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PHYSIOLOGICAL AND CLINICALASPECTS OF SOME RECENT WORK ON THE

CARDIO -VASCULAR SYSTEMBy PROFESSOR 0. G. EDHOLM, M.R.C.S., L.R.C.P.

Department of Physiology and Biochemistry Royal Veterinary College and Hospital, London, N. W.i

The close relationship between physiologicalresearch and progress in clinical work is selfevident. Nevertheless there are certaindifficulties in assessing the clinical applicationsof recent advances in physiology. It is notpossible to cover the whole field of physiologyand discuss the possible clinical implications;impossible because of lack of knowledge andlack of space. This article has, therefore, beenlimited to such aspects as are familiar to thewriter, those problems concerned with thecardio-vascular system. It is not suggestedthat advances in this field are amongst themost important, other physiologists wouldalmost certainly select quite different exampleswith no doubt greater cogency.

In general it is true that there is a con-siderable time lag between a physiologicaldiscovery and its application to clinicalmedicine. This is not necessarily due to thereluctance of clinicians to apply physiology tomedicine (although this may be a factor) or dueto ignorance of advances in physiology. Thereare more serious difficulties, primarily that it israre to find an immediate obvious clinicaldevelopment of physiological work. This isprobably the reason why many clinicians feelthat it is a waste of time to keep up to date intheir physiology. Critics ignore the fact thatthe study of physiology is not undertaken onlyto help in the solution of clinical problems, butis a subject worthy of study in its own right.This raises the old problem of the distinctionbetween pure and applied research. There isno true difference, it is essentially a question oftime, the applied work of today being based onthe pure research of the past. The time lag issometimes very short, e.g. Minot's successfultreatment of pernicious anaemia followingWeed's work on the liver, but usually there isa long delay. It is quite probable that thesedelays will be worse in the future. The dis-tinction between clinical work and physiologybecomes greater with increased specialization.In the past many of the active members of the

Physiological Society were physicians who notonly listened, but contributed. This is un-usual today; and the two sciences will be-come completely separated unless the gap isfilled. An intermediary is needed between thephysiologist and the clinician, someone whohas interests on both sides, the man workingon applied physiology.

Developments during the war have shownthat the problems of applied physiology arenot only of great practical importance butfrequently are of real theoretical interest.Many physiologists have had to work onproblems specifically those of war, e.g. onpoison gases, problems which are notapparently directly related to those occurringin civil life. But there has also been very activeresearch on such problems as the effects ofhigh and low environmental temperature onthe human body, the effects of gravity asillustrated by the high accelerations of modernaircraft, of anoxia, high pressure oxygen andso on. Much of this work will undoubtedlyhave a clinical application. The war there-fore' has stimulated interest in appliedphysiology, and it is to be hoped that thisinterest will be continued in peace time.

It should be clear that it is not very useful totry and discuss the clinical applications ofrecent physiological work as such discussionwould be highly speculative. For example, inthe field of cardio-vascular physiology some ofthe most striking work of recent years has beenthat on the foetal circulation. New and in-genious methods have been adopted and ourknowledge both of the circulation of the foetusin utero and of the changes occurring in thecirculation at birth has been greatly extended.2But try and apply this work to clinicalproblems. All one can say is that we may beable to interpret the dynamics of congenitalheart disease more skilfully. But there can belittle doubt that eventually this work will be ofthe greatest practical importance, At presentthere are only vague possibilities. The work

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of the applied physiologist in the field of ex-perimental medicine is of more interest andcan be linked to the original work in purephysiology.

In the applied field, interest has begun tocentre on recent developments in the techniqueof measuring cardiac output. Such measure-ments have been and will be of the greatestvalue in studying cardiac disease. Many ofthe methods used to measure cardiac outputare based on the principle, first enunciated byFick in i870. This states that the cardiac out-put (C.O.) can be calculated from the oxygenconsumption of the subject and the arterio-venous difference in oxygen content of the

0blood. C.O.- (the carbon dioxide

A-Voutput and A- V difference can equally wellbe used). The great difficulty of applying theFick principle in man has always been theproblem of collecting samples of mixed venousblood, i.e. of blood having the same oxygenand carbon dioxide content as 'that enteringthe pulmonary circulation. It is no useobtaining samples of venous blood from aperipheral vein, the gas contents are notnecessarily representative, being dependent onthe metabolism of, and rate of blood flowthrough, the part drained by that particularvein. Satisfactory, samples can only beobtained from the right auricle or rightventricle. In animals this can be done bydirect cardiac puncture. Although this tech-nique has been employed in man (in Germany)most people would justifiably hesitate beforedrawing blood direct in this way. Manyingenious methods have been developed to tryand get over this difficulty. The equilibrationof gas mixtures in the lungs with the venousblood is one such method. Hence by knowingthe composition of the alveolar air which isfound to be in equilibrium with the venousblood, the oxygen and carbon dioxide contentof this blood can be calculated. Other methodsinvolve the inhalation of acetylene or carbonmonoxide. It is unnecessary to discuss indetail the technical problems involved in all ofthese methods. Valuable information has beenobtained by their use, but they all requiregreat skill on the part of the operator and con-siderable training of the subject. For these

reasons the various indirect Fick methodshave only a limited clinical application.The introduction of the technique of cardiac

catheterization is, therefore, of first-rate im-portance. The technique and the resultsobtained are fully described in recent publica-tions by Cournand4 and his colleagues inAmerica and McMichael and Sharpey-Schafergin this country. Briefly, the method consistsof the introduction of a non-wettable X-rayopaque ureteric catheter into either the left orright antecubital vein. The catheter is pushedon via the vein into the right auricle, itsposition being checked. by screening. Notonly can samples of right auricular blood bewithdrawn via the catheter but it is alsopossible to measure the venous pressure in theright auricle by connecting the catheter to amanometer, filled with heparinized saline. Inpractice a steady drip "of heparin saline ismaintained between readings of venouspressure and the taking of blood samples, sopreventing the formation of a thrombus at thetip of the catheter. Cardiac catheterizationusually seems a dangerous and alarming pro-cedure to those who are unfamiliar with it.However more than i ,8oo catheterizationshave now been carried out in man withoutaccidents which could be attributed to thecatheter. It is, in the right hands, perfectlysafe and its use has been overwhelminglyjustified.

In order to discuss the results that have beenobtained, it is necessary to refer back tophysiological work. As long ago as 19I0-I5Starling and his associates worked out thefundamental principles of cardiac dynamics,using a highly simplified version of the circu-lation, the heart-lung preparation. In this,nervous influences could be excluded, venousreturn controlled and the peripheral resistanceto the outflow of blood from the heart adjustedwithin wide limits. The various experimentalfindings were brought together by Starlingwhen he formulated his famous law of theheart; ' the larger the diastolic volume of theheart, the greater the energy of its contrac-tion,' Like all physiological principles thiswas shown to be true only within limits. Assoon as the diastolic volume fell very low orrose above a critical value the heart failed. Inthe intact animal measurement of diastolic

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volume is not easy. Starling showed, however,that there was a very important relationshipbetween cardiac output and venous .pressureas measured in the right auricle. As thevenous pressure rose the cardiac output in-creased up to a maximum; but a further riseof venous pressure was associated with a fallin cardiac output.9The direct application of these results to

man could not be said to be certain, withoutfurther experiment. Much animal workshowed that Starling's conclusions were validin the intact animal, even though they were notexclusive. In particular it was shown that asthe venous return increased so the pressure inthe right auricle rose.

It has been difficult to obtain evidence inman. For many years it has been known thatvenesection in congestive heart failure may bebeneficial. This has been explained on thegrounds that the heart has been distended, andthat venesection relieved the distension. Thisexplanation is superficial and it is reasonable tosay that although the value of venesection wasnot in doubt detailed knowledge of the effectsof venesection was lacking.The study of cardiac output in man, both in

health and disease has clearly demonstratedthe relationship of right auricular pressure andcardiac output. McMichael and Sharpey-Schafer6 were able to show that the dataobtained by Starling in the heart-lung prepara-tion was valid for man. In congestive heartfailure the right auricular pressure is high andthe cardiac output is low. Venesection re-duces the right auricular pressure and thecardiac output increases. In normal subjectsthe right auricular pressure is also lowered byvenesection but the cardiac output falls. Theexplanation of the benefit of venesection is nowclear. In congestive failure the venous fillingpressure is very high, so high that it is beyondthe physiological optimum, i.e. over the crestof the curve and the heart is in fact over-stretched. As a result the cardiac output islow. When the pressure in the right auricleis reduced the cardiac output increases, and itis this increase in the cardiac output which, inpart at any rate, is responsible for the improve-ment in the condition of the patient. Thenormal heart is working on the rising side ofthecurve, and here a fall in V.P. - fall in C.O.

The effect of venesection and of haemor-rhage has been studied in other conditions.The effects of haemorrhage has been theobject of innumerable animal experiments. Itmight well be thought that on this subject wewere reasonably well informed. On the con-trary work on man has produced some totallyunexpected findings which could not have beenpredicted from animal work. Following re-peated haemorrhage, e.g. in cases of pepticulcer, a severe anaemia with a low bloodvolume and a low haemoglobin develops. Thecardiac output in these cases has beenmeasured, and is found to be not decreased,but greatly increased. Further the rightauricular pressure is raised.10 At first sightthis is a surprising observation, but it is, infact, essential for the survival of the individualthat the cardiac output should be increasedunder these conditions. With a low haemo-globin and a low blood volume, the totaloxygen capacity of the blood is greatly reduced.The oxygen requirements of the body will notbe diminished so it follows that there are onlytwo mechanisms for maintaining an oxygensupply. There may be increased reduction ofhaemoglobin in the tissues and the rate ofblood flow round the body may be increased.There is a definite limit to the degree of re-duction of haemoglobin that is possible, andin these cases it is found that the blood fromthe right auricular is not greatly reduced. Sothe main compensatory mechanism is in factan increased cardiac output.There are several important consequences

of this finding, clinical and physiological.Clinically, the obvious treatment of anaemia isblood transfusion, but this may be disastrousunless certain precautions are taken. When ablood transfusion is given the right auricularpressure rises and, in normal subjects, there isan increased cardiac output. But in chronicanaemia, the cardiac output is already veryhigh and the right auricular pressure is raised.When blood is transfused into such a subjectthe right auricular pressure rises still higherand cardiac failure may ensue. So when ablood transfusion is given, packed red cells,not whole blood, are used and given veryslowly and cautiously as if a powerful drugwere being injected. In this way raising theright auricular pressure may be avoided.

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A second clinical point is that in severeanaemia cardiac failure may result, notdirectly due to the anaemia but owing to thelong maintained high resting cardiac output.The physiologist is interested in the

mechanisms by which this hyperdynamicphase is brought about. The immediateeffects of haemorrhage are a fall in rightauricular pressure and a diminished cardiacoutput. At some time after a severe haemor-rhage the change over takes place from thehypodynamic to the hyperdynamic phase. Themechanisms involved which bring about thischange are at present unknown. But it isclear that in considering the adjustments ofthe circulation to haemorrhage, these longterm effects which may take several days areas important as the better known immediatereactions. The existence of this problemcould hardly have been discovered except byclinical work, since the bulk of animal work isacute, and covers only a short time period.So much for the delayed effects of

haemorrhage. There have also been somecurious findings on the early effects, whichemphasize the differences between man andanimals. Many different measurements havebeen made on subjects after bleeding; Hb.values, blood potassium, urine flow, etc.Peripheral blood flow has also been studied bymeans of the plethysmograph, an instrumentwhich has a long history. Lewis, and Grantare chiefly responsible for the design used inthis country. Both in America and in thiscountry the peripheral circulation is and hasbeen studied in health and disease with theplethysmograph. Abramson has recently pub-lished a monograph reviewing the resultsobtained'.By means of the plethysmogiaph the

changes which occur in the peripheral vesselsas a result of haemorrhage can be examined.When healthy individuals are subjected to avenesection, e.g. blood donors, fainting mayoccur. Increase in the volume of the vene-section raises the incidence of fainting, somuch so that removal of i litre of blood pro-duces fainting in almost every subject. It is,therefore, highly likely that fainting is aninvariable consequence of haemorrhage if it isof sufficient volume. Fainting, or the vaso-vagal syndrome as it was called by Sir Thomas

Lewis, is a phenomenon which appears to bepeculiar to man. At any rate there is as yetno definite evidence of a similar reaction inanimals. Admittedly the reactions of animalsto haemorrhage are usually examined underan anaesthetic, but fainting can take placeunder anaesthesia in man. Plethysmographicexamination showed that a marked vaso-dilatation occurred in the muscle vessels at thetime of the faint, a somewhat surprisingfinding. A full discussion of these findingshas recently been published elsewhere (Bar-croft and Edholm, I946).3 The phenomenonis mentioned here to illustrate the fact that thecirculatory changes in man and animals arenot necessarily the same, and to provide onemore example to show that studies in appliedphysiology frequently provide problems offundamental interest.There are some other striking differences

between man and experimental animals inregard to haemorrhage. The rate of dilutionof blood is very variable in man but is in-variably much slower than has been found inanimal work. After bleeding a dog one fifthor one quarter of its blood volume, thehaematocrit rapidly falls indicating an increasein the volume of plasma due to dilution withtissue fluid. Blood volume measurementsshow that the original blood volume is restoredvery rapidly by this dilution, in a few hours atthe most. In man this may take 24-48 hours.This is one line of evidence indicating that therole of the spleen and other blood depots inman is far less prominent than in dogs or cats.The best known effects of haemorrhage, the

cardinal signs are an increased pulse rate andpallor. Both these have been extensivelystudied, but there are still several outstandingproblems. The increased heart rate is usuallyexplained as a consequence of the fall in bloodpressure affecting the pressoreceptors in thecarotid sinus and the aorta. But the increasein heart rate is out of all proportion to the fallin blood pressure. Haemorrhage in man has tobe considerable before a significant fall inblood pressure takes place (apart from thechanges due to fainting). So it is highly un-likely that the arterial pressure change is theessential factor. On the other hand it ispossible that the fall in right auricular pressureis responsible. The opposite effect is well

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known as the Bainbridge reflex, i.e. a rise inpressure in the right auricle causes a reflex in-crease in heart rate, but an increased heart ratedue to a fall in pressure here has not yet beenclearly demonstrated.The pallor following haemorrhage is usually

considered to be a part of the peripheral vaso-constriction, which is generally accepted as oneof the most important mechanisms com-pensating for the diminished blood volume.However, in man, moderate haemorrhage upto i litre does not appear to alter the rate ofblood flow through the forearm. And yetthere must be vasoconstriction somewhere, asthe blood pressure is maintained in spite of thefall in cardiac output. The surprising fact is,that this vasoconstriction is not where onemight expect it to be, in the muscle vessels.Provisionally the splanchnic vessels must bechosen, as -it is not yet possible to investigatethese in man, and therefore this conclusioncannot be contradicted. It is, of course,possible that after more severe haemorrhage inman that the muscle vessels constrict also, butthis has not been proved.What practical value is there in these

findings ? They may be of some assistance inthe investigation of traumatic shock, but thereis one point of immediate clinical interest. Theheart rate is increased in haemorrhage and inassessing the extent of the blood loss therapidity of the pulse is taken into considera-tion. If the subject has had a vasovagal attackthe pulse rate slows markedly during theattack and following recovery does not increaseagain to the level before the attack. So thepulse rate may be deceptively slow even aftersevere haemorrhage.There has been a considerable increase in

our knowledge of the effects of haemorrhage inman during the war years. In spite of, orrather because of this new information it isrealized that there are very big gaps still to befilled in.The separate study of cardiac output and

peripheral blood flow has provided, and willcontinue to provide, many valuable data. Ithas also been found useful to measure cardiacchanges and peripheral reactions simul-taneously. Such combined operations make iteasier to assess the total vascular pattern. Inparticular the profound effect of cardiac

changes on the peripheral circulation and viceversa has become obvious. In some cases ofosteitis deformans (Paget's disease) dyspnoea,oedema and a very high pulse pressure suggestthe 'diagnosis of cardiac failure due to aorticincompetence.5 More detailed examinationhas shown that thei e is no organic lesion of theheart in these cases. The cardiac output ishigh and the venous pressure is raised. Theexplanation of the apparent cardiac failure isto be found not in the heart, but in the peri-pheral circulation. Examination of the peri-pheral blood flow showed that there was anenormously increased blood flow through theaffected bones, an increase that was estimatedto be 'twenty-fold. When the disease isextensive, the bone flow alone may amount toseveral litres per minute, and a conditionexists which is similar to a series of artedio-venous shunts. This accounts for the in-creased venous pressure and raised cardiacoutput. If these are maintained at high levelsfor long, cardiac failure may ensue.A somewhat similar state of affairs is found

in cases of traumatic arteriovenous aneurysm.When large vessels are involved and a con-siderable volume of blood is shunting throughfrom artery to vein, the venous pressure israised and so is the cardiac output. Suchpatients may also show signs of cardiacfailure, although there is no cardiac lesion.These two examples demonstrate the effect ofperipheral vascular disorders on the functionof the heart. There are also many examplesof changes within the heart altering the peri-pheral circulation. Plethysmograph recordingof the peripheral blood fl6w in certain casesof left heart failure has shown an intenseperipheral vasoconstriction. When vene-section is performed, the peripheral bloodflow increases considerably, although bloodpressure may fall. In these cases the rightauricular pressure is high and it is probablyraised in the pulmonary vessels and the leftauricle also. A raised right auricular pressurealone does not appear to be associated withperipheral vasoconstriction, but a raisedpressure in the left auricle or pulmonaryvessels may be responsible for a reflex peri-pheral vasoconstriction. Considerable workwill be needed both to confirm this finding andto decide where the pressoreceptors concerned

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are sited. Other examples could be quoted toshow that there are very frequently markedperipheral reactions to cardiac disease.

It is common practice both in physiologyand in medicine to study the body systematic-ally. This is both necessary and inevitableconsidering the degree of complexity of thebody. In treating the cardiovascular system,the heart and the peripheral circulation are alsoconsidered separately. Again this is to adegree inevitable but the result is that cardiacdisease is dealt with entirely apart from thestate of the blood vessels and vice versa. So itis extremely important to stress the obvious,the physiological unity of the cardiovascularsystem. This is equally true when methods oftreatment are under review. In recent pub-lications6 it has been shown that part of the-action of digitalis is exerted peripherally. Thisis shown by the reduction of right auricularpressure by digitalis in cases of cardiacfailure. It is suggested that digitalis may actas a vasodilator. If this is confirmed it wouldindicate that treatment of the peripheralvascular system is as important in cardiacdisease as treatment directly applied to theheart.

It has been pointed out above that theremay well be cardiac effects on the circulationand vice versa. Such effects are probablyexerted by reflex paths. It may be of someinterest to consider some of the recent woik onthe vasomotor supply of peripheral bloodvessels. Much of this has been done onpatients who have been subjected to a sym-pathectomy. All blood vessels are suppliedwith vasomotor nerves, but the arteriolesprobably have the richest innervation. Bothvasoconstrictor and vasodilator nerves arefound. The formel predominate in the peri-phery, in fact some would claim that vaso-dilator nerves have not been shown to exist inman in the vasomotok- supply of skin andmuscle blood vessels. The arteriovenousanastamoses or shunts which ale found par-ticularly in the skin of the hands and feet,Jeceive a very rich vasomotor innervation. TheJate of blood flow through the skin is greatlyincreased when these shunts are open; theyprovide an extra mechanism in addition tovasodilatation for increasing the rate of blood.flow. In the hands and feet where these

shunts are numerous there is a large range ofblood flow. When the vessels are fully dilatedthe blood flow is at least one hundred timesgreater than the minimal blood flow. Thereis a continuous variation in the state of theblood vessels of the fingers, largely due toalterations in -vasomotor tone. Considerablechanges in blood flow can be evoked by quitetrivial stimuli, a pinch, a sudden noise. Apainful stimulus to any part of the body isfollowed by vasoconstriction of the fingers,which is due to vasomotor impulses. Thecirculation here is extremely labile and, owingto the rich vasomotor supply, is sensitive tomany changes occurring elsewhere in the body.After sympathectomy these reflex alterationsin blood flow are no longer obtained. Onlylocal and humoral agencies can alter thecirculation.Muscle blood vessels on the other hand are

more sensitive to humoral and physical stimulithan to vasomotor effects. However thesevessels do receive vasoconstrictor nerves andthere is evidence that they have a vasodilatornerve supply as well.Under ordinary conditions of life the state

of the blood vessels in the extremities variescontinually. Sympathectomy removes thisvariable character, so the rate of blood flow ismuch more constant. The main effect ofsympathectomy is the abolition of vaso-constrictor tone, so an immediate dilatationand an increased blood flow results. Thisvasodilatation is thought to be responsible forthe success of the procedure. The increasedblood flow removes products of metabolismwhich may have accumulated and be res-ponsible amongst other things. for pain. Ifexcessive vasoconstrictor tone were responsiblefor peripheral vascular insufficiency, sym-pathectomy would undoubtedly be the rationaltreatment. At present evidence of such acondition as a dominant factor in peripheralvascular disease is not convincing. That doesnot mean such a condition does not exist, butit has not been demonstrated. However whenthere is evidence of vasospasm as in Reynaud'sdisease sympathectomy is frequently verysuccessful. It is difficult to explain thissuccess. The increased blood flow aftersympathectomy does not persist. The de-nervated blood vessels recover or partially

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February, 9 CARDIOVASCULAR SYSTEM 105recover their tone within a few weeks. In theforearm the resting blood flow may be in-creased threefold by sympathectomy butreturns to the pre-operative level within tfiree-four weeks. In the hand the blood flowdiminishes from the high post-operative levelbut the vessels do not as a general rule com-pletely recover their tone so the hand flowremains at a higher level more or less per-manently.Two other conditions have been success-

fully treated by sympathectomy, intermittentclaudication and hypertension. But ourpresent knowledge is inadequate to explainthese results. The pain of* intermittentclaudication is frequently relieved for longperiods by sympathectomy, but in these casesthe resting blood flow in the legs is not in-creased for more than a few weeks at the most.It is for this and other reasons that Lericheand others have postulated that afferent fibresare interrupted;by sympathectomy. This viewwas vigorously opposed by Lewis,7 and therethe matter rests. It is clear that more researchis required to study the effects of sympathec-tomy, and also on the anatomy of the sym-pathetic. Sheehan and his colleagues havebeen working on the anatomical problems forsome years. Their results will undoubtedly beof the greatest importance in this respect.Similarly it is hard to understand the excellentresults which have recently been described forthe treatment of hypertension by extensivesympathetic denervation. A widespread vaso-dilatation could certainly reduce bloodpressure, but the vessels recover their tone andthe blood pressure still remains down.

It may be worth emphasizing now theimmense value of direct work on man. In thefirst place the results obtained are directlyapplicable to clinical problems; animal work,lssential though it is, may sometimes be mis-leading. The vascular system of man differsin many ways from four-legged animals,presumably owing to man's upright posture.$everal such examples have been given above.

', In the second place the human subject isusually conscious and co-operative. Animalexperiments in general are performed under

anaesthesia, and this is a serious complicatingfactor. All anaesthetics produce changes inthe circulation as, for instance, haemocon-centration. Failure to appreciate these effectshas frequently invalidated the conclusionsdrawn from such experiments. On the otherhand in human work it is essential to reduceemotional factors to a minimum. Procedureshave to be carefully planned to obviate pain anddiscomfort. It was pointed out above that theperipheral circulation is remarkably labile, andmarkedly affected by emotional upsets orphysical discomfort. This is also true ofcardiac output. However, the subject canhimself inform the observer about thesefactors, and so make it possible to eliminatethem. These apparent disadvantages arereally of value, as their removal is usuallysimple and the final experiment will be doneunder satisfactory conditions. The informa-tion obtained from the subject regardingsensations, etc., are also of the utmost value.

It could almost be claimed that the greatextension of human experimentation in recentyears, and particularly during the war, con-stitutes the main advance in physiology ofclinical importance.The chief conclusion that can be drawn from

this cursory survey of recent work is that bothphysiologists and clinicians stand to gain fromapplied research. It is to be hoped that infuture there will be far greater contact betweenthe physiologist and the clinician. Thephysiologist will certainly profit by finding ahost of problems, even though the clinicianmay not get his reward for some time.

REFERENCES

I. ABRAMSON, D. I. (i944), " Vascular responses in the e-tremities of man in health and disease," Chicago.

2. BARCLAY A. E FRANKLIN, K J., and PRITCHARD,M. M. L. (09;, " The Foetal Circulation," Blackwell.

3. BARCROFT,- H., -and EDHOLM, 0. G. (1946), Lancet, ii,513.

4. COURNAND, A., and RANGES, H. A. (094), Pe.c. Soc.exp. Biol. N. Y., 46, 462. I

5. EDHOLM, 0. G., HOWARTH, S., and McMICHAEL, J.}(194S). Cln. SaCi, 5,249-.

6. HOWARTH, S., McMICHkEL, J., and SHARPEY-iSCHAFER, E. P. (I946), Cin. Sd., 6, 4!.

7. LEWIS, T. (1942), Pain, New York.8.. McMICHAEL, J., and SHARPEY-SCHAFER, E. P. (19).s,

Brit. Heart. ., 6, 33.'9. PATTERSON. S. W.- and STARLING, E. H. (1914), 7.

Physiol, 48, 357.zo. SHARPEY-SCHAFER, E. P. (0944), CUMn Sd., 5, 12S.

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