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HE USE OF ANTIDOTES IN ANAESTHESIABy B. A. SELLICK, M.B., D.A., F.F.A., R.C.S.Consultant Anaesthetist, The Middlesex Hospital, W. I

The number of effective antidotes in thepharmacopoeia of the modern anaesthetist can becounted on the fingers of one hand. It is thepurpose of this paper to discuss the value of thesefew drugs and describe their method of administra-tion and mode of action. For this purpose theyhave been grouped into four.

i. Antidotes to the Muscle Relaxant DrugsThe introduction of the muscle relaxant drugs

has been the greatest advance in clinical anaesthesiaof this century. It has enabled profound muscularrelaxation to be obtained by the use of virtuallynon-toxic drugs in the presence of the lightestlevels of anaesthesia. The respiratory depressionor paralysis associated with this degree of re-laxation is overcome by the related techniques ofassisted or controlled' ventilation. Poisoning byexcessive anaesthetic dosage to secure relaxation isnow avoided and vasomotor tone is maintainedwith a consequent lowering in the incidence ofperipheral circulatory failure.

Muscle relaxant drugs exert their action at theneuromuscular junction. The complex chemicaltransmission of nerve impulses into muscularactivity is not completely known. Normally motornerve impulses cause a liberation of acetylcholineat the nerve endplate in contact with the musclefibre. The acetylcholine attaches itself to an end-plate receptor which leads to a depolarization of themuscle fibre in the region of the endplate. Thedepolarization spreads along the fibre and a con-traction follows. For a fraction of a second themuscle fibre is refractory to further stimulation butthe acetylcholine is almost instantaneously de-stroyed by the enzyme cholinesterase. Re-polarization of the fibre then occurs and is onceagain receptive of further stimulation.

Muscle relaxants can be broadly divided intotwo groups. The curare group which includesthe purified extract d-tubocurarine chloride, gal-lamine triethiodide ( ' Flaxedil'), and laudolissencauses neuromuscular block by competing for theendplate receptor for acetylcholine. Acetyl-choline continues to be formed as a result of motor

nerve impulses but it can no longer cause de-polarization. Electrically the curarized muscleremains charged and can still be made to contractby direct stimulation,The other group of the relaxants, the de-

polarizing group, resemble acetylcholine in theiraction and cause muscle relaxation by attachingthemselves to the endplate receptor and depolariz-ing the muscle fibre. This explains the muscularfasciculations that are seen as paralysis occurs withthese drugs. Being less easily destroyed thanacetylcholine they persist for varying periods andthe fibre remains depolarized. During this de-polarization the muscle fibre is not susceptible todirect stimulation. The most important drugs inthis group are decamethonium iodide and bromideand suxemethonium (' Scoline ').(a) Antagonists to the Curare Group

It has long been known that adrenaline andephedrine have a decurarizing effect on skeletalmuscle, but their mode of action is unknown andthe action is insufficient for clinical purposes.K+ also reverses curare; it is thought that acetyl-choline itself produces depolarization through themedium of liberated potassium (Samson Wright,I952).

Physostigmine (' Eserine '). A naturally occurringcompound extracted from the calabar bean wasthe first anticurare drug to be used. It is an anti-choline-esterase and by preventing the destructionof naturally formed acetylcholine at the endplate,curare is displaced from the receptor. If nervousactivity is depressed acetylcholine is formedslowly and the onset of action of physostigmine isdelayed.The instability of this drug in solution and its

marked action on the smooth muscle of the gutprecludes its clinical use. The carbamate group inthe molecule (see diagram) is the effective portion.

Tensilon. This is a synthetic anticurare drugthat has an ammonium grouping similar to thatof acetylcholine. Its action is a direct one on theendplate which it resensitizes to acetylcholine. Itsaction is rapid in onset but does not persist and

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September I955 SELLICK: The Use of Antidotes in Anaesthesia 469

repeated doses may be needed. This is a dis-advantage in clinical anaesthesia as the patient mayrelapse into respiratory depression on return to theward. The advantage of tensilon is its freedomfrom undesirable side effects, particularly those onthe cardiovascular system.

Acetylcholine.-o

CH Br. 0

CH3 - --C2 H4-O -C-CH3CH33

Neostipmine. (ProstiAmine)

CH3 Br. 0 CH2CH N .--C6H O--C-N

CH3 CH2

-ensilon.CH Br.

C2H -C6C HO H

CH3

Phyaostigmine.

CH2 CH H

H2c C- iC6 H0-C--NN C-N CH3

CH I3 CH,

Neostigmine (' Prostigmine '). This is the anti-curare drug of choice and, in the writer's opinion,should be used as a routine and integral part ofcurare administration. As will be seen from itsformula, it possesses both a carbamate and am-monium grouping. Its action is thought to betwofold: It stimulates endplate activity directlyand by means of its anticholinesterase action itprevents the rapid destruction of acetylcholine.Neostigmine has an action that is rapid in onsetand persistent; in fact once curare has been dis-placed from the endplate receptor by neostigmineit cannot re-exert a neuromuscular block withoutfurther dosage.

Side effects of neostigmine. If given in largedoses to an uncurarized animal it causes musclefasciculations and paralysis. In normal clinicaldosage its side effects are those of parasympathetic

overactivity, i.e. bradycardia, increased intestinaltone and mucus secretion. In susceptible patientsthe cardiac effects may progress to heart block oreven cardiac standstill.These side effects can be eliminated if a suitable

dose of atropine precedes the neostigmine. Atro-pine paralyses parasympathetic nerve endings caus-ing an inhibition of intestinal contractions, a de-crease in mucus secretion and an increase in heartrate. This mutually antagonistic effect of atropine-and prostigmine has recently been utilized in-thetreatment of accidental atropine poisoning (Poppand Niebauer, 1954). Neostigmine withoutatropine has been found useful to steady rapid orirregular hearts during thoracic surgery and is pro-tective against excess adrenaline (Sellick, 1955).Method of administration of neostigmine. Pre-

liminary atropine. Atropine causes a transientslowing of the heart before its vagal depressanteffect becomes established. For this reason itshould never be given mixed with neostigmine lesta combination of vagal effects leads to a fatalcardiac inhibition. For the same reason rapidintravenous injection of atropine alone should beavoided.

For a normal adult who has had the usualpre-operative atropine or scopolamine a furtherdose of atropine, 1/100 to I/50 gr., should be givenintravenously a few minutes before it is intended togive the neostigmine. A rise in pulse rate willdemonstrate the activity of the atropine.

If complete respiratory paralysis still remainsfrom the curare controlled ventilation should becontinued and the neostigmine withheld untilsome attempts at spontaneous respiration returns.From the anaesthetist's point of view the muscle

relaxant is only one of many causes of respiratoryparalysis. Others include carbon dioxide excess,carbon dioxide depletion, excessive dosage ofnarcotic or anaesthetic drugs or respiratory in-hibition from stimulation of, for example, theinflated cuff of an endotracheal tube. It is goodpractice to eliminate all these causes of respiratoryarrest before administering neostigmine. Theoptimum time to give the drug is on the return ofsome attempts to breathe spontaneously-typicallyheralded by diaphragmatic breathing and trachealtug.The practice of using one of the short acting

depolarizing agents (see below) at the end of anoperation to facilitiate closure of the wound callsfor especial care in the administration of neostig-mine which must not be given until signs ofelimination of the depolarizer are present. Thepresence of respiratory movement indicates thatacetylcholine is being formed and that centraldepression is not complete; as a result the actionof neostigmine will be greater. The duration of

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47d POSTGRADUATE MEDICAL JOURNAL September 1955

relaxation following a dose of curare is largelydependent on the degree of central depression ofefferent nerve impulses by deep anaesthesia andconsequent inhibition of acetylcholine formation.

Dosage of neostigmine. Following atropine theusual adult dose of neostigmine is from I.0 to 2.5mg. Doses of 5.0 or even 7.5 mg. may on rareoccasions be necessary, but if 2.5 mg. has to beexceeded further atropine will probably benecessary first.

(b) Antagonists to the Depolarizing GroupThe depolarizing group of drugs simulate

acetylcholine in their action and they are usuallyshort acting. Idiosyncrasy does occur and veryprolonged paralysis can occur after repeated dosesor in association with deep anaesthesia. There isno satisfactory antidote.

Decamethonium can be displaced from the end-plate receptor by lower members of its homologousseries. Hexamethonium (C6) has been used forthis purpose, but the profound fall in bloodpressure that this drug causes is a strong contra-indication to its use in these circumstances.

Suxemethonium (' Scoline ') is the ultra short-acting relaxant from which have come the mostreports of idiosyncrasy. Normally the paralysisfrom this drug is of two or three minutes' duration,but a ' scoline apnoea ' of six or eight hours is notunknown. It has been suggested (Evans et al.,1953) that a low plasma cholinesterase is the ex-planation and that the administration of this sub-stance either as an extract or in fresh blood wouldovercome the apnoea. Argent et al. (1955) suggestthat the low plasma cholinesterase would onlyaccount for a slight prolongation and they postulatea central depression as the cause.

Experimentally, as one might expect from itsammonium grouping, neostigmine enhances andprolongs the action of scoline. Argent et al. (1955)found neostigmine of use in the later stages oftreatment of some of their cases. This suggeststhat scoline had already been eliminated from theendplate region and that the neostigmine was re-inforcing the depleted acetylcholine formationconsequent upon central depression and reducedmotor nerve activity. Further proof of theirhypothesis comes from the successful response insome of these cases to analeptic drugs. Theadministration of nikethamide or methylamphet-amine is frequently followed by return of spon-taneous respiration.From what has been said it is concluded that it is

unwise to use neostigmine in the first 20 minutes ofa scoline apnoea but after this time it may have a

place in the treatment of this condition.2. Antidotes to the Barbiturates

Barbiturate overdosage causes an immediate

respiratory and cardiovascular depression. De-layed hepatic or renal damage may occur. Indealing with barbiturate emergencies the firstconsideration is the establishment of a clear airwayand maintenance of adequate tidal exchange bymeans of assisted or controlled ventilation. Ifcardiovascular depression is present as well, thismust be treated before consideration is given toantagonising the barbiturate itself. The hypo-tensive state resulting from the barbiturates isdiscussed later.

It is only after these more immediate problemshave been overcome that the question of antidotesarises. In the past the standard method of dealingwith oral barbiturate overdosage has been gastriclavage, oxygen and the repeated doses of analepticdrugs. This method of cerebral stimulation pois-ing the patient on the brink of a convulsion greatlyincreases the metabolic demands of the patient andthis in association with the reduced respiratoryfunction probably contributed to the fatal outcomeof many cases (Nilsson, 195 ). Nilsson advancedthe theory that the use of assisted or controlledventilation and maintenance of fluid balance pend-ing the spontaneous elimination of the barbiturateis a more rational method. The use of cortisonehas been suggested in the treatment of these cases(when has it not?) but the writer has no experienceof its use for this purpose.

Within the last few months an antidote to thebarbiturates has been given a clinical trial andthere have been a few reports of its use inanaesthetic practice (Harris, '955). The drug isP3methyl ethyl glutarimide, megimide, or NPI 3.

CH3 CH2- COC NH

C2H5 f CH2 -CO

From the brief reports so far available NP 13appears to be an innocuous drug which in doses of50 mg. has no side effects. In large doses in un-anaesthetized animals it causes muscular fascicula-tion and convulsions. It has been used in com-bination with 2-4-diamino-5-phenylthiazole-amorphine antagonist which has a slight antagonismto the barbiturates-in cases of suicidal barbiturateoverdosage.

Patients anaesthetized by thiopentone, 0.5 g.,after atropine premedication for short manipulativeprocedures regained consciousness almost im-mediately after injection of 50 mg. of NP 13. Inthose who had longer operative procedures afteromnopon and scopolamine premedication con-

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September x955 SELLICK: The Use of Antidotes in Anaesthesia 471

sciousness was regained within three to sevenminutes after injection of the drug.Much work will have to be done before this

drug becomes accepted by anaesthetists, but if itsearly promise is maintained it will have manypossibilities. Whether it crosses the placenta ornot will determine much of its usefulness inobstetrics. Until these researches have beencarried out the method of treating barbiturateoverdosage must remain that of Nilsson-main-tenance of ventilation, circulation and fluid balancepending spontaneous elimination of the drug.The safety of analeptics such as nikethamide

and picrotoxin in the treatment of barbiturateoverdosage is questionable.3. Antidotes to Morphine and Analagous Drugs

Opiate overdosage is characterized by profoundrespiratory and cardiovascular depression similarto that produced by the barbiturates and requiringa similar method of immediate treatment. Untilthe last few years analeptics and supportive therapytogether with doses of atropine was the basis oftreatment.

It has long been known that N-allyl-nor-codeineantagonized the respiratory depression ofmorphine(Pohl, 1915) but not until N-allyl-nor-morphinewas synthesized (Weijlar and Erickson, I942) was ameans of reversing morphine in clinical medicinecontemplated (Hart, I943). Since I95I this drughas been given extensive clinical trials and it hasbeen found to exert an antagonism to the respira-tory and circulatory depression of many drugsanalagous to morphine including pethidine (' De-merol'). It has no action on the barbiturategroup.

Chemistry. N-allyl-nor-morphine is obtained bysubstituting an N-allyl group for the N-methylgroup in morphine. It is also known as ' Nalor-phine' and ' Lethidrone' and has the followingstructural formula.

/ -C2CH'CH

Ho 0 0 OH

Pharmacology. N - allyl - nor - morphine whengiven alone in doses of 5 to 15 mg. has an actionsubstantially that of an equal amount of morphine.It produces, perhaps, a lesser degree of analgesia

but has the unpleasant property of causing hal-lucinations in some patients. When given to apatient who has had a small or even normal dose ofmorphine the drug may increase the morphineeffect and produce some degree of respiratory andcirculatory depression. Its main effect is noticedwhen a large or an overdose of a morphine typedrug has been given. The respiratory and circula-tory depression is then reversed by doses of io to30 mg. of N-allyl-nor-morphine. The level ofanalgesia is somewhat lessened and althoughsedation does not seem to be materially altered,the stuporose patient is more readily roused.Another interesting action of this drug is on drugaddicts who develop severe withdrawal symptomsafter its administration. It has been used in thisway as a diagnostic test for addiction (Wickler andCartier, 1952).Mode of action. N-allyl-nor-morphine is

thought to compete with morphine for the cellmembrane receptors.

Clinical uses. From the anaesthetists' point ofview N-allyl-nor-morphine is useful in two typesof case. The first is where simple overdosage bymorphine or its analogues has occurred and res-piratory and cardiovascular depression has re-sulted. This may occur in a number of ways:Inadvertant overdosage of premedication in sus-ceptible patients, for example in the shocked,debilitated and aged, and as a result of repeatedsmall doses of pethidine given during somemethods of anaesthesia.

If respiratory rate and depth are inadequate iomg. of N-allyl-nor-morphine can be given to anadult in the first instance. This may be repeatedonce or twice more if some response is obtained,but it must always be remembered that it is adoubled edged weapon and an increased de-pression may result from too liberal use.

Obstetric analgesia. N-allyl-nor-morphine, likeother morphine derivatives, crosses the placentainto the blood stream of the foetus. The use ofmorphine or pethidine for the relief of pain duringlabour has frequently led to respiratory depressionin the newborn. Timing of doses of analgesic forthe mother is notoriously difficult and it has fre-quently meant that the child has been deliveredwithin a short time of a large dose of analgesic. Inthese cases newborn depression of respiration canfrequently be minimized by the use of N-allyl-nor-morphine, 10 to 20 mg. given to the motherintravenously several minutes before delivery. Thedrug rapidly crosses the placental barrier andantagonizes the narcotic already in the foetus.

Giving the drug to the mother before deliveryis a more satisfactory method than giving it to thechild afterwards. But if the newborn child is slowin establishing a satisfactory rate and depth of

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POSTGRADUATE MEDICAL JOURNAL

respiration the drug can be given into the um-bilical vessels in very small doses, 0.2 mg. dilutedin 2.0 cc. water (Eckenhoff et al., I953).The factors influencing the initiation of adequate

respiration in the newborn are many and theirdifferential diagnosis frequently difficult, particu-larly after instrumental delivery, so that the in-discriminate use of N-allyl-nor-morphine forrespiratory inadequacy is to be deprecated. If therespiratory depression in the child is due to oneof many other causes, e.g. trauma or excessivematernal anaesthesia, N-allyl-nor-morphine willincrease rather than lessen it.

4. Antidotes to Hypotensive StatesHypotension occurring during anaesthesia may

be accidental or deliberately induced. Accidentalhypotension following loss of circulating bloodvolume after haemorrhage or trauma must betreated by transfusion either of whole blood,plasma or its substitutes. No drug is a safe anti-dote to loss of circulating blood volume. Thiscondition is characterized by vasoconstriction andvasopressors merely increase the constrictionpossibly at the expense ofthe blood supply to somevital organ such as the kidney. Reflex hypo-tension may follow surgical stimulation in theunder-anaesthetized; the treatment is to requestthe surgeon to stop operating until anaesthesia hasbeen deepened. Hypotension may follow acci-dental overdosage by the barbiturates or opiatesand is the consequence of central depression andperipheral vasodilatation.

Deliberately induced hypotension by means ofganglion blocking agents is gaining favour for someoperations in which haemorrhage would otherwisemake the surgery difficult if not impossible. Thedrugs used for this purpose are mainly hexa-methonium bromide or iodide and 'arfonad'[(+)-3,4 (I',3'-dibenzyl-2'-keto-imidazolido) 1,2-*tri methylene thiophanium d-camphorsulphonate].The peripheral vasodilatation produced by thesedrugs can be antagonized by the vasopressor drugs.

Adrenaline, noradrenaline, ephedrine and manyothers have been used as antidotes to vasodilatedand central depressant hypotension (Dripps et al.,1946). In the writer's opinion n-methyl-amphet-amine (' Methedrine ') is the drug of choice. Thisdrug has a rapid and very sustained action (Prest-cott et al., I944). Its mode of action is both centraland peripheral. Centrally it is a cerebral stimulant,it lightens anaesthesia and increases vasomotortone. Peripherally it is a vasoconstrictor actingdirectly on the blood vessels. Providing adequateblood volume is present its vasoconstriction is notdetrimental to vital organs. There is an increasein renal blood flow and renal excretion; a factmade use of by the writer to secure ureteric

catheter specimens of urine under thiopentoneanaesthesia.

Intravenously 5 to 10 mg. seldom needs to beexceeded at one time. Intramuscularly up to30 mg. may be given. Methedrine in excess causeshypertension, tachycardia and cardiac arrhythmiaand must be administered with care to patientswith cardiovascular disease.

DiscussionIt is argued that to need an antidote at all in

anaesthesia is to confess lack of skill, and it istrue that the more experienced the anaesthetist thefewer occasions he finds it necessary to use anantidote unexpectedly. It is perhaps fortunatethat during the formative years of modern intra-venous anaesthesia so few antidotes have beenavailable; there is nothing more conducive toskill and care in the administration of a potentdrug than the knowledge that it has no antidote.The knowledge of anaesthetists is being applied

more and more to other branches of clinicalmedicine. The work of Nilsson in the treatment ofbarbiturate poisoning is one example, and the needfor an effective antidote for this type of case cannotbe denied. Apart from the advantages in shorten-ing barbiturate anaesthesia for minor outpatientsurgery the use of NP I3 seems limited. It is to behoped that it will not be used to awaken on theoperating table those patients who have beensubjected to major surgery and who benefit fromthe more gradual return to reality that accom-panies the spontaneous elimination of the bar-biturates.No drugs are perfect and the use of an antidote

to antagonize certain undesirable features so thatfuller use can be made of the drug is an essentialpurpose of antidotes in surgical anaesthesia. Theuse of atropine and neostigmine to reverse theeffects of the curare compounds is probably themost important use to which an antidote is put inpractice. The saving in poisonous doses of otherdrugs and the protection from surgical shock thataccompanies the muscle relaxation of this drugmore than justifies the necessity for controlledrespiration and the need for an antidote to cutshort its action.As yet not so well proven is the value of N-allyl-

nor-morphine to reverse the depressant effects ofmorphine and pethidine so that greater safety canbe obtained in obstetric analgesia.S mmaryThe antidotes to the muscle relaxants, bar-

biturates, opiates and hypotensive states aredescribed. Their dosage, mode of action and sideeffects are described. Their value in anaesthesiais discussed.Bibliography continued on pag3 488.

September i 955472

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stetrics, lecture demonstrations, Mondays, Tuesdaysand Fridays, 9.15 a.m., Maternity Lecture Theatre,Radcliffe Infirmary. Gynaecology, ward rounds,Wednesdays, 10.30 a.m. and 5 p.m., Radcliffe Infirmary.Obstetrics and Gynaecology, concilia, monthly,alternate Thursdays and Fridays, 3 p.m., MaternityLecture Theatre, Radcliffe Infirmary. Ante-natalclinics, out-patients, Mondays, a p.m., MaternityHome Radcliffe Infirmary and Churchill Hospital,Thursdays, 2 p.m., Radcliffe Infirmary MaternityHome, Fridays, 9.15 a.m., Maternity Lecture Theatre.Post-natal clinics, out-patients, Tuesdays, o a.m.,Wednesdays, 2 p.m., Radcliffe Infirmary MaternityLecture Theatre.General practitioners wishing to avail themselves of theacilities set out in this schedule should apply to theSecretary, Postgraduate Medical Committee, I KebleRoad, Oxford.

CONFERENCES, PRIZES, Etc.Butterworth Gold Medal is to be presented annuallyto the College of General Practitioners (by Messrs.Butterworth & Co., Medical Publishers) for an essaynot exceeding Io,ooo words, written by a member orassociate of the College, on a subject connected withgeneral practice. The title for I955 is 'The influenceof home conditions during the first five years of lifeon the physical and mental health of children.'Essays must be submitted to the Chairman of the AwardsCommittee, the College of General Practitioners, 14 BlackFriars Lane, London, E.C.4, by September 3oth, 1955.They should be typewritten and headed with a motto-the name and address of the sender being enclosed in asealed envelope with the motto written outside.Queen Square Prize in Neurology. A prize of Ixoowill be awarded annually to the postgraduate student,or ex-student, of the Institute of Neurology whopresents the best written paper describing clinical workcarried out or initiated at the National Hospitals forNervous Diseases. Entries must be submitted not laterthan September 30 each year.Full particulars from the Dean, Institute of Neurology,(Queen Square), The National Hospital, Queen Square,London W.C.x.Buckston Browne Prize Essay. The prize, consisting

of a medal, together with the sum of £Ioo, will beawarded for the best essay on 'Hypertension,' sub-mitted by August 31, I956. The prize is open to anymember of the medical profession registered in theBritish Isles or Dominions, and is limited to candidatesunder 45 years of age.Further particulars may be obtained from the HonorarySecretaries, Harveian Society of London, i ChandosStreet, Cavendish Square, London, W.I.Sir David Wilkie Research Fellowship in Surgeryand/or Medicine is offered by the Faculty of Medicineof the University of Edinburgh. The Fellowship, of thevalue of 800o to £9oo (Sterling) per annum, with apossible allowance for approved expenses of research,and tenable for two years (with possible extension tothree years at the discretion of the Senatus Academicus),will be open for award in October, I9561 The Fellow-ship is open to graduates of any University. The holderwill be required to carry out approved research work insurgery and/or medicine in the University, and he mustattend the honours class in physiology, unless he isalready a graduate in physiology or in science. Whileundertaking the research work he will be expected tomaintain contact with clinical work, but the time to bedevoted to this will be restricted to two half-days perweek. During his tenure the Fellow will not be per-mitted to study for or to present himself for any examina-tion leading to a higher diploma in medicine or surgery.Applications must be submitted on a prescribed form, acopy of which may be obtained from the Dean of theFaculty of Medicine, or from the undermentionedpersons.Applications from graduates in the following countriesmust be received by October 31, I955: Australia. TheChairman, National Health and Medical ResearchCouncil, Dpt. of Health, Canberra, A.C.T., Australia.Canada. The Awards Officer, National ResearchCouncil, Ottawa, Ont., Canada. New Zealand. TheSecretary, Medical Research Council, Dept. of Health,P.O.B. 5013, Wellington, New Zealand. South Africa.The Director, South African Institute for Medical Re-search, Hospital Street, Johannesburg, South Africa.Applications from graduates in the United Kingdom orcountries other than those listed above must be received byMarch I, 1956, addressed to Dean, Faculty of Medicine,University New Buildings, Edinburgh, 8, Scotland.

Bibliography continued from tage 471-B. A. Sellick, M.B., F.F.A.R.C.S., D.A.BIBLIOGRAPHY

ARGENT, D. E., DINNICK, O. P., and HOBBIGER, F. (1955),Brit. J. Anaes., Vol. 27, No. I, p. 24.

DRIPPS, R. D., and DEMING, M. VAN N. (1946), Surg. Gynec.Obstet., 83, 312.

ECKENHOFF, HOFFMAN, and FUNDERBURG (1953), Amer.J. Obstet. Gynec., 65, 1269.

EVANS, FRANKIS T., GREY, P. W. S., LEHMANN, H., andSILK, E. (I953), Brit. med. J., i, 136.

HARRIS, T. A. B. (I955), Lancet, Jan 22, I8i;HART, E. R. (i943), Fed. Proc., 2, 82.

NILSSON, E. (OS9I), Acta Med. Scand., Suppl., 253.POPP, A., and NIEBAUER, G. (I954), Dtsch. med. Wschr., 79,

1221.

PRESTCOTT, F. (I944), Brit. Heart J., 6, 214.SELLICK, B. A. (i955), unpublished findings.SHAW, F. H., SIMON, S. E., CASS, N., SHULMAN, A.,

ANSTER, R., and NELSON, E. A. (i954), Nature, Lond.,173, 402.

WICKLER, A., and CARTIER, R. L. (1952), Fed. Proc., It, 402.WRIGHT, S. (1952), 'Applied Physiology,' 9th edition, Oxford

Medical Publications, p. 519.

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