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USE OF MUSCLE RELAXANTSBy FRANCIS F. FOLDES, M.D.,

Director, Department of Anaesthesia, Mercy Hospital; Associate Professor of Anaesthesiology, University of PittsburghSchool of Medicine, Pittsburgh, Pa., U.S.A.

I. Basic ConsiderationsThe purpose of muscle relaxants is to provide

muscular relaxation by selective depression ofneuromuscular transmission without the need fordeep general anaesthesia with its inherent dangers.To use these agents intelligently, it is essential tounderstand the physiology of neuromusculartransmission and the mode of action of the neuro-muscular blocking agents.Neuromuscular TransmissionWhen a nerve impulse reaches the neuro-

muscular junction, acetylcholine is liberated at theendplate. Acetylcholine is adsorbed to thecholinergic receptors, depolarizes the endplate,and creates the endplate potential which in turninitiates muscular contraction. Within a fewmilliseconds, the acetylcholine is hydrolyzed bythe acetylcholinesterase present at the endplateand the endplate becomes repolarized and ready totransmit the next nerve impulse. Anything thatinterferes with either the depolarization or therepolarization phase of neuromuscular trans-mission will produce neuro-muscular block.'

Neuromuscular BlockClassification. The type of neuromuscular block

of primary interest to the anaesthetist is that pro-duced by the quaternary ammonium compounds.All these compounds act by preventing the accessof acetylcholine to the cholinergic receptors of theendplate.1 Some of them, called non-depolarizingor 'competitive' relaxants, do not change theelectrical properties of the endplate and causeneuromuscular block by preventing the depolar-ization of the endplate by acetylcholine. Thedepolarizing muscle relaxants produce an acetyl-choline-like depolarization and for variable periodsprevent the repolarization of the endplate.3 Afterprolonged exposure to depolarizing relaxants, thecharacter of the block may change and becomesimilar to a non-depolarization block.4 Undersuitable circumstances, all quaternary ammoniumtype neuromuscular blocking agents may produceeither a depolarization or a non-depolarization

block.5 The type of block will depend on: i, thechemical structure of the relaxant6; 2, the pro-perties of the particular endplate investigated7;and 3, the duration of exposure of the endplate tothe relaxant.4

Non-depolarization Block. Certain quaternaryammonium compounds [e.g. d-tubocurarine,gallamine (Flaxedil)], under physiological cir-cumstances, will produce a typical non-depolar-ization block, characterized by flaccid paralysis,not preceded by signs of stimulation, in allamphibian, avian and mammalian species in-vestigated. The variation in the mg./kg. dose ofnon-depolarizing muscle relaxants between variousmammals is relatively low8 (fourfold). Ether, andto a lesser extent cyclopropane and procaine, in-crease the effects of non-depolarizing relaxants.The block is antagonized by acetylcholine, neos-tigmine (Prostigmin), edrophonium (Tensilon) andpotassium.

Depolarization Block. The myoneural effect ofthe depolarizing muscle relaxants [e.g. decame-thonium (Syncurine), succinylcholine (Scoline)]is less uniform. Depending on the sensitivity ofthe endplate to depolarization and the duration ofexposure, the block produced may be either atypical depolarization block or similar to a non-depolarization block. In amphibians and avians,the depolarizing relaxants will produce spasticparalysis preceded by signs of stimulation.2 Inmammals sensitive to depolarization (e.g. cat,man), the flaccid paralysis produced is precededby signs of stimulation.2 In other mammals (e.g.monkey), the initial signs of stimulation may beabsent.9 In mammals, sensitivity to depolarizingrelaxants varies inversely with sensitivity to non-depolarizing agents. For example, the cat is moresensitive to decamethonium and relatively lesssensitive to d-tubocurarine; the rat is sensitive tod-tubocurarine but less so to decamethonium.There is marked (eighty fold) species variation inthe mg./kg. dose of depolarizing relaxants inmammals.8 Ether and cyclopropane do notpotentiate depolarizing muscle relaxants andacetylcholine, neostigmine and edrophonium, in-

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stead of antagonizing, potentiate their effect.2' 10In certain mammals (e.g. rabbit) on prolongedexposure4 depolarizing relaxants produce a non-depolarization block which can be antagonized byneostigmine,9 edrophonium"l and potassium.4 Inothers (e.g. monkey, dog) whose endplate is moreresistant to depolarization, this will occur afterrelatively short exposure. Parallel with the de-creasing sensitivity of the endplate to depolariz-ation, its sensitivity to non-depolarizing relaxantsincreases. Depending on the sequence andduration of their administration, the depolarizingand non-depolarizing relaxants may have mutuallyantagonistic or additive effects. Thus the ad-ministration of small doses of non-depolarizingrelaxants protect against the myoneural effects oflarge doses of depolarizing agents.5 Similarly, de-polarizing relaxants may antagonize the neuro-muscular block induced by non-depolarizing re-laxants.'2 On the other hand, clinically ineffectivedoses of d-tubocurarine or gallamine will causeprofound and long-lasting myoneural block afterprolonged administration of succinylcholine ordecamethonium.5, 12 The sensitivity of the end-plate to depolarization may change under patho-logical circumstances. After chronic denervation,non-depolarizing relaxants may produce a de-polarization block'3; and in myaesthenia gravis,depolarizing muscle relaxants cause a non-depolarization block which is reversible byneostigmine.7

Because of the qualitative and quantitativespecies variation in response to muscle relaxants,the experimental findings in laboratory animalsare not always applicable to man. Before theirclinical application, the neuromuscular and otherpharmacological effects of the relaxants should,therefore, be carefully studied in man.'Of the clinically used muscle relaxants, d-

tubocurarine, dimethyl-tubocurarine, gallamine(Flaxedil), laudexium (Laudolissin) and benzo-quinonium (Mytolon) are non-depolarizing, anddecamethonium, succinylcholine (suxamethonium,Scoline, Brevedil-M, Anectine) and suxethonium(Brevedil-E) are depolarizing relaxants.

Other Pharmacological EffectsCentral Effects. In anaesthetized animals, the

muscle relaxants may depress the activityof the respiratory centre.'5 In paralyzingdoses, the clinically used relaxants have noappreciable central effects in unanaesthetizedman.'6 However, the possibility cannot be ex-cluded that under pathological circumstances,the muscle relaxants may have a central depressantaction in anaesthetized man.

Autonomic Effects. The autonomic effects of

muscle relaxants are also due to competition withacetylcholine for the cholinergic receptors of theautonomic ganglia. After their adsorbtion to thesereceptors, they may either inhibit or facilitate thetransmission of ganglionic impulses. d-Tubo-curarine has the most marked autonomic effect ofthe relaxants in current clinical use. The gang-lionic effects of other relaxants are restricted tocertain components of the autonomic nervoussystem. For example, gallamine has a selectiveinhibitory effect on the cardiac vagus and benzo-quinonium in clinical doses stimulates, and inlarger doses inhibits, the vagus.

Respiratory Effects. Muscle relaxants may in-fluence respiration by paralysing respiratorymuscles, by depressing the activity of the res-piratory centre, and by bronchoconstriction causedby histamine release.'7 The sensitivity of thediaphragm to relaxants is usually less than that ofother muscles. Bronchoconstriction caused byhistamine release has been observed only withd-tubocurarine.

Circulatory Effects. In clinical doses the musclerelaxants have no appreciable effect on cardiacmuscle. The circulatory effects of the relaxantsare related to their autonomic effects and theirhistamine releasing properties, and are mani-fested by changes in heart rate and blood pressure.Gallamine may cause acceleration of the heartwith moderate rise in blood pressure; benzo-quinonium may decrease the heart rate. d-Tubo-curarine, by inhibiting the sympathetic vaso-constrictors and liberating histamine, occasionallycauses hypotension. The elevation of bloodpressure seen after large doses of succinylcholine,or after relaxant doses in light anaesthesia, isprobably due to its stimulating effect on thesympathetic system.

Histamine Release. Signs of histamine releaseare encountered most frequently with d-tubo-curarine or laudexium. As already stated, histaminerelease may cause bronchospasm or hypotension.

Miscellaneous Effects. Decreased peristalsis andintestinal distension has been observed after theuse of d-tubocurarine.'8 The effect of other re-laxants on the tone and motility of the intestines isnegligible.

Salivation and increased bronchial secretionmay be caused by muscle relaxants, particularly bybenzoquinonium.19

Uterine muscle is not significantly affected bymuscle relaxants. 19

Succinylcholine may cause sustained elevationof the intraocular pressure both in laboratoryanimals and in man.20

Muscle relaxants have a variable inhibitoryeffect on both the true and pseudo-choline-

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July 1958 FOLDES: Use of Muscle Relaxants 369

sterases.21 There seems to be no relationshipbetween the anticholinesterase activity and theneuromuscular effect of the relaxants.21

Fate of Muscle RelaxantsFollowing intravenous administration of the

relaxants, a rapid distribution equilibrium de-velops between the plasma and the neuromuscularjunction. When the concentration of the relaxantat the endplate reaches a certain critical levelneuromuscular block develops. As the concentra-tion of the relaxant in the plasma diminishesbecause of excretion, decomposition and dis-tribution into inactive tissue depots, the relaxantdiffuses back from the endplate into the plasma.This rediffusion accounts for the termination ofthe myoneural block; there is no significantbreakdown of muscle relaxants at the endplate.22

After relatively small doses of relaxants, re-distribution into inactive tissue depots is primarilyresponsible for re-establishment of neuromusculartransmission. After doses large enough to saturatethe inactive tissue depots, the role of excretion anddecomposition will be primarily responsible forterminating the neuromuscular block.Of the clinically used muscle relaxants, galla-

mine, benzoquinonium, laudexium and decame-thonium are excreted mostly unchanged, d-tubocurarine and dimethyl-tubocurarine are partlybroken down and partly are excreted unchanged,and succinylcholine and suxethonium are almostcompletely hydrolyzed by plasma cholinesterase.19The hydrolysis of succinylcholine occurs in twosteps. First, it is hydrolyzed relatively quickly tosuccinylmonocholine and choline, and then muchmore slowly, to succinic acid and choline.Succinylmonocholine also has considerable neuro-muscular blocking effect.23

Antagonists of Muscle Relaxants

Specific antagonists of decamethonium24 andsuccinylcholine 25 are also available, but only theantagonists of the non-depolarizing muscle re-laxants have clinical importance. The latterprobably exert their effect by a dual mechanism:i, Inhibition of cholinesterases allowing accumula-tion of acetylcholine at the endplate; and 2, dis-placement of the muscle relaxant from the end-plate where they exert a direct depolarizing actionof their own. Of the clinically used antagonists,neostigmine and pyridostigmine (Mestinon) prob-ably act mainly by the first and edrophonium bythe second mechanism. Under certain circum-stances, the effects of the depolarizing relaxantsmay also be antagonized by anticholine-esterases.4, 9, 1

II. Clinical ApplicationChoice of Muscle RelaxantsThe choice of muscle relaxants is influenced by:

I, the expected length of the operative procedure;2, the general anaesthetic used; and 3, thepatient's condition. For very short procedures,the agent of choice is succinylcholine or suxe-thonium. For procedures lasting between io and20 minutes, a single dose of a long-acting relaxantmay be used. For prolonged muscular relaxation,succinylcholine in continuous intravenous drip ofan o.I to 0.2 per cent. solution or fractional dosesof a long-acting relaxant are recommended. Ingeneral, the use of succinylcholine offers greaterflexibility. Excellent control of the degree of re-laxation can also be obtained by the combined useof small doses (2 to 6 mg.) of d-tubocurarine andether.26 The use of muscle relaxants in patientswith altered sensitivity will be discussed later.

Maintenance of Adequate Respiratory ExchangeAdequate respiratory exchange can be achieved

either by assisted or controlled respiration. Inthe majority of cases, assisted respiration ispreferable to controlled respiration because: i,it does not interfere with the autorhythmicity ofthe respiratory centre; 2, the pattern of respirationis physiological (the volume of the thoracic cageincreases first, and alveoli open up early duringrespiration); 3, there is less interference withvenous return; 4, valuable information may beobtained regarding the degree of muscular re-laxation and the depth of general anaesthesia fromthe respiratory rate, rhythm and depth; and 5,occasionally the apnoea produced for controlledrespiration is not readily reversible post-operatively.27 28

For controlled respiration the patient may berendered apnoeic by the depression of the res-piratory centre with general anaesthetic agentsand/or hyperventilation, or the paralysis of allrespiratory muscles with a relaxant and hyper-ventilation. Because of its more favourable cir-culatory effects, positive-negative pressure con-trolled respiration is preferable to intermittentpositive pressure.19Mode of AdministrationLack of space prevents full description of the

conventional methods of the employment of musclerelaxants. However, a few important aspects oftheir clinical use will be given.

Use of Long-acting Relaxants. The dose of thelong-acting relaxants depends inter alia on thegeneral anaesthetic agent used. In general, largerdoses are required when anaesthesia is maintainedby nitrous-oxide-oxygen supplemented by thio-pentone alone, or in combination with analgesics

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TABLE ITHE RECOMMENDED DOSES OF REAXANTS WITH VARIUS ANAESTHETIC AGENTS

Range of Initial Doses Range of Fractional Dosesin mg. with in mg. with

RelaxantThio- Cyclo- Thio- Cyclo-

pentone propane Ether pentone propane Ether

d-Tubocurarine chloride ... 5-20 3-12 2-6 2-8 2-6 1-2Dimethyl tubocurarine iodide .. 2-8 I-6 0.5-2 1-3 1-2 0.5-IGallamine triethiodide .. .. .. 40-00 30-80 25-60 10-40 10-30 I0-20Benzoquinonium chloride . .. 5-20 4-16 3-12 2-8 2-5 1-4Laudexium methyl sulphate . . 10-40 6-30 4-Io 4-16 4-12 2-4Decamethonium bromide .. .. 1-4 1-4 1-4 I-2 1-2 I-2Succinylcholine chloride.. . .. o-60 o1-60 io-6o Administered in continuous dripSuxethonium iodide .. .. .. 20-120 20-I20 20-120 for prolonged relaxation

than when anaesthesia is maintained by ether orcyclopropane. The recommended initial andfractional doses of the long-acting relaxants withdifferent methods of general anaesthesia are givenin table i.The initial and first fractional doses of the long-

acting relaxants are chosen empirically and correctdosage depends on the experience of the anaes-thetist. If the last dose of the relaxant is ad-ministered at the start of the peritoneal closure,satisfactory spontaneous respiration will be presentat the termination of surgery in the majority ofcases. With careful management, post-operativerespiratory depression will be encountered in notmore than 2 per cent. of patients.29

The Use of Succinylcholine. The single dose ofsuccinylcholine is about o.6 mg/kg. In patientswith known or suspected low plasma cholinesteraselevel, the initial dose should be markedly de-creased. Larger doses of succinylcholine (I.0 to1.5 mg./kg.) are recommended, however, for thetreatment of laryngeal spasm where an inadequateresponse to a smaller dose may endanger thepatient's life.When succinylcholine is used to produce pro-

longed muscular relaxation, an o.I to 0.2 per cent.solution is administered, at first rapidly, in con-tinuous intravenous drip.19 As soon as the de-crease of the tidal volume indicates the onset ofmuscular relaxation, the drip is slowed down andendotracheal intubation is performed. Followingintubation, depending on whether the patient isbreathing spontaneously or not, the drip is tem-porarily stopped or adjusted to the rate expectedto maintain adequate relaxation. If the selectedrate is excessive and causes apnoea, the drip is tem-porarily discontinued' and restarted at a slower rateafter the return of spontaneous respiration. Whenthe selected rate fails to give satisfactory relaxation,the drip is run faster until relaxation becomesadequate and then continued at a rate higher thanthe one which failed to give relaxation. With thistechnique, adequate muscular relaxation can be

maintained without the dangers of prolonged post-operative apnoea. When controlled respiration isbeing used, there is a danger of administeringexcessive doses of succinylcholine. This can beavoided by periodically discontinuing the drip andwatching for signs of return of spontaneousrespiration.

The Combined Use of Relaxants. Depending onthe sequence of administration, the combined useof depolarizing and non-depolarizing relaxantsmay be permissible or extremely dangerous. Noobjections can be raised to using d-tubocurarine orgallamine for the maintenance of surgical re-laxation, after a single dose of succinylcholinegiven for endotracheal intubation. On the otherhand, the use of succinylcholine to facilitate peri-toneal closure after administration of d-tubo-curarine or gallamine is inadvisable. Under suchcircumstances, because of the pronounced antago-nistic effect of subparalytic doses of non-depolariz-ing relaxants against depolarizing agents,5 ex-cessive doses of succinylcholine may be necessaryto obtain adequate relaxation. Prolonged apnoeamay result from these excessive doses. Adequaterelaxation can be obtained with small doses ofd-tubocurarine (o. o to 0.15 mg./kg.) or galla-mine (0.50 to 0.75 mg./kg.) after the prolongedadministration of succinylcholine.5 This method,however, is still experimental and is not recom-mended for general clinical use.The use of fixed mixtures of relaxants and barbi-

turates1, 32s or analgesics 34 has been recom-mended. Although these methods may havepractical advantages, their application cannot bejustified by pharmacological considerations and,indeed, may be dangerous. The relaxant andbarbiturate or analgesic requirements of patientsfrequently vary in opposite directions and theadministration of fixed mixtures may result ingross overdosage with either component.35Use ofRelaxants in Patients with Altered Sensitivity

Besides the muscularity of the patient, the

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July I958 FOLDES: Use of Muscle Relaxants 371

TABLE 2THE MG./KG. DOSES OF MUSCLE RELAXANTS IN INFANTS

AND CHILDRENInitial

Relaxant Dose Fractional Dose

d-Tubocurarine* o. 10-0.20 0.05-o. 10Gallamine 1.00-1.50 0.30-0.50Decamethonium 0.05-0.08 0.02-0.03Succinylcholine 0.40-0.80 In continuous

intravenous drip* With ether the dose of d-tubocurarine should be

reduced to one-fifth to one-third of the above dose.

relaxant requirements are also influenced by ageand by various pathological conditions.The recommended19 mg./kg. doses of relaxants

for the newborn and young children are shown intable 2.

In the aged, the dose of relaxants, as that ofother drugs, will depend on the patient's physicalcondition. In general, dosage should be reducedby one-third to one-half. In doubtful cases, asmall test dose may be tried.The myaesthenic patient is extremely sensitive

to non-depolarizing relaxants36 37 and with theexception of the affected muscles, is resistant todepolarizing agents.38 Nevertheless, because ofthe incalculable effects of the depolarizing agentson the involved muscles, the use of very smalldoses of non-depolarizing relaxants is recom-mended. A test dose of 0.75 mg. of d-tubo-curarine or 5.0 mg. of gallamine should be ad-ministered. If adequate relaxation does notdevelop within 4 minutes, the dose should berepeated at 5-minute intervals until adequate re-laxation is obtained. Residual effects of the non-depolarizing relaxants can be antagonized at thetermination of surgery by edrophonium (Io to 20mg.) or neostigmine (I.o to 2.0 mg.) preceded byatropine. Ether, because of its effect on themyoneural junction, is contraindicated in myaes-thenic patients.

Patients with severe fluid and electrolyte dis-turbances are usually sensitive to both the de-polarizing and non-depolarizing relaxants. Thelong-acting agents should be administered cau-tiously in repeated small doses, allowing sufficienttime between doses for the maximal effect todevelop, until relaxation is obtained. Withsuccinylcholine, slow infusion of an o.I per cent.solution is recommended. Whatever agent isused, apnoea should not be allowed to develop forunder these conditions it is frequently prolongedand occasionally irreversible.28

Patients with liver disease are often sensitive tosuccinylcholine 39 (the breakdown of which de-pends on cholinesterase manufactured by theliver), and may show decreased sensitivity to non-depolarizing relaxants.40 In clinical practice, how-

ever, increased sensitivity to non-depolarizing re-laxants may also be encountered19 probably be-cause of the poor physical condition of many ofthese patients. Consequently, it is advisable touse both types of relaxants cautiously in thepresence of liver damage.

In patients with kidney disease the duration ofaction of those relaxants which are primarily de-pendent on urinary excretion (e.g. decamethonium,gallamine, benzoquinonium) may be unduly pro-longed. These agents should, therefore, be ad-ministered in smaller and less frequent doses thanin normal individuals.

Complications of the Use of RelaxantsMost of the complications encountered with

muscle relaxants are due to the use of excessivedosage. The most serious of these complicationsis prolonged post-operative apnoea caused bylarge doses of relaxants used in conjunction withcontrolled respiration, or given for the facilitationof peritoneal closure. As already mentioned, theadministration of succinylcholine after d-tubo-curarine or gallamine may also precipitate thiscomplication. As with any other complication,prevention is preferable to treatment. When theapnoeic technique is used, especially if this ismaintained by the continuous infusion of succinyl-choline, the anaesthetist should make certain atintervals that no more relaxant is used than isnecessary to paralyze all the respiratory muscles.When apnoea is encountered at the termination

of surgery, it must be ascertained that it is due tothe paralysis of the respiratory muscles and not toother causes. The latter may include reflex breathholding due to stimulation by the endotrachealtube in the lightly anaesthetized patient, centraldepression by other agents used and hypocapnoeacaused by hyperventilation.The treatment of the apnoea caused by relaxants

will depend on the type of agent used. After non-depolarizing relaxants, 10 to 20 mg. of edro-phonium should first be tried. If this only has atemporary effect, 0.75 to 1.5 mg. of neostigminepreceded by 0.4 to 0.6 mg. atropine should begiven intravenously. If the first dose of neostig-mine results in partial recovery, additional small(0.5 mg.) doses can be given 5 minutes apart.Tidal volume must be tested after each dose.Further doses should be discontinued when noimprovement resulted from the administration ofthe previous dose. Large doses of neostigmine,because of their effects on the coronaries, may bedangerous, especially in cardiac patients. Further-more excessive doses, instead of antagonizing thenon-depolarization block, may cause a persistentacetylcholine block. If edrophonium or neostig-mine is not effective, 0.3 per cent. KC1 may be

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372 POSTGRADUATE MEDICAL JOURNAL July 1958

administered at 80 to Ioo drops per minute. Auretheral catheter should be inserted before thestart of the KCI administration. In the absenceof urinary excretion, KCI administration shouldbe avoided to prevent hyperkalemia. As a lastmeasure, diuresis may be provoked by an osmoticdiuretic (e.g. 50 to 00oo ml. of 50 per cent. dextroseor sucrose) given intravenously. Controlled res-piration, with alternating positive-negative pres-sure, should be maintained as long as necessary.Recovery of spontaneous respiration may occurafter many hours.When prolonged apnoea is encountered after

succinylcholine, treatment at first should beexpectant. If recovery does not start in 20 to 30minutes, it is possible that succinylcholine pro-duced a non-depolarization block.5 This should betreated first by edrophonium and then if this istemporarily effective, by atropine and neostigmine.If edrophonium is ineffective, neostigmine shouldnot be tried because if the apnoea was caused bysome other mechanism, neostigmine might de-teriorate the situation.41 The administration ofKC1 and the production of diuresis should be triedwhen prolonged succinylcholine apnoea is re-fractory to anticholinesterases.The treatment of prolonged apnoea after the

combined use of non-depolarizing and depolariz-ing relaxants should follow along the same lines asdescribed above.

Miscellaneous Use of RelaxantsBesides their use for the production of surgical

relaxation, the muscle relaxants have other im-portant therapeutic applications. Of these, fromthe point of view of the anaesthetist, their use inelectroshock therapy and the treatment of tetanusare the most important.The diagnostic use of relaxants in myaesthenia

gravis, because of its dangers, has been almostcompletely replaced by the use of edrophonium.Discussion of the therapeutic and diagnostic use of

relaxants is beyond the scope of this brief paper.The interested reader is referred for information toother sources.19

I. FOLDES, F. F. (1954), Brit. J. Anaesth., 26, 394.2. PATON, W. D. M., and ZAIMIS, E. J. (1952), Pharmacol. Rev.,

4, 219.3. BURNS, B. D., and PATON, W. D. M. (x95i), J. Physiol,

15 41.4. JENDEN, D. J., et al. (I951), J. Pharmacol., 103, 348.5. FOLDES, F. F., et al. (i957), Anesth. W Analg., 36, (5) 23.6. BOVET, D. (I95g), Ann. N.Y. Acad. Sci., 54, 407.7. ZAIMIS, E. J., et al. (I952), Nature, 170, 6I7.8. PATON, W. D. M., and ZAIMIS, E. J. (1949), Brit. J. Phar-

macol., 4, 381.9. ZAIMIS, E. J. (1953), J. Physiol., 122, 238.

Io. RANDALL, L. O. (ig95), Ann. N.Y. Acad. Sci., 54, 460.II. FOLDES, F. F., et al. (x957), .. Pharmacol, 119, I45.12. BRENNAN, H. J. (1956), Brit. J. Anaesth., 28, 159.13. McINTYRE, A. R., and KING, R. E. (1943), Science, 97, 5i6.14. BULBRING, E., and DEPIERRE, F. (1949), Brit. J. Phar-

macol., 4, 22.IS. ELLIS, C. H., et al. (1952), J. Pharmacol., zo6, 353.16. SMITH, S. M., et al. (i947), Anesthesiology, 8, I.17. LANDMESSER, C. N. (1947), Ibid., 8, o56.18. GROSS, E., and CULLEN, S. C. (1945), Ibid., 6, 231.19. FOLDES, F. F. (I957), 'Muscle Relaxants in Anesthesiology,'

Ch. C. Thomas, Springfield, Ill., U.S.A.20. LINCOFF, H. A., et al. (I955), Amer. J. Ophthal., 40, 501.21. FOLDES, F. F., et al. (1957), J. Pharmacol., x19, 130.22. FOLDES, F. F. (1956), Proc. World Congr. of Anesth., p. 310,

Scheveningen, Sept. 5-10, I956.23. FOLDES, F. F., et al. (1954), Brit. med. J., I, 967.24. VANDAM, L. D., et al. (I953), Anesth. & Analg., 32, 113.25. ELLIS, C. H., et al. (1953), Feder. Proc., 12, 39.26. KEUTMANN, E. (I954), Nord. Med., 51, 823.27. DRIPPS, R. D. (1953), Ann. Surg., 137, I45.28. HUNTER, A. R. (I956), Brit. med. J., 2, 919.29. FOLDES, F. F., et al. (1952), J. Amer. med. Ass., i50, I559.30. HODGES, R. J. H. (1953), Lancet, I, 143.31. BAIRD, J. W. (1947), Anesthesiology, 8, 75.32. ORGANE, G. (1949), Lancet, I, 733.33. EVANS, F. T., and GRAY, P. W. S. (1953), Anaesthesia, 8, I04,,34. LANCASTER, F. M., and LEVIN, J. (1956), Brit. med. J.,

I, 381.35. FOLDES, F. F., and MACHAJ, T. S. (1951), Anesthesiology,

12, 366.36. BENNETT, A. E., and CASH, P. T. (1943), Dis. nerv. Syst.,

4, 299.37. DUNDEE, J. W. (I951), Brit. J. Anaesth., 23, 39.38. CHURCHILL-DAVIDSON, H. D., and RICHARDSON,

A. T. (1952), Neurol., Neurosurg. & Psychiat., 15, 129.39. FOLDES, F. F., et al. (1956), Anesthesiology, 17, 559.40. DUNDEE, J. W., and GRAY, T. C. (I953), Lancet, 2, I6.41. FOLDES, F. F., et al. (I956), Anesth. & Analg., 35, 609.

RUTHIN CASTLE, NORTH WALESA Clinic for the diagnosis and treatment of Internal Diseases (except Mental or Infectious Diseases). The

Clinic is provided with a staff of doctors, technicians and nurses.The surroundings are beautiful. The climate is mild. There is central heating throughout. The annual

rainfall is 30.5 inches, that is less than the average for England.The Fees are inclusive and vary according to the room occupied.

For particulars apply to THE SECRETARY, Ruthin Castle, North Wales.Telegrams: Castle, Ruthin Telephone: Ruthin 66

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