R88 REFRESHER COURSE OUTLINE
The new relaxants: are they worth it? David 1L Bevan MB MRCP FRCA
UCH of the current neuromuscular and seems to be nearly as rapid as succinylcholine s drug development prOgrams are con- (Table II). The quick onset of succinylcholine is relat- cerned with the search for a replace- ed to its prompt metabolism and plasma clearance. M ment for the rapid onset, short When metabolism is impaired, i.e. in the presence of duration succinylcholine. This has led to re-evaluation atypical cholinesterase, the onset is also slower. 4 and re-definition of muscle relaxants by the FDA Similarly, the onset of action of mivacurium is consid- according to their onset and duration of action in a erably increased in the presence of atypical plasma dose of 2 x ED9s (Table I). ~ It is unlikely that any neu- cholineseterase, s romuscular blocking drug will be introduced into clin- After iv administration of NMBDs, peak plasma ical practice unless it is almost free of cardiovascular concentrations are achieved almost immediately. activity. The purpose of this presentation is to describe However, when subparalyzing doses are given, maxi- factors leading to the development of new drugs and mum block may not be achieved for 5-7 min. This to review the pharmacology of the recently introduced delay has led to the concept that the neuromuscular intermediate-acting neuromuscular blocking drugs - junction lies within a compartment (effect compart- rocuronium, mivacurium, cisatracurium and rapacuro- ment) separate from plasma or central compartment, nium. One of the problems in the development of the where drug effect is related to concentration. Access "Ideal Relaxant" is cost. An attempt will be made to from the central compartment to this effect compart- put the price of muscle relaxants into perspective. ment is controlled by a rate constant, k o.6 Onset of action is inversely proportional to k~o - drugs with Onset of Action higher kr have a more rapid onset (Table III). 7 Onset depends on the arrival at the receptor of suffi- The time to maximal block is almost independent cient molecules either to produce depolarization of of dose if < 100% block is attained. In doses producing the endplate (depolarizing NMBDs) or to prevent total paralysis, the latter is achieved before the maxi- acetylcholine from reaching enough receptors to cause mal effect at the junction. The time to disappearance neuromuscular transmission (non-depolarizing of twitch decreases with increasing dose. Clinicians NMBDs). Speed of onset is affected mainly by the rate using non-depolarizing drugs to facilitate tracheal of delivery of the drug to the junction. It is modified intubation may use larger doses than necessary to by drug potency and its metabolism. The onset of accelerate the production of good/excellent intubat- non-depolarizing relaxants is inversely proportional to ing conditions. their potency. 2 Thus, of the five recently introduced relaxants - doxacurium, mivacurium, pipecuronium, Pharmacology of the new drugs rocuronium, cisatracurium, the most potent, dox- acurium (EDs0 0.015 mg-kgq) has the slowest onset Rocuronium (10 - 15 min) and the least potent, roccuronium Rocuronium was developed from a series of monoqua- (EDs0 0.15 mg.kg-Z), the most rapid (1.5 - 2.5 min) ternary aminosteroids because of its rapid onset of
TABLE I FDA definitions of neuromuscular blocking drugs according to onset and clinical duration (time to T,s) after 2 x ED9s dose (After FDA, 1995q) ONSET- rain CLINICAL DURATION- rain
Ultra-rapid Rapid Inter-mediate Slow Ultra-short Short Inter-mediate Long <1 1 - 2 2 - 4 ~ 4 < 4 4- 20 20-50 >50
From the Department of Anesthesia, Vancouver Hospital & Health Sciences Centre, 910 West 10th Avenue, Vancouver, B.C. V5Z 4E3 Canada.
CAN J ANESTH 1999 / 46:5 / pp R88-R94 Bevan: THE NEW RELAXANTS R89 action and absence of cardiovascular side effects in ani- tram (57.4%), cis-trans (36.2%) and cis-cis (6.4%) of mals. In humans, it is about one sixth as potent as which the last is pharmacologically inactive. It is a vecuronium and has a more rapid onset of action, potent, non- depolarizing relaxant (ED9s: 60-80 although this is slower than after succinylcholine.8 }ag.kg-1 in adults 12 and 90-100/ag.kg -1 in children, is Nevertheless, tracheal intubating conditions 60 sec after (Table II). The onset of action is not as rapid as suc- rocuronium (0.6 mg.kg-1 [2 x ED9s]) were similar to cinylcholine but recovery is quick due to metabolism those produced by succinylcholine (1 mg.kg-1 x by plasma cholinesterase. The rate of recovery is twice EDgs]). 9 Optimal intubating conditions after rocuronl- as rapid as that from vecuronium or atracufium and is um, as for other neuromuscular relaxants, occur before similar whether administered by bolus or by continu- maximal block is obtained in the peripheral thumb mus- ous infusion to maintain the neuromuscular block. des probably because the laryngeal muscles have an ear- Recovery is so rapid that acceleration by anti- lier onset of effect, l~ When given in large doses, 1.2 cholinesterases is very small so that routine reversal mg.kg-1, intubation conditions 30 sec after administra- may not be necessary. However, if patients are trans- tion were similar to those after 1.5 mg.kg-1 succinyl- ferred to PACU soon after the end of surgery, they choline although the clinical duration was prolonged to may exhibit residual weakness if reversal agents are 46 min. n Apart from its more rapid onset of action, the avoided, i4 Edrophonium is preferred to neostigmine pharmacodynamic behaviour of rocuronium is similar as the latter inhibits plasma cholinesterase and may to vecuronium in duration, recovery and reversal. It is prolong the block. Recovery is considerably pro- potentiated by inhalational anesthetics and the onset longed (> six hours) in patients with atypical plasma and duration of action are prolonged in the elderly. cholinesterase 27 even after small test doses of 0.014 Rocuronium is excreted in the urine and its elimination mg.kg-i,s and the infusion rate required to maintain is decreased in patients with renal failure. constant block is correlated with the plasma cholinesterase activity. Mivacurium is rapidly cleared Mivacurium from the plasma but more slowly in patients undergo- Mivacurium is a bisquaternary benzylisoquinoline ing hepatic transplantation due to the decreased plas- compound consisting of three stereoisomers: trans- ma cholinesterase synthesis. Mivacurium is potentiated by isoflurane and by enflurane. If mivac- urium is given rapidly, over 10-15 sec, it is followed by TABLE II Typicalneuromuscular activity of non-depolarizing a brief, < 5 min, decrease in systolic blood pressure, blocking drugs. cutaneous erythema and histamine release. Is Usually, Potency (ED9s), Onset to maximum effect,25-75% Recovery. the hypotension is mild but in some patients may be Index (RI), and time to 25% T l recovery(Tg0) after 2 x EDgs severe enough to require treatment with vasopressors. dose in adults.
EDgs lag.kg-l Onset 25-75% Cisatracurium Recovery Recovery 25% T 1 Atracurium consists of 10 stereoisomers: cisatracurium MAn index - min min Rapacuronium 750 1 - 1.5 10- 15 12 - 20 is one and comprises approximately 15% of the mix- dTC 500 5 - 6 25 - 35 70 90 rare. It is approximately four times as potent as Atracurium 200 5 - 6 10 - 15 25 35 atracurium (Table II) and has been developed because Cisatracurium 50 7 - 8 8 - 9 25 3O it does not release histamine. There are no clinical car- Doxacurium 25 10- 14 30- 50 80 100 diovascular effects in doses exceeding the clinical range Metocurine 280 4 - 6 30 - 40 8O 9O Mivacurium 80 - 150 2 - 3 10 - 15 15 20 and it does not produce cutaneous flushing. 16 It has a Pancuronium 60 4 - 5 25 - 30 50 60 slightly slower onset than atracurium, probably a result Pipecuronium 60 5 - 6 30 - 40 80 90 of its increased potency, but a slightly more rapid Rocuronium 300 2 - 3 10 - 15 25 35 recovery. It is metabolized, like atracurium, by Vecuronium 80 4 - 5 10 - 15 25 35 Hoffmann clearance. However, only 23% of the elimi- nation is organ dependent compared with 61% for atracurium. Cisatracurium, like atracuri ,um, demon- TABLE III Relationship between onset of action and kco.Q strates considerable synergism with aminosteroids such keo (min -~) as rocuronium. 17 Cisatracurium has few advantages adductor pollicis laryngeal adductors over atracurium other than the absence of cardiovascu- Rapacuronium 0.41 0.63 lar effects and histamine release. Its current popularity Rocuronium 0.17 0.26 in North America is more a reflection of attractive pric- Vecuronium 0.12 0.18 ing than superior pharmacological activity. R90 CANADIAN JOURNAL OF ANESTHESIA
TABLE IV Intubation 90 sec after succinylcholine or mivacuriumw Increasing the dose of any non-depolarizing relaxant
Intubation TOF accelerates the appearance of maximum block and @ 90 sec count acceptable intubating conditions but at the price of Excellent Good 0 4 considerable delay in recovery. Succinylcholine 1 mg.kg-l: dTc 50 pg.kg-1 - 3 min 97 81 10 53 43 Divided doses - ~priming" ~timing" Mivacurium 0.25 mg.kg-1 divided: Although onset can be accelerated with small "prim- 0.15 & 0.1 mg.kg-1 @30 sec 91 51 38 2 88 ing" doses of non-depolarizing relaxant three minutes before the main dose, the effect is small. Priming car- ties the risk of aspiration and difficulty in swallowing, and visual disturbances are uncomfortable for the patient. The practice has largely been superseded by Rapaeuronium the introduction of rocuronium. The latest in the aminosteroid series of neuromuscular Attempts to make use of the rapid recovery of relaxants is rapacuronium and it is currently undergo- mivacurium have included administration of 0.15 and ing pre-clinical evaluation. Preliminary studies suggest 0.1 mg-kg-1, 30 sec apart. 2i After induction of anes- that the ED95 is approximately 1 mg.kg-L is Doses of thesia with propofol, intubating conditions after 90 2 mg.kg -i produce good-excellent intubating condi- sec were similar after succinylcholine, preceded by a tions in 90% of adults with a mean clinical duration of defasciculating dose of d-tubocurarine, and divided 18 min and recovery to 70% TOF in 45 rain. ~9 Onset dose mivacurium (Table IV). and recovery are slower in elderly patients. An unique Using the "timing principle" rocuronium, 0.6 aspect of rapacuronim is the observation that the mg.kg -1, is given before anesthesia which is induced as block can be reversed soon after administration. After soon as ptosis is observed. Using this technique, tra- 1.5 mg.kg -1 followed by 0.07 mg.kg -1 neostigmine 2 cheal intubation was performed at 45 or 60 sec and min later return to TOF0. 7 occurred in 16-18 rnin) ~ was achieved with similar conditions as after 1.5 mg.kg -1 succinylcholine preceded by vecuronium. 22 Rapid Onset Clinical Strategies Succinylcholine Early reversal Despite the frequency of severe complications, succinyl- The experimental rapid onset, intermediate duration choline remains the NMBD most frequently used to relaxant, rapacuronium, has a similar onset of block as facilitate tracheal intubation, particularly in emergency rocuronium. However, when administered in a bolus of situations in the presence of a full stomach. In addition, 1.5 mg.kg -1 (c. 1.5 2 x ED9s)during it is the least expensive option. However, the difficulty N20/O2/halothane anesthesia, 7 reversal of the block in recognising children with undiagnosed Duchenne with neostigmine two minutes after its administration muscular dystrophy which results in hyperkalemia and produced an onset and recovery profile that was similar death after succinylcholine has provided some urgency to that of succinylcholine 19 (Table V). Further North in seeking a replacement for succinylcholine. American experience demonstrated that, under bal- anced anesthesia, reversal of 1.5 mg-kg-1 at two or five Non-depolarizing relaxant minutes led to recovery of TOF o.7 in 16-18 min. 2~ The rapid onset of rocuronium, although not as quick as succinylcholine, produces good/excellent intubat- Residual neuromuscular block ing conditions within 60 sec that are indistinguishable In 1979, Viby-Mogensen and his colleagues demon- from those of succinylcholine. However, the duration strated a high incidence of residual neuromuscular of action is much longer - clinical duration after an blockade in patients in the Post-Anesthesia Care Unit intubating dose of 0.6 mg.kg -1 is 30-40 min. (PACU)3 s They examined 72 patients, who had
TABLE V Onset and Recovery after succinylcholine or rapacuronium with/without reversal at 2 min sg
n Onset - see Tz~ - rain Tgo - rain TOFo. ~ - rain
Sux 1 mg-kg-1 15 67 • 20 8.0 • 2.5 10.6 • 3.3 Rap 1.5 mg.kg-1 15 8.0 • 1.9 16.4 • 5.8 24.1 • 6.2 Rap 1.5 mg.kg-1 + neo 15 83 • 38 5.7 • 0.6 10.8 • 3.5 11.6 • 1.4 Bevan: THE NEW RELAXANTS R91 received a variety of long-acting relaxants (d-tubocu- TABLE VI Postoperative pulmonary complications and choice rarine, gallamine and pancuronium), after the anes- of relaxant. 29 thetist had left the patient to the care of the PACU Pancuronium, n=226 Atra or gee, n=450 staff. In 30 (42%), the TOF ratio of the adductor pol- Pts with POPC Pts with POPC licis was less than 0.7 although 67 had received n n % n n % neostigmine to reverse the block. Of the 68 who were TOF z 0.7 167 8 4.8 426 23 5.4 sufficiently awake and cooperative, 16 (24%) were TOF < 0.7 59 10 16.9 24 1 4.2 unable to maintain a five-second head lift. Other stud- ies, performed in several countries have reported a similar high incidence of residual paralysis although the incidence of weakness (TOF < 0.7) was reduced to less than 10% when the intermediate agents, atracuri- that TOF <0.7 after pancuronium was a potential risk um and vecuronium, were used. 24 factor for development of POPC (Table VI). 29 The decreased incidence of residual block when intermediate or short duration relaxantg are used has led to the gradual disappearance of long-acting relax- The development of new, intermediate neuromuscular ants such as pancuronium, d-tubocurafine, or dox- blocking drugs has allowed not only the near replace- acurium despite the potential reduction in anesthetic ment of succinylcholine and its multitude of side costs that might be achieved with generic pancuroni- effects but als0 the avoidance of residual block after um. 2s However, Kopman et aL have suggested that if long-acting relaxants such as pancuronium. However, neuromuscular blocking drug administration is titrat- such developments have a price. ed carefully with continuous neuromuscular monitor- ing, then residual block is not seen, after the use of Cost of relaxants either mivacurium or pancuronium, z6 However, on Several of the Cost Minimization Analyses concerning closer inspection, it appears that patients in Kopman's anesthesia drugs have been concerned with neuromus- study did not reach the PACU until 30 min after cular blocking drugs. By converting from the interme- reversal of block. In most previous studies patients diate drugs atracurium, vecuronium to reached the PACU within 15 min, or less, after rever- pancuronium, the possibility of large savings without sal. The more time that is allowed and the less'intense added risk have been claimed. 2~ Atracurium and the block that is antagonised, the less likely is residual vecuronium are considered to'be expensive because of block to occur. the large price differential between the cost of these agents and pancuronium or d-tubocurarine at the time Clinical Importance of their introduction; current availability of generic pan- Only recently, has the clinical importance of residual curonium; and the uncontrolled use of very large quan- block been proved. In volunteers receiving continuous rifles of muscle relaxants, mainly vecuronium, in the infusion of atracurium or vecuronium, mild degrees of ICU. However, any return to the greater use of pan- block have been shown to be associated with ventilato- curonium in place of atracurium or vecuronium is like- ry and esophageal disturbances. Eriksson et al. showed, ly to be associated with residual paralysis in the Post in awake volunteers receiving a continuous infusion of Anesthetic Recovery Room even after intraoperarive vecuronium to maintain constant n-m block, that at neuromuscular monitoring and reversal of their effects. TOF of 0.6-0.7, the ventilatory response to hypoxia, The acquisition costs of relaxant drugs to facilitate but not hypercapnia, was impaired and did not return tracheal intubarion (approx 2 x ED9s ) varies from $1 to normal until TOF ~ 0.9. 27 The likely cause is that for succinylcholine to $13-$16 for atracurium, vecuro- neuromuscular blocking drugs impair the nicotinic nium or mivacurium. The cost of maintaining adequate carotid body receptors. In a similar study, the same relaxation during surgery (> 90% block) varies from $6 authors showed reduced pharyngeal muscle coordina- per hr for succinylcholine to $2.25 for pancuronium tion and shortened pharyngeal bolus transit time. Six of and $8 for atracurium or vecuronium. Costs of reversal 14 volunteers demonstrated laryngeal penetration by agents are similar for atropine-neostigmine and videoradiography at TOF 0.6-0.8. 2s Finally, in a large, atropine-edrophonium ($1.50) which is a little less than controlled study of post-operative pulmonary complica- for glycopyrrolate-neosrigmine ($2.50). However, such tions in 693 subjects randomised to receive pancuroni- data require considerable interpretation to be useful. um, vecuronium or atracurium for abdominal, For example, how can the cost of muscle pains after suc- gynecological or orthopedic surgery Berg et al. showed cinylcholine or the morbidity of prolonged ~,eakness in R92 CANADIAN JOURNAL OF ANESTHESIA
TABLE VII "Best Practice" consensus group guidelines. TABLE VIII Cost per minute of various activities: (After Lubtsky et all 6) $ per minute Primary Choice Options Anesthesia drugs $0.5 IV Induction Thiopentone Propofol Operating room $10 if history of PONV Boeing 747 on runway $80 Muscle relaxant Succinylcholine Rocuronium or vecuroni- Anesthesiology fee $2 um Pancuronium only if HR a concern Opioid Fentanyl Sufentanil if high dose technique + early extubation Inhalation Isoflurane FGF ~ 1 L/min IV Fluids Normal saline or Colloid if massive hem or also include the personnel (Physicians generating Ringer's Lactate endothelial leak guidelines, Arkive purchase ($60,000 = $15,000 per site), computer programming, on-going data collec- tion and distribution. No doubt the choice of some drugs for the "best-practice" consensus guidelines the recovery room after long-acting relaxants be esti- might be different as new data concerning periopera- mated? Drug costs depend on the number of ampoules tive complications are reported. For example, it would opened and not on the amount of drug given. Savings be difficult to support the continued use of pancuro- might be possible if a sufficient number of anesthesiol- nium after the demonstration, in Copenhagen, of the ogists converted to using short-acting relaxants such as considerable increase in Postoperative Pulmonary mivacurium allowing earlier discharge from the Complications following its use compared with that Recovery Room but these would only be achieved if the after atracurium or vecuronium. The outcome number of nursing staff in the area was decreased. analysed at Duke in the PACU may not have been able to collect such information. Interestingly, the cost of Cost Reduction Strategies anesthesia drugs in Vancouver in 1996 without direct Several strategies have been used in an attempt to control was $40CAN! It is important in examining reduce cost during anesthesia. Almost all have exam- each report to compare the pattern of surgery and the ined drug costs and a variety of educational programs, pre-testing use of drugs with that in one's own hospi- mandatory practice guidelines, and feedback of indi- tal to determine whether such reductions can be vidual performance data. In general, educational pro- achieved elsewhere. Berman and Simon reported that grams have had limited success in maintaining a the cost of anesthetic drugs by residents was reduced pattern of low cost prescription. For example by an individual cost feedback system that compared Johnstone and Jozefczyk were able to produce con- the individual drug use and cost, with that of the siderable savings during the education period but, department average. Not surprisingly, the use of more within two months, drug costs had returned at least to expensive drugs decreased and follow-up, three their previous level, s~ In a more imaginative approach months later, showed considerable rebound in cost. at Duke University, practice guidelines for drug use during anesthesia were generated by physicians (Table Perspective VII). A drug distribution process was developed (i.e. At a time of cost awareness, it is perhaps appropriate drug availability was controlled), and adherence to to remember that the acquisition cost of anesthesia guidelines was noted using an automated anesthesia drugs is likely to amount to approximately 0.25% of record keeper (Arkive| sl Clinical outcome data in the total hospital budget and is only a fraction of the the PACU and times indicative of patient flow were cost of running an operating room.(Table VIII) coUected, s2 With this system, the cost per case ($66.08US)[$24.52 per hr] in 1994 decreased to Conclusion $32[$11.46] in 1996 and, apparently, have been In the development of new neuromuscular blocking maintained at this level without any measurable dete- drugs the anesthesiologist is now provided with drugs rioration in patient outcome. Previous educational that are almost free of unwanted effects, have a time attempts produced little change in the pattern of drug course of action that allows great control of their use. However, these results were achieved at some activity and, in most cases, allow us to substitute them cost. Drug choice was restricted and the costs should for succinylcholine. Muscle Relaxants are Cheap. Bcvan: THE NEW RELAXANTS R93
References 14 Bevan DR, Kahwaji R, Ansermino JM, et aL Residual 1 Bedford RE. From the FDA. Anesthesiology 1995; 82: block after mivacurium with or without edrophonium 33A. reversal in adults and children. Anesthesiology 1996; 2 Bowman WC, Rodger IW, Houston J, Marshall R J, 84: 362-7. McIndewar I. Structure: action relationships among 15 SavaresefJ, Ali HI-I, Basra SJ, et al. The cardiovascular some desacetoxy analogues of pancuronium and effects of mivacurium chloride (BW B1090U) in vecuronium in the anesthetized cat. Anesthesiology patients receiving nitrous oxide-opiate-barbiturate 1988; 69: 57-62. anesthesia. Anesthesiology 1989; 70: 386-94. 3 Magorian T, Flannery KB, Miller RD. Comparison of 16 LepageJ-Y, Malinovsky J-M, Malinge M, et al. rocuronium, succinylcholine, and vecuronium for Pharmacodynamic dose-response and safety study of rapid-sequence induction of anesthesia in adult cisatracurium (51W89) in adult surgical patients during patients. Anesthesiology 1993; 79: 913-8. N20-O2-opioid anesthesia. Anesth Analg 1996; 83: 4 Hickey DR, O, ConnorJP, Donati F. Comparison of 823-9. atracurium and succinylcholine for electroconvulsive 17 Naguib M, Samarkandi AH, Ammar A, Elfaqih SR, therapy in a patient with atypical plasma cholinesterase. Al-Zahrani, Turkistani A. Comparative clinical phar- Can J Anaesth 1987; 34: 280-3. macology of rocuronium, cisatracurium, and their 5 Vanlinthout LE, Barrels CF, Lockridge O, Callens K, combination. Anesthesiology 1998; 89: 1116-24. Booij Lift. Prolonged paralysis after a test dose of 18 Kahwaji R, Bevan DR, Bikhazi G, et al. Dose-ranging mivacurium in a patient with atypical serum study in younger adult and elderly patients of ORG cholinesterase. Anesth Analg 1998; 87: 1199-202. 9487, a new rapid-onset, short-duration muscle relax- 6 Sheiner LB, Stanski DR, Vozeh S, Miller R_D, Ham J. ant Anesth Analg 1997; 84: 1011-8. Simultaneous modelling of pharmacokinetics and phar- 19 Wierda JM, van den Broek L, ProostJH, Verbaan BW, macodynamics: application to d-tubocurarine. Clin Hennis PJ. Time course of action and endotracheal Pharmacol Ther 1979; 25: 358-71. intubating conditions of Org 9487, a new short-acting 7 Wright PMC, Brown R, Lau M, FisherDM. A pharmaco- steroidal muscle relaxant; a comparison with succinyl- dynamic explanation for the rapid onset/offset of choline. Anesth Analg 1993; 77: 579-84. rapacuronium bromide. Anesthesiology 1999; 90: 16-23. 20 Purdy R, Bevan, DR, Fowler C, Donati F, LichcorfL. 8 Wierda JMKH, Kleef U~, Lambalk LM, Kloppenburg Early reversal of rapacuronium with neostigmine. WD, Agoston S. The pharmacodynamics and pharmaco- Anesthesiology (accepted for publication). kinetics of Org 9426, a new non-depolarizing neuro- 21 Ali HH, Lien CA, Witkowski T, et al. Efficacy and safe- muscular blocking agent, in patients anesthetized with ty of divided dose administration of mivacurium for a nitrous oxide, halothane and fentanyl. Can J Anaesth 90 second tracheal intubation. J Clin Anesth 1996; 8: 1991; 38: 430-5. 276-81. 9 Phringer FK, Khuenl-Brady KS, Koller J, 22 Sieber TJ, Zbinden AM, Curatolo M, Shorten GD. Mitterschiffthaler G. Evaluation of the endotracheal Tracheal intubation with rocuronium using the "timing intubating conditions of rocuronium (ORG 9426) and principle". Anesth Analg 1996; 86: 1137-40. succinylcholine in outpatient surgery. Anesth Analg 23 Viby-MogensenJ, Jargensen BC, Ording H. Residual 1992; 75: 37--40. curarization in the recovery room. Anesthesiology 10 Meistelman C, Plaud B, Donati F. Rocuronium (ORG 1979; 50: 539-41. 9426) neuromuscular blockade at the adductor muscles 24 Bevan DR, Smith CE, Donati F. Postoperative neuro- of the larynx and adductor pollicis in humans. Can J muscular blockade: a comparison between atracurium, Anaesth 1992; 39: 665-9. vecuronium, and pancuronium. Anesthesiology 1988; 11 Mazurak A J, Re B, Harm S, Kim JI, Castro B, Cot~ CJ. 69: 272-6. Rocuronium versus succinylcholine: are they equally 25 Orkin FK. Moving toward value-based anesthesia care. effective during rapid-sequence induction of anesthesia. J Clin Anesth 1993; 5: 91-8. Anesth Analg 1998; 87: 1259-62. 26 Kopman AA, Ng J, Zank LM, Neuman GG, Yee PS. 12 SavaresefJ, Ali HH, Basta SJ, et al. The clinical neuro- Residual postoperative paralysis. Pancuronium versus muscular pharmacology of mivacurium chloride (BW mivacurium, does it matter? Anesthesiology 1996; 85: B 1090U ): a short-acting nondepolarizing ester neuromus- 1253-9. cular blocking drug. Anesthesiology 1988; 68: 723-32. 27 Eriksson LI, Sundman E, Olsson R, et al. Functional 13 Goudsouzian NG, Alifimoff fK, Everly C, et al. assessment of the pharynx at rest and during swallow- Neuromuscular and cardiovascular effects of mivacuri- ing in partially paralyzed humans. Anesthesiology um in children. Anesthesiology 1989; 70: 237-42. 1997; 87: 1045-43. R94 CANADIAN JOURNAL OF ANESTHESIA
28 Eriksson LI, Lennraarken C, Johnson A. Attenuated ven- tilatory response to hypoxemia after vecuronium induced neuromuscular block. Acta Anaesthesiol Scand 1992; 36: 710-5. 29 Berg H, Viby-MogensenJ, Roed J, et al. Residual neuro- muscular block is a risk factor for postoperative pul- monary complications. Acta Anaesthesiol Scand 1997; 41: 1095-103. 30 Johnstone RE, Jozefczyk KG. Costs of anesthetic drugs: experiences with a cost education trial. Anesth Analg 1994; 78: 766-71. 31 LubarskyDA, Glass PSA, Ginsberg B, et al. The success- ful implementation of pharmaceutical practice guide- lines. Anesthesiology 1997; 86: 1145-60. 32 Lubarsky DA, Sanderson IC, Gilbert WC, et al. Using an anesthesia information management system as a cost containment tool. Anesthesiology 1997; 86: 1161-9. CONF]~B.ENCE D ~AGTUALISATION R95
Les nouveaux myorela- xants : en valent-ils le A David R. Bevan MB MRCP FRCA cout?
L A plupart des programmes de recherche 0,15 mg-kg-1), est le plus rapide (1,5 - 2,5 min) et sem- actuels sur les mrdicaments neuromuscu- ble &re ~ peu pros aussi rapide que la succinylcholinea hires tentent de trouver un substitut possi- (Table II). L'action prompte de la succinylcholine est ble ~ la succinylcholine dont le drbut lire ~ la rapidit6 de' son m&abolisme et de sa clairance d'action est rapide mais l'effet de courte dur&. C'est plasmatique. Quand le m&abolisme est altrrr, en ce qui a amen6 la FDA ~ r66valuer et ~ redrfinir les pr&ence de cholinestrrase atypique par exemple, le myorelaxants d'apr& leur rapidit~ et leur dur& d'ac- drbut d'action est ralenti. 4 I1 en va de m~me avec le tion en utilisant une dose de 2 x EDgs (Table I). 1 Tout mivacurium, s nouveau mrdicament myorelaxant introduit en cli- Apr& l'administration iv de myorelaxant, les con- nique devra sans aucun doute n'avoir pratiquement centrations plasmatiques maximales sont presque aucune action cardiovasculaire. Nous voulons prrsen- immrdiatement atteintes. Cependant, l'administration ter ici une description de ce qui guide l'41aboration de doses insuffisantes pour paralyser ne permettra un des nouveaux mrdicaments et une revue de la phar- blocage maximal qu'apr~s 5-7 minutes. Ce qui a fait macologie des myorelaxants ~ action intermrdiaire penser que la jonction neuromusctdaire se situe ~ Fin- nouvellement offerts : le rocuronium, le mivacurium, trrieur d'un compartiment (compartiment d'effet) le cisatracurium et le rapacuronium. L'un des prob- srpar6 du plasma ou du compartiment central o~ l'ef- 16rues de d&eloppement du <
TABLE I Drfinitions des myorelaxants selon leur d~but d'action et leur durre clinique (temps vers T2s ) apr~s une dose de 2 x ED9s (FDA, 1995q)
D[IBUT- rain DUR~E CLINIQUE - min Ultra-rapide Rapide Interm~diaire Lent Tr~s courte Courte Intermrdiaire Longue 50,
CAN J ANESTH 1999 / 46:5 / pp R95-R100 R96 CANADIAN JOURNAL OF ANESTHESIA
Pharmacologie des nouveaux m~dicaments r&up&ation et le renversement. I1 est potentialis6 par Rocuronium les anesth6siques administr~s par inhalation et, chez Le rocuronium a ~t~ ~labor~ ~ partir de s&ies les gens fig&, son d6but d'action et sa dur& sont pro- d'aminost&o~des monoquaternaires en raison de sa long&. Son 61imination, dans l'urine, diminue chez les rapidit~ d'action et de l'absence d'effets secondaires patients atteints d'insuffisance r~nale. cardiovasculaires chez les animaux. Chez les humains, sa puissance ~quivaut ~ un sixi~me environ de celle du Mivacurium v&uronium et il a une plus grande rapidit~ d'action, Le mivacurium est tm compos6 benzylisoquinol6ique quoique plus lente que la succinylcholine, s biquaternaire constitu6 de trois st&6o-isom6res : N&nmoins, les conditions d'intubation endotra- trans-trans (57,4 %), cis-trans (36,2 %) et cis-cis (6,4 ch~ale, 60 s apr& l'administration de rocuronium (0,6 %) dont le dernier n'a pas d'action pharmacologique. mg.kg-l[2 _ ED9s]) sont similaires ~ celles qui sont C'est un curarisant puissant, non d6polarisant (ED95 : produites avec la succinylcholine (1 mg.kg-~ x 60-80 }ag-kg-1 chez les adultes 12 et 90-100 ~ag.kg-l EDgs]). 9 Les conditions optimales d'intubation apr~s chez les enfants 13 (Table II). II n'a pas la rapidit6 d'ac- le rocuronium, comme avec les autres myorelaxants, t_ion de la succinylcholine, mais permet une r&up&a- se pr&entent avant que le blocage maximal ne soit tion rapide, car m&abolis6 par la cholinest&ase atteint dans les muscles p~riph~riques du pouce, sans plasmatique. La r&up&ation, deux fois plus rapide doute parce que l'effet du m~dicament est plus rapide qu'avec le v&uronium ou l'atracurium, n'est pas sur les muscles larynges. ~~ Quand on l'administre en influenc& par le mode d'administration, en bolus ou fortes doses, 1,2 mg.kg-~, les conditions d'intubation en perfusion continue. En fait, la r&up&ation est si 30 s apr~s l'administration sont similaires ~ celles rapide que l'acc61&ation produite par l'anti- qu'on a observ&s apr& 1,5 mg.kg-I de succinyl- cholinest6rase est tr6s faible, de sorte que la d&urari- choline bien que la dur& du bloc se prolonge jusqu'~ sation de routine ne sera peut-6tre pas n&essaire. 46 min. H Mis ~ part sa rapidit~ d'action, le comporte- Toutefois, les patients transf&& ~ la salle de r~veil dis ment pharmacodynamique du rocuronium est sem- la fin de l'op&ations peuvent ressentir une faiblesse blable ~ celui du v&uronium pour la dur&, la r&idueUe si un d&urarisant n'est pas administr& 14 L'6drophonium est pr6f&able dans ce cas ~ la n6ostig- mine, puisque cette derni6re inhibe la cholinest&ase TABLE II Acfivit~ neuromusculaire typique des myorelaxants plasmatique et peut prolonger le bloc. La r&up&ation non d~polarisants est consid&ablement prolong6e, plus de six heures, Puissance (ED9s), Du d~but ~ l'effet maximal, Index de r&up&a- chez les patients qui pr&entent une cholinest&ase tion 25-75 % (IR), et le temps pour une r&up&ation de 25 % plasmatique atypique,27 m6me apr& de faibles doses Tl(Tg0 ) apr~s une dose de 2 • EDgs chez les adultes test de 0,014 mg.kg-1,s, et la vitesse de perfusion ED9s }ag.kgq D~but Index de n&essaire pour maintenir un bloc constant est en cor- R&up&ation 25 % T l r&up&ation r61ation avec l'activit6 de la cholinest&ase. Le miva- Min 25-75 % - min rain Rapacuronium 750 1 - 1,5 10 - 15 12 - 20 curium est 61imin6 rapidement du plasma, mais plus dTC 500 5 - 6 25 - 35 70 - 90 lentement chez les patients qui subissent une trans- Atracurium 200 5 - 6 10 - 15 25 - 35 plantation h6patique et cela ~ cause de la synth6se d6fi- Cisatracurium 50 7 - 8 8 - 9 25 - 30 ciente de cholinest6rase plasmatique. Le mivacurium Doxacurium 25 10 - 14 30 - 50 80 - 100 est potentialisl par l'isoflurane et l'enflurane. S'il est M&ocurine 280 4 - 6 30 - 40 80 - 90 Mivacurium 80 - 150 2 - 3 10 - 15 15 - 20 administr6 rapidement, 10-15 s, il s'ensuit une chute Pancuronium 60 4 - 5 25 - 30 50 - 60 br6ve, < 5 min, de tension art6rielle systolique, un &y- Pip&uronium 60 5 - 6 30 - 40 80 - 90 th6me cutan~ et une lib6ration d'histamine. Is Rocuronium 300 2 - 3 10 - 15 25 - 35 Habituellement, l'hypotension est mod&&, mais chez V&uronium 80 4 - 5 10 - 15 25 - 35 certains patients elle peut ~tre assez s&~re pour exiger un traitement vasopresseur.
TABLE III Relation entre le d~but d'action et la kr Q Cisatracurium keo (min -1) L'atracurium comporte 10 st&6o-isom~res, le adducteur du pouce adducteurs larynges cisatracurium en est un et compte pour 15 % environ Rapacuronium 0,41 0,63 du m61ange. Environ quatre fois plus puissant que l'a- Rocuronium 0,17 0,26 tracurium (Table II), il a 6t~ commercialis6 parce qu'il V&uronium 0,12 0,18 ne lib~re pas d'histamine. II n'y a pas d'effets cardio- Bcvan: L~ NOUVEAUX MYORELAXANTS : EN VALENT-ILS LE COOT? R97
TABLE IV Intubation 90 s apr~s la succinylcholine ou le mivac- Strat6gies diniques d'action rapide urium w Succinylcholine Intubation compte Malgr6 la fr4quence de s6v6res complications li&s @ 90 s TD~. son usage, la succinylcholine demeure le myorelaxant Excellente Bonne 0 4 le plus utilis6 pour faciliter l'intubation endotrach6ale, Succinylcholine 1 mg.kg-~ : en particulier dans les situations d'urgence avec dTc 50 ~ag-kgq - 3 rain 97 81 10 53 43 l'estomac plein. En outre, c'est le choix le moins cher. Mivacurium 0,25 mg.kg-~ Toutefois, la difficult6 ~ reconnaltre la myopathie de fractionn6 : Duchenne chez des enfants non diagnostiqu6s a 0,15 & 0,1 mg.kgq @ 30 sec 91 51 38 2 88 provoqu6 de l'hyperkali6mie et la mort apr& l'emploi de succinylcholine eta fait voir l'urgence de trouver un m6dicament de remplacement. vasculaires appr&iables pour des doses qui d6passent les valeurs cliniques et ne produit pas de rougeur Myorelaxant non d~polarisant cutan&. 16 II a un d6but d'action 16g6rement plus lent La rapidit~ d'action du rocuronium~ bien qu'in- que l'atracurium, r6sultat probable de sa puissance, f&ieure ~ celle de la succinylcholine, permet des con- mais permet une r&up6ration 16g6rement plus rapide. ditions d'intubation de bonnes ~ exceUentes en moins II est m&abolis6, comme l'atracurium, par la clairance de 60 s, ce qui est tout ~ fait comparable ~ la succinyl- de Hoffmann. Cependant, 23 % seulement de l'6limi- choline. Par contre, la dur& d'action est beaucoup nation d6pend de l'organe en comparaison de 61% plus longue, 30-40 min apt& une dose d'intubation pour l'atracuriurn. Le cisatracurium, comme l'atracu- de 0,6 mg.kg -1. Accroltre la dose de tout myorelaxant rium, d6montre une synergie consid6rable avec les accd~re l'apparition du blocage maximal et la mise en aminost6roides comme le rocuronium, w Le place des conditions acceptables d'intubation, mais au cisatracurium a peu d'avantages par rapport ~ l'a- prix d'un d61ai de r&up~ration important. tracurium si ce n'est l'absence d'effets cardiovascu- laires et la lib6ration d'histamine. Sa popularit6 Dosesfractionn3es -,,amorfage,, ,,minutage, actueUe en Am6rique du Nord tient plus ~ son prix Bien que la rapidit~ d'action puisse &re am~lior& avec attirant qu'~ son activit~ pharmacologique sup~rieure. de petites doses d'~amorqage, de myorelaxant non d~polarisant trois minutes avant la dose principale, Rapacuronium l'effet est minime. L'amorqage comporte le risque Dernier de la s6rie aminost4roide des myorelaxants, le d'aspiration et des difficult& de d4glutition, et des rapacuronium est pr6sentement en &aluation pr6- troubles visuels d&agr~ables pour le patient. La pra- clinique. Des &udes pr6liminaires indiquent que la tique a 6t~ largement abolie et remplac& avec l'arriv& ED95 est approximativement de 1 mg.kg-L is Des du rocuronium. doses de 2 mg.kg -1 produisentdes conditions d'intu- Les essais r&lis& dans le but d'ufiliser la r&up~ra- bation de bonnes ~ excellentes, chez 90 % des adultes, tion rapide du mivacurium ont indus l'administration d'une dur6e clinique moyenne de 18 min et la de 0,15 et 0,1 mg.kgq, ~ 30 s d'intervaUe. 21 Apr~s l'in- r&up6ration ~ 70 % du TDQ en 45 min. 19 Le d6but duction de l'anesth&ie avec du propofol, les conditions d'action et la r&up6ration sont plus lents chez les d'intubation &aient, apr~s 90 s, similaires ~ celles qu'on patients ~g6s. Le rapacuronium pr&ente un caract6re obtient ~ la suite de la succinylcholine, pr&~d& par une unique en ce que le blocage qu'il produit peut ~tre dose de d6fascicttlation de d-tubocurarine, et d'une renvers~ t6t apr6s l'administration. Apr~s l'administra- dose fractionn& de mivacurium (Table IV). tion de 1,5 mg.kg -1 suivie de 0,07 mg.kg -~ de n6ostig- Utilisant le ,~principe du minutage,, 0,6 mg.kg -~ de mine 2 min plus tard, le retour au TDQ0, 7 s'est rocuronium est administr~ avant l'anesth&ie qui est produit en 16-18 min. 2~ induite aussit6t que le ptosis est observ& Selon cette
TABLE V D6but et r&up&adon apr~:s la succinylcholine ou le rapacuronium avec/sans inversion A 2 rain 3s
n D~but- see T25- rain Tgo - rain TDQo, z- rain
Sux 1 mg.kg-I 15 67 • 20 8,0 • 2,5 10,6 + 3,3 Rap 1,5 mg.kg-1 15 . 8,0 • 1,9 16,4 • 5,8 24,1 • 6,2 Rap 1,5 mg.kgq + n~o 15 83 • 38 5,7 • 0,6 10,8 • 3,5 11,6 • 1,4 R98 CANADIAN JOURNAL OF ANESTHESIA
technique, l'intubation endotrach&le est r&lis& ~ 45 TABLE VI Complications pulmonaires postop&atoires et choix ou 60 set dans des conditions similaires ~ ce qu'on de myorelaxanta9 retrouve apr& l'administration de 1,5 mg.kg -x de Pancuronium, n = 226 Atra ou V~c, n = 450 succinylcholine pr6c~dge de v&uronium. ~ Pts avec CPPO Pts avec CPPO n n % n n % D~curarisation pr3coce TDQ ~ 0,7 167 8 4,8 426 23 5,4 Myorelaxant de dur& interm~diaire et de rapidit~ TDQ < 0,7 59 10 16,9 24 1 4,2 d'action confirm& par l'exp&ience, le rapacuronium pr&ente un dtbut d'action similaire ~ celui du rocuro- nium. Cependant, quand on l'administre en bolus de 1,5 mg.kg -1 (c. 1,5 - 2 x ED95 ) pendant une anesthtsie au N20/OJhalothane, ~la d&urarisation graient la salle de r&eil en 15 min ou moins apr& la avec de la n~ostigmine deux minutes apr~s son admi- d&ttrarisation. Plus le temps allou~ est long et moins rfistration laisse voir un profil de dtbut d'action et de le blocage ~ contrer est intense, moins il y a de chance r&uptration semblable ~ celui de la succinylcholine 19 qu'un bloc r~siduel persiste. (Table V). Une exp&ience nord-am&icaine compl& mentaire a d~montr6 que, sous une anesth&ie ba- Importance clinique lanc&, la d&urarisation de 1,5 mg.kg q ~ deux ou cinq Ce n'est que r&emment qu'on a prouv~ l'irnportance minutes conduit ~ une r&uptration du TDQ0, 7 en 16- clinique du bloc r&iduel. On a montr6 chez des 18 min. 20 volontaires qui recevaient une perfusion continue d'a- tracurium ou de v&uronium des blocs faibles associ& Bloc.age neuromusculaire r~siduel des dtsordres ventilatoires et oesophagiens. Eriksson En 1979, Viby-Mogensen et ses coU~gues ont dtmon- et coll. ont montrt, chez des volontaires &eillts rece- tr6 une forte incidence de blocage neuromusculaire vant une perfusion continue de v&urouium afin de rtsiduel chez des patients ~ la salle de r~veil. 23 Ils ont maintenir un blocage neuromusculaire constant, examin~ 72 patients, qui avaient requ une vari&~ de qu'au moment d'un TDQ de 0,6-0,7, la r6action res- myorelaxants ~ action prolong& (d-tubocurarine, gal- piratoire ~t l'hypoxie, mais non ~ l'hypercapnie, &ait lamine et pancuronium). Chez 30 d'entre eux (42 %), alttr& et ne revenait pas ~ la normale avant le TDQ le ratio du TDQ de l'adducteur du pouce &ait plus 0,9. 27 C'est probablement caus6 par le fait que les bas que 0,7 m~me si 67 patients avaient eu de la myorelaxants alt~rent les r&epteurs nicotiniques du n~ostigmine pour renverser le blocage. Parmi les 68 glomus carotidien. Dans une &ude similaire, les patients suffisamment &eill& et cooptratifs, 16 (24 %) m~mes auteurs ont fait la preuve d'une rtduction de la n'ont pu maintenir la t&e soulev& pendant cinq se- coordination des muscles pharyngiens et un transit condes. D'autres &udes, rtalis&s dans diff6rents pays, &ourt6 du bolus pharyngien. Chez 6 des 14 volon- ont montr6 une incidence similaire de paralysie r&idu- taires, on a observt, par vid~oradiographie, une ptn& elle m~me si l'incidence de faiblesse (TDQ < 0,7) &air tration laryngienne au TDQ 0,6-0,8. 2s Enfin, darts r6duite ~ moins de 10 % avec des agents interm6- une importante dtude contrtlde des complications diaires, comme l'atracurium et le v&uronium. 24 pulmonaires postop6ratoires chez 693 sujets rdpartis L'incidence d&roissante de blocage r&iduel en au hasard et qui ont requ du pancuronium, du v&uro- pr&ence de myorelaxants ~ action br~ve ou interm& nium ou de l'atracurium pour une intervention diaire a provoqu6 la disparition graduelle des myore- abdominale, gyndcologique ou orthopddique, Berg et laxants de longue dur& comme le pancuronium, la d- coll. ont montr6 qu'un TDQ < 0,7 apr& le pancuro- tubocurarine, ou le doxacurium malgr~ la r6duction nium repr&entait un facteur de risque potentiel de potentieUe du cofit de l'anesthtsique qu'on pourrait ddveloppement de CPPO (Table VI)39 r&liser avec le pancuronium g~n&ique. 2s Cependant, Kopman et coll. ont avanc6 que l'administration de R3sum3 myorelaxant bien dost, et sous monitorage continu du L'61aboration de nouveaux myorelaxants intermtdi- bloc neuromusculaire, 61imine le blocage r6siduel aires a permis non seulement le quasi remplacement apr~s l'emploi de mivacurium ou de pancuronium. 26 de la succinylcholine et l'6limination de ses nombreux En y regardant de plus pros, on constate que les effets secondaires, mais aussi la possibilit6 d'&iter un patients de l'&ude de Kopman n'ont 6t6 transf6r& ~ la bloc rtsiduel apr& l'usage de myorelaxant ~ action salle de r~veil que 30 min apr~s la d&urarisation. Dans prolong& comme le pancuronium. Malgr~ tout, de la plupart des &udes pr&6dentes, les patients int6- telles innovations ont un prix. Bevan: LES NOUVEAUXMYORELAXANTS : EN VALENT-ILSLE COOT? R99
TABLE VII Recommandationsdu consensus sur la ~Meilleure TABLE VIII Cofitpar minute de diverses activit& : pratique~. (Lubtsky et coll)~) $ par minute Principal choix Options Anesth6siques 0,5 $ IV Induction Thiopental Propofol Salle d'op6ration 10 $ si ant&6dents de NVPO Boeing 747 eu piste 80 $ Myorelaxant Succinylcholine Rocuroniumou v&uro- Prix de l'anesthEsie 2 $ nium Pancuronium seulementsi la FC pr6occupe Opio'fde Fentanyl Sufentanil si c'est une technique ~ forte dose + extubation pr&oce laires apr6s l'usage de succinylcholine ou la morbidit6 Inhalation Isoflurane de la faiblesse prolong& en salle de r6veil apr6s avoir FGF ~ 1 L/min utilis6 des myorelaxants de longue dur& ? Le cofit des IV Liquides Solution sal6e ou Colloide si k6m massive m6dicaments d6pend du nombre d'ampoules ouvertes Lactate de Ringer ou fuite endoth6fiale et non de la quantit6 de m6dicament administr&. Des 6pargnes sont possibles si un nombre suffisant d'anesth&iologistes se convertissent ~ l'usage de myorelaxants de courte dur& comme le mivacurium qui permet un d6part plus h~tif de la salle de r6veil Le coflt des myorelaxants mais cela ne seralt envisageable qu'avec la r6duction de Quelques analyses de r6duction des cofits, concernant personnel infirmier. les m6dicaments anesth&iques, ont port~ sur les curarisants. En passant des m6dicaments ~ action Strategies de compression des d~penses interm6diaires - atracurium, v&uronium - au pan- Certaines strat6gies ont &6 utilis&s pour tenter de curonium, on a pr&endu qu'il &ait possible d'~par- r~duire le cofit de l'anesth&ie. Dans la plupart, on a gner sans risque additionneh 2~ On consid~re que l'a- &alu6 le cofit des m~dicaments et une vafi&~ de pro- tracurium et le v&uronium sont chers ~ cause de la grammes de formation, des recommandations de pra- grande diff6rence entre le prix de ces agents et celui du tique clinique obligatoires et les r6actions ~ la pancuronium ou de la d-tubocurarine au moment de cueillette de donn&s sur le rendement des individus. leur introduction, de la disponibilit6 actuelle de pan- En g~n&al, les programmes d'6ducation avaient eu un curonium g6n6rique et de l'emploi incontr616 de succ& mitig~ quant au maintien d'un module de pres- grandes quantit6s de myorelaxants, le v&uronium cription ~ meilleur prix. Par exemple, Johnstone et surtout, dans les USI. Cependant, tout retour ~ un Jozefczyk ont pu faire des beaucoup d'&onomies pen- usage plus fr6quent de pancuronium, ~ la place de l'a- dant la p6riode de formation, mais en moins de deux tracurium ou du v&uronium, sera probablement asso- mois, le cofit des m~dicaments &ait revenu au moins ci6 ~ une paralysie r&iduelle dans la salle de r6veil son niveau pr&6dent, s~ Selon une m&hode plus m6me apr6s un monitorage neuromusculaire per- imaginative mise en vigueur ~ l'universit~ Duke, les op6ratoire et un renversement de leurs effets. recommandations de pratique pour l'utilisation des Le prix d'achat des myorelaxants qui facilitent l'in- m6dicaments pendant l'anesth&ie ont &6 ~labor&s tubafion endotrach6ale (approx 2 x EDgs ) varie de 1 $, par les m6decins (Table VII). Un syst~me de distribu- pour la succinylcholine, ~ 13 $ - 16 $ pour l'atracuri- tion de m~dicaments a &~ mis en oeuvre (c.-~-d. la urn, le v&uronium ou le mivacurium. Le cofit du disponibilit~ des m~dicaments &ait contr61&), et l'a- maintien du rel~chement musculaire ad6quat pendant dh&ion aux recommandations a ~t~ not& en utilisant la chirurgie (> 90 % de blocage) varie de 6 $/h pour un registre anesth~sique automatis~ (Arkive| 31 Les la succinylcholine ~ 2,25 $ pour le pancuronium et 8 donn&s sur les r6sultats cliniques dans la saUe de r&eil $ pour l'atracurium ou le v&uronium. Le prix des et les temps indicateurs du d~bit de patients ont &~ d&urarisants est similaire pour les combhaaisons d'at- enregistr&) 2 D'apr& ce syst~me, le cofit par personne ropine-n6ostigmine et d'atropine-6drophonium ( 1,50 $) (66,08 $ US)[24,52 S/hi en 1994 a baiss~ ~ 32 $ ce qui est un peu plus bas que celui de la combinaison [11,46 $] en 1996 et, apparemment, a ~t6 maintenu de glycopyrrolate-n6ostigmine (2,50 $). Toutefois, ce niveau sans d&~rioration mesurable de l'~volution une interpr&ation pouss& est n&essaire pour prouver des patients. Les tentatives ant~riettres de formation l'utilit6 de ces donn&s. Par exemple, comment n'ont rapport~ que peu de changement dans la faqon estimer le cofit du soulagement des douleurs muscu- d'utiliser les m~dicaments. Toutefois, ces r&ultats ont R100 CANADIAN JOURNAL OF ANESTHESIA dtd obtenus moyennant un certain prix. Le choix des mddicaments &air restreint et le cofit devait inclure le personnel : les m6decins produisant les recommanda- tions, l'achat du syst~me Arkive (60 000 $ = 15 000 $ par site), la programmation informatique, la cueillette permanente de donndes et la distribution. Le choix de certains mddicaments en vue de rdpondre aux recom- mandations consensuelles pour une -meilleure pra- tique~, dtait sans aucun doute diffdrent ~ mesure que les dorm&s concernant des complications pdriopdra- toires &aient rapportdes. Par exemple, il aurait dtd dif- ficile d'appuyer l'usage du pancuronium apr~s la d6monstration, ~ Copenhague, d'une augmentation considdrable de complications pulmonaires postopdra- toires ~ la suite de son utilisation en comparaison avec l'atracurium ou le vdcuronium. II est possible que l'analyse des rdsultats ~ Duke dans la salle de rdveil, n'ait pu quantifier ces donndes. Fait intdressant noter, le cofit des anesth&iques ~ Vancouver en 1996, sans contr61e direct, &ait de 40 $ CAN! II est impor- tant, en &aluant chaque rapport, de comparer le mo- dule de chirurgie et d'usage de mddicament prd-tests avec les donn&s de son propre h6pital afin de d&er- miner si des rdductions semblables ne pourraient ~tre faites dans un ai~tre ddpartement. Berman et Simon ont rapportd que le cofit des anesth&iques par les r&i- dents &ait rdduit au moyen d'un syst~me off l'usage individuel de mddicaments et leur cofit sont not6s et compards ~ la moyenne du ddpartement. Comme on pouvait s'y attendre, l'emploi des mddicaments les plus chers a diminud, mais la v&ification, trois mois plus tard, a montrd un rebond important du cofit. Perspective Au moment off on prend conscience des cofits, il est peut-&re approprid de rappeler que le prix d'achat des anesth~siques est d'environ 0,25 % du budget total d'un h6pital et ne repr~sente qu'une fraction du cofit de fonctionnement d'une saUe d'op~ration (Table VIII).
Conclusion Avcc Ic ddvcloppcmcnt dc nouvcaux myorclaxants, l'ancsthdsiologistc a maintcnant ~ sa disposition dcs mddicamcnts qui sont prcsquc sans cffcts sccondaircs, ont unc durdc d'acfion qui pcrmct dc bicn contr61cr Icur acfivitd ct, darts la plupart dcs cas, pcrmct~cnt dc Ics subsritucr ~ la succinylcholinc. L~s myorclaxants sont bon m3xchd. l~f-drences (Voir page R93)