Sivilingham T. Neuromuscular block: atracurium and vecuronium compared and combined. European Journal of Anaesthesiology 1985; 2: 29-37. 9. Donati F, Lahoud J, Walsh CM, Lavelle PA, Bevan DR. Onset of pancuronium and d-tubocurarine blockade with priming. Canadian Anaesthetists Society Journal 1986; 33: 571-577. 10. Gerber HR, Romppainen J, Schwinn W. Potentiation of atracurium by pancuronium and d-tubocurarine. Canadian Anaesthetists Society Journal 1986; 33: 563-570. 11. Savarese JJ, AH HH, Antonio RP. The clinical pharmacology of metocurine. Anesthesiology 1977; 47: 277284. 12. Shanks CA. Pharmacokinetics of the nondepolarising neuromuscular relaxants applied to calculation of bolus and infusion dosage regimes. Anesthesiology 1986; 64: 72-86. 13. Lund I, Stovner J. Dose response curves for tubocurarine, alcuronium and pancuronium. Ada Anaesthesiologica Scandinavica 1970; (Suppl.) 37: 238-242.
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PRIMING WITH ALCURONIUM AND TUBOCURARINE ACCELERATES THE ONSET OF NEUROMUSCULAR BLOCKf B. J. POLLARD Downloaded from http://bja.oxfordjournals.org/ at Indiana University Library on July 22, 2015
The ideal neuromuscular blocking agent should have a rapid onset of action and a non-depolar- SUMMARY izing character [1]. In order to accelerate the rate The individual rate of onset of action of tuboof onset of action, several techniques have been curarine and alcuronium has been examined with described, including the administration of a large and without a priming dose of the same agent or bolus dose several times that required to achieve the other agent, by measurement of changes in full neuromuscular block [2], and preliminary the evoked compound e/ectromyogram of the priming with a small subparalytic dose of the drug adductor pol/icis muscle. Priming was associated [3]. For optimum effect using the technique of with acceleration of the onset of neuromuscular priming, the first dose should be approximately block. 15-20% of the intubating dose [4], which may cause symptoms of partial neuromuscular block in a significant proportion of the population [5]. It has been suggested also that the priming dose of choice would include neuromuscular block. should be given 6-8 min before the main Ethics Committee approval was granted for the intubating dose for the greatest effect [4]. study. Patients with a known history of renal, Combination of some pairs of non-depolarizing hepatic, neurological or neuromuscular disorder neuromuscular blocking agents exhibits syner- and those taking drugs known to affect neurogism of action [6-8]. It is possible that priming muscular transmission were excluded. Each one blocking drug with a different synergistic patient was premedicated with diazepam by mouth agent may also accelerate the rate of onset. This 1 h before operation. In the anaesthetic room, has been tested with combinations of pancuro- surface electrodes were placed over the ulnar nium, tubocurarine and atracurium and the onset nerve at the wrist and over the ipsilateral adductor of neuromuscular block was increased, but to only pollicis muscle, after the skin was cleaned with a limited extent [9,10]. It was decided, therefore, acetone. The electrodes were connected to a to examine further this technique of synergistic Medelec MS6 system and the evoked compound priming, with a pair of non-depolarizing neuro- electromyogram (EMG) from the adductor polmuscular blocking agents which exhibit strong licis muscle was displayed and recorded. synergy of action—tubocurarine and alcuronium Anaesthesia was induced with a sleep dose of [6]. thiopentone and the nerve stimulated with trains of four stimuli (0.2 ms duration, supramaximal PATIENTS AND METHODS voltage) at 12-s intervals. The preliminary (primInformed consent was obtained from patients ing) dose of blocker was given, and the main (ASA I or II) in whom the anaesthetic technique intubating dose 3 min later. During this time, anaesthesia was maintained with increments of thiopentone as required and ventilation assisted This article is accompanied by Editorial I. B. J. POLLARD, B.PHARM., M.B., CH.B., F.F.A.R.C.S. ; Department with 67% nitrous oxide in oxygen, maintaining of Anaesthesia, Manchester Royal Infirmary, Oxford Road, normocapnia. Manchester M13 19WL. Accepted for Publication: January The intubating doses of tubocurarine and 20, 1989. 1 t An abstract of this work was presented to the Anaesthetic alcuronium were 0.5 mg kg" and 0.25 mg kg"', Research Society, November 1987. respectively; priming doses were 10% of the
BRITISH JOURNAL OF ANAESTHESIA TABLE I. Allocation and doses of neuromuscular blocking agents
Group 1 2 3 4 5 6 7 8
Preliminary agent
Intubating agent
Saline Tubocurarine 0.05 mg kg"1 Alcuronium 0.025 mg kg"1 Saline Alcuronium 0.025 mg kg"1 Tubocurarine 0.05 mg kg"1 Saline Saline
Tubocurarine 0.5 mg kg"1 Tubocurarine 0.5 mg kg"1 Tubocurarine 0.5 mg kg"1 1 Alcuronium 0 .25 mg kg"1 Alcuronium 0.25 mg kg"1 Alcuronium 0.25 mg kg" Tubocurarine 0.55 mg kg"1 Alcuronium 0.275 mg kg"
RESULTS
There were no significant differences between the groups with respect to mean age, weight and sex ratio (table II). There was no detectable change in neuromuscular transmission resulting from administration of the priming dose. There was no difference between the mean maximum neuromuscular block reached in each group (table II). A neuromuscular block of 100% was exceeded only in four patients, two each in groups 3 and 6. There was no significant difference between the two control groups at any time for the change in
TABLE II. Demographic patient data and maximum block reached (means (SEM))
Group
Age (yr)
Weight (kg)
37.1(3.4) 44.1(6.2) 36.4(4.7) 39.0(4.7) 34.5(3.5) 38.0(6.5) 32.0(3.7) 37.2(7.3)
70.1(5.3) 62.1(3.2) 65.6(4.9) 72.9(7.1) 64.2(3.8) 61.0(1.8) 69.6(3.1) 55.8(2.6)
Maximum block Sex(F:M) (%) 6:2 7:1 7:1 6:2 7:1 7:1 6:2 7:1
90.6(1.9) 91.6(2.7) 96.2(1.3) 91.9(1.7) 93.1(2.0) 97.0(0.9) 92.5(1.7) 93.5(2.8)
1OCH
80-
60-
o 3 40-
20-
Time (min)
FIG. 1. Percent reduction in EMG amplitude of first response of train-of-four (Tl) with time for tubocurarine as the intubating relaxant. • = Saline—tubocurarine 0.5 mg kg"1; O = saline-tubocurarine 0.55 mg kg"1; • = tubocurarine—tubocurarine; A = alcuronium-tubocurarine. Significant differences from saline groups (no priming): *P < 0.05; **P < 0.01; iP < 0.025; ft/ 5 < 0.005.
Downloaded from http://bja.oxfordjournals.org/ at Indiana University Library on July 22, 2015
intubating doses. Thus six groups were created: an intubating dose of each relaxant preceded by a priming dose of the same drug, the second agent, or normal saline (table I). Two further groups (7 and 8) were included also, using normal saline as the priming agent and an intubating dose equivalent to the sum of the first and second doses in the previous groups; that is, 110% of the intubating dose. The patients were allocated randomly to the respective groups. The degree of neuromuscular block was calculated as the percentage change in EMG amplitude of the first response of the train-of-four (Tl) from that before administration of any relaxant (TO) and also the train-of-four ratio (amplitude of fourth response/amplitude of first response: T4/T1). Data from the pairs of control groups (1 and 7; 4 and 8) were analysed using one-way analysis of variance at each time point. The aggregated data from groups 1 and 7 together were compared with those from groups 4 and 8 together. Two-way analysis of variance was carried out at each time point to see if there was any difference between the three agents given first, between the two agents given second, and to determine if the magnitude of any difference between the means was dependent on which drug was given first.
ALCURONIUM AND TUBOCURARINE PRIMING 100-i
-tt#** *
.
* J. *
t ! * *
10
80-
^ 6 0
40-
20-
50 Tl inhibition (%)
100
FIG. 3. Change in train-of-four ratio with change in Tl amplitude for tubocurarine and alcuronium without priming. V = Saline-tubocurarine; A = saline-alcuronium. Time (min)
FIG. 2. Percent reduction in EMG amplitude of first response of train-of-four (Tl) with time for alcuronium as the intubating relaxant. • = Saline-alcuronium 0.25 mg kg"1; O = saline-alcuronium 0.275 mg kg"1; T = alcuronium-alcuronium; A = tubocurarine-alcuronium. Significant differences from saline group (no priming): *P<0.05; **P<0.01; | P < 0.025; + t ^ < 0.005.
1.0
T l : T 0 ratio for those groups in which tuboi 0.5curarine was used to facilitate intubation (fig. 1). o Both of the lines for the two groups in which priming was used (groups 2 and 3) were significantly different from the control lines at the points indicated (fig. 1). Although the line for group 3 (alcuronium before tubocurarine) lies to the left of that for group 2 (tubocurarine before tubocurarine) there was no significant difference between these two groups. 100 50 Figure 2 illustrates data for those patients in Tl inhibition (%) whom alcuronium facilitated intubation; it reFIG. 4. Change in train-of-four ratio with change in Tl amsembles figure 1. There was no significant differ- plitude for tubocurarine and alcuronium when each primed ence between the two control lines at any time. with the other. V = Alcuronium-tubocurarine; A = tubocurarine—alcuronium. The lines for the two groups in which priming was used (groups 5 and 6) are significantly different from the control lines as indicated on the groups 1 and 7 together and groups 4 and 8 figure. Although the line for group 6 (tubo- together revealed no significant difference at any curarine before alcuronium) lies markedly to the time between the rates of onset of tubocurarine left of that for group 5 (alcuronium before and alcuronium when given alone. The changes in mean train-of-four ratio with alcuronium), there was no significant difference. Comparison of the tubocurarine and alcuro- changes in Tl :T0 are shown in figure 3 (control nium control groups using the aggregated data of groups 1 and 4: tubocurarine alone and alcuro-
Downloaded from http://bja.oxfordjournals.org/ at Indiana University Library on July 22, 2015
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10
BRITISH JOURNAL OF ANAESTHESIA
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nium alone) and figure 4 (groups 3 and 6, in which acetylcholine receptors, other acetylcholine reeach agent was primed with the second one). ceptor systems exist on the prejunctional region Tubocurarine demonstrated slightly more fade [22] and different neuromuscular blocking drugs than alcuronium, a difference which was not are thought to possess a unique spectrum of significant and not present when priming with the actions on the whole receptor system. It is likely that synergism between some pairs of nonsecond agent had been used. depolarizing neuromuscular blocking agents appears when two agents with dissimilar activity DISCUSSION spectra are combined. The acceleration of neuroTubocurarine and alcuronium were chosen be- muscular block resulting from the priming dose of cause they are known to exhibit synergism of the second agent in this study was slightly greater action which is stronger than tubocurarine and than when the relaxant was primed with itself. If pancuronium in vitro [6]. In order to compare a pharmacokinetic effect alone is proposed for equipotent doses, the ED95 of each was selected as priming, one might expect priming with a differthe intubating dose with a priming dose of 10 % of ent agent to be no more effective, or even less effective than priming with itself. This was not the ED95. Savarese [11] suggested a dose of 0.51 mg kg"1 observed in the present study. It is interesting to as the ED 95 for tubocurarine and Shanks [12] an note that the rate of onset of alcuronium was overall mean for all published data of 0.48 mg accelerated to a greater extent by tubocurarine kg"1. A value of 0.50 mg kg"1 was therefore chosen than was tubocurarine by alcuronium. for ease of calculation. There are fewer data for Although no detectable block was found to alcuronium than for tubocurarine. Shanks [12] result from the priming dose in this study, suggested an ED95 of 0.22 mg kg"1 and Lund and administration of a small dose of a non-depolarStovner [13] suggested a relative potency of izing neuromuscular blocking agent has been alcuronium and tubocurarine as 1.8:1. A value of shown to cause unpleasant partial paralysis in 0.25 mg kg"1 was chosen, therefore, as an ED95 for some patients [5, 23]. Under some circumstances, this study. It is clear from inspection of the mean this might be hazardous [24]. maximum neuromuscular block reached (table II) The increase in rate of onset when alcuronium that these two doses were near to equivalence. and tubocurarine are primed with each other is There is a large margin of safety in neuro- marked, 80 % neuromuscular block being reached muscular transmission such that approximately in just over 60 s. With suxamethonium 1 mg kg"1 75 % of receptors have to be occupied by 100% block is reached in approximately 70 s [25]. antagonist molecules before failure of trans- The time response curve with suxamethonium is mission begins [14]. After a single bolus dose, steeper, however, and suxamethonium causes a receptor occupancy has to increase from zero to more profound block. more than 75 % before depression of Tl is seen. If a small priming dose is administered, sufficient to ACKNOWLEDGEMENT produce receptor occupancy of just less than 75 %, the addition of a second intubating dose has The author is grateful to Miss Linda Hunt, Lecturer in to increase receptor occupancy just above this Medical Statistics, University of Manchester, for her figure. An additional pharmacokinetic mechanism assistance in the analysis of these data. has been proposed also [15]. Because the concentration of blocking drug at the neuromuscular REFERENCES junction determines neuromuscular block, pre1. Savarese JJ, Kitz RJ. The quest for a short acting nondosing allows that drug to reach an effective depolarising neuromuscular blocking agent. Acta Anaesthesiologica Scandinavica 1973; 53 (Suppl.): 43-48. concentration sooner, thereby accelerating the 2. Casson WR, Jones RM. Vecuronium induced neuroonset of block. Whichever mechanism is operamuscular blockade. The effect of increasing dose on speed ting, onset would be expected to be more rapid, as of onset. Anaesthesia 1986; 41: 354-357. observed in this study and in previous studies 3. Doherty WG, Breen PJ, Donati F, Bevan DR. Accelerated with tubocurarine [4, 16], alcuronium [4, 17], onset of pancuronium with divided doses. Canadian Anaesthetists Society Journal 1985; 32: 1—4. vecuronium [18], atracurium [19, 20] and 4. Foldes F. Rapid tracheal intubation with non-depolarizing pancuronium [3, 21]. neuromuscular blocking drugs: The priming principle. British Journal of Anaesthesia 1984; 56: 663. In addition to the classical postjunctional
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