LECTURES ON THE HEART BY THE SAME AUTHOR THE MECHANISM OF THE HEAET BEAT. With Especial Eeference to its Clinical Pathology . . . $7.00 NET CLINICAL DISORDERS OF THE HEART BEAT. A Handbook for Practition- ers and Students .... 2.00 CLINICAL ELECTROCARDIOGRAPHY 2.00 HEART. A Journal for the Study of the Circulation. Edited by Thomas Lewis. Per Volume 5.00 " PAUL B. HOEBER 67-69 East 59th Street, New York LECTURES ON THE HEAET COMPRISING THE HERTER LECTURES, (BALTIMORE) ; A HARVEY LECTURE, (NEW YORK) AND AN ADDRESS TO THE FACULTY OF MEDICINE AT McGILL UNIVERSITY, (MONTREAL). BY THOMAS LEWIS, M.D., F.R.C.P., D.Sc. Physician City of London Hospital, Assistant Physician and Lecturer in Cardiac Pathology, University College Hospital, London. NEW YORK PAUL B. HOEBER 1915 Copyright, 1915 Bv PAUL B. HOEBER Published March, 1915 Printed in the U. S. A. QPi L67 PREFACE The five lectures comprising this book were delivered during a brief visit to the American continent in the Autumn of 1914. The Herter lectures were written to emphasise the advantages of intimately combining clinical and labora- tory observations. Co-operation between wards and laboratories, as my visit has clearly taught me, is no- where more freely or widely cultivated than in the Medi- cal Schools of America. To these lectures, the Harvey lecture, which deals with questions of physiological in- terest, seems a fitting introduction. The address at Mon- treal serves to illustrate in a more extended manner the application of laboratory methods to questions of imme- diate and practical consequence. It is a pleasure to acknowledge my indebtedness to the Committee of the Herter Foundation, and to the Harvey Society, who have kindly sanctioned the publication of the lectures in this form. THOMAS LEWIS. November 3rd, 1914. 6346 CONTENTS. PAGE CHAPTER I. THE EXCITATION WAVE IN THE HEART " . . . . . . . . 3 A lecture delivered before the Harvey Society, New York, October 25th, 1914. The three Eerier Lectures upon " Clinical Medicine and Laboratory Methods " delivered at the 25th Anniversary of the Johns Hop- kins Hospital, Baltimore, October 6th, 8th and 9th, 1914- CHAPTER II LECTURE 1. THE METHOD OF ELECTROCARDIOGRAPHY EXEMPLIFIED 35 CHAPTER III LECTURE 2. "THE RELATION OF AURICULAR SYSTOLE TO HEART SOUNDS AND MURMURS " . . . . . . . . . . 53 CHAPTER IV LECTURE 3. " OBSERVATIONS UPON DYSPNCEA, WITH ESPECIAL REF- ERENCE TO ACIDOSIS " . . . . 81 CHAPTER V OBSERVATTONS UPON CARDIAC SYNCOPE " . . . . . . . . 99 Delivered at the opening of the Faculty of Medicine, McGill University, Montreal, October 5th, 1914- HAEVEY LECTURE ON " THE EXCITATION WAVE IN THE HEAKT " DELIVERED BEFORE THE HARVEY SOCIETY, YORK, OCTOBER, 25TH, 1914. CHAPTER I * THE EXCITATION WAVE IN THE HEART Mr. President and Gentlemen, May I preface what I have to say to-day by telling you how much I appreciate your invitation to deliver this Harvey lec- ture. How clearly the great physician, with whose name this Society associates itself, to whose name it delights to do honour, saw that the natural and safe advance of Medicine should follow its advance guard, physiology. Has he not fitly been named the Father of that Science ? Is it not a matter of profound satisfac- tion and pride to us that this pioneer of experimental physi- ology should have been of our profession and that his greatest discovery should have been prompted by observations upon the human being ? As Harvey by physiological study laid the foundation of Medicine as an exact science, so to-day, if we have learned the lesson which his writings should teach us, we shall maintain this tradition, preserving the closest intimacy between our conceptions of the physiology and pathology of man- kind. If we as students of the heart are exponents of such new methods as clinical electrocardiography, should we not in aspir- ing to become the humble disciples of this great teacher, first probe the normal phenomena of the heart's electric forces to the utmost ? Can we who are met to emphasise the name and works of this man, for all time the first exponent of the heart's mechan- ism and function, more fittingly employ ourselves than by earnestly considering the natural heart beat? Gentlemen, in these questions you will find my reason for attempting to ex- 4 Chapter I plain to you the origin and course of the natural excitation wave. Harvey our master chose as his illustration the heart of a King's deer ; we his disciples may select a less regal beast, the dog. General principles. That the heart beat is accompanied by an electric discharge was first clearly shown by Kolliker and Miiller in 1856. These workers laid upon the beating ventricle the nerve of a nerve muscle preparation, and noticed that at each contraction of the ventricle the nerve became excited. In that simple yet ingeni- ous experiment our knowledge of the excitatory process com- mences. Since that time,, a great number- of workers have examined the mammalian ventricle from the point of view of the electric currents found in it. It will not be possible in this address to do justice to them, for the last chapters of the story are in themselves of undue length. I do not propose therefore to treat these questions historically, but to describe to you in language as simple as possible the results of recent observation. For some five years my laboratory has been engaged in the study of this question, and I have been joined in the work by a number of collaborators. These collaborators have been, for the most part, your countrymen, and it is a lively pleasure to me to know that several of them are here to-night. The Drs. Oppenheimer of this city published with me one of our first papers. Dr. Meakins of Montreal and Dr. White of Boston joined in these researches at a later date; and most recently I have had the help of Dr. Rothschild of Mt. Sinai Hospital. Let us in the first place examine the electric events which are associated with the contraction of a simple strip of muscle, and formulate the general laws which are to guide us in our examination of so complex a structure as the heart. If we connect a simple strip of muscle, (P-D, Fig. 1) by means of non-polarisable electrodes to a sensitive galvanometer, and stim- ulate one end of this muscle (P), the galvanometer exhibits The Excitation Wave in the Heart two deflections. The meaning of these deflections, together forming when recorded a diphasic curve, is known. The first deflection accompanies the commencement of muscle activity in the neighbourhood of P (Fig. 1ft)? and this deflection has the same direction as has the deflection obtained when the zinc terminal of a copper-zinc couple replaces the active muscle P. When muscle is active, therefore, it is in a state of relative negativity, in precisely the same sense that the zinc of-a battery is relatively negative. This negativity and the passage of a current from the inactive point through the galvanometer to the active point, produces the first swing of the string recorder, a swing which is upright in our curves. It is a large swing be- cause it is unbalanced; the re- gion of the other contact re- maining for the time inactive. The second deflection of which I have spoken is due to similar conditions; it is produced after the excitatory process, associ- ated with the contraction, has travelled in a wave from the proximal (P) to the distal end (D) of the muscle strip. D is active while at P activity has subsided (Fig. Id). The portion of the muscle which has the electric charge of similar kind to our zinc terminal becomes transferred as the wave of activity passes from P to D. Con- sequently after the active process reaches D the swing of the galvanometer is reversed ; a current passes from P through the galvanometer to D, and develops the second deflection which is Fig. 1. A diagram, illustrating the development and subsid- ence of activity (and negativ- ity) in a single muscle strip, responding to a stimulus ap- plied at P. The correspond- ing and successive phases of the galvanometric curve are shown in the four lines a, b, c and d. 6 Chapter I of opposite direction to the first. Thus the two phases of our recorded curve are due to a change in the relation of the active point to the two leading off contacts, and this change produces a reversal of direction, the two deflections together comprising a diphasic effect. The culmination of the first phase can be shown theoretically and experimentally to coincide with the ar- rival of the excitatory process at the distal end, in short strips of muscle (Fig. 16). For when this occurs a balance begins to be established between the electric state under the two con- tacts. Evidently when the first phase is complete and the curve is about to cross the base line, activity is exactly equal under the contacts (Fig. Ic). Now this is a simple experiment and easily understood, once it is recognised that electrically active muscle is relatively negative to inactive muscle. Simple as it is, it is fundamental to electrocardiograph^ ; the whole of our interpretations are ulti- mately based upon it. It leads us immedi- ately to our second law, which tells us that the direction which the ex- citation wave takes, governs the form of the resulting curve. And when I speak of excita- tion wave, you should recollect that this wave is intimately bound up with the contraction wave; it precedes it by an extremely short in- terval, and is presum- ably the result of those physico-chemical processes which at any point immediately precede actual contraction. That the LLL II Pig. 2. A similar diagram, illustrating the inversion of the curve when the order of contraction is reversed, and its isopo- tentiality when the ends of the strip are activated simultaneously. The di- rections in which contraction is driven are indicated by the arrows. The Excitation Wave in the Heart 7 shape of our curve is governed by the direction of the wave is readily shown by our simple strip of muscle, for let us reverse the direction of contraction by stimulating the originally distal end (D), and forcing the wave to travel from D to P. We still obtain a diphasic curve; but compared with our first curve, each phase is now reversed in direction < T (Fig. 2a and c) ; it is easy to see why this is so, for having reversed the contraction, we have reversed I I I the order in which the ends of the strip become relatively negative. But supposing that the same strip is stimulated at its centre point (Fig. F.-I x j ,1 ,T ,. Fig. 3. A similar diagram: 26), and that the contraction wave 6 to show that maximal travels with equal rapidity to the excursion of the galvano- metric recorder is ob- two ends, where our contacts are ar- tained when the interval ranged "Fach pnrl thpn hpomnpcs of dela ^ between the ar ' mgea. j!,ac rival of the excitation negative at the same instant and the wave at the contacts is two effects neutralise each other. In these circumstances there will be no swing of the recording instrument. Further, supposing that the excitation wave is started now at P and then at a series of regularly placed points up to a centre point (Fig. 3), then a graduated series of curves will be obtained, from a simple and large diphasic curve at one end of the scale, through curves of gradually diminishing ampli- tude, to a horizontal line at the other. From observations of this kind it is clear that the amplitude of the first phase is greatest when the time interval between the receipt of the exci- tation at the two contacts is greatest. If the time interval is nothing, a state of isopotentiality is established, and as the time interval is longer and longer, so the effects are more and more unbalanced, and the culmination, occurring later and later, has more and more opportunity to develope. When we deal with a 8 Chapter I sheet of muscle, for example the auricle, as opposed to a strip, then the same statement applies ; if a point is stimulated on the surface and a pair of contacts is ar- ranged at a little distance away, then the amplitude is greatest when the contacts are radial * to the point of stimulation (Fig. 4a) for with these conditions the interval between the arrival of the wave at the two con- tacts is maximal. In these observations we have the stnts 6 shirt 6 of "ZE basis of fl ^ investigations of the cle, excited at a, b or mammalian heart. c, and examined at two central contact points. The excursion of the QF ElXC ITATION recorder is greatest when the contacts are WAVE IN THE AURICLE. in the line of the exci- tation wave; i.e., when T]w ^ w ^ fe ^ relatively nega- the muscle is stimu- L lated at a; it is least tive io all outlying ones. when stimulation is at Ln" ttiX T U SI H P lace a Pr of contacts upon multaneously developed a given area of the mammalian auricle at the contacts. , ,, ., , , - and rotate them through an angle of 90 degrees, our curve varies in amplitude. We are able quickly to isolate a line which yields the greatest amplitude when the contacts are placed along it. Such lines are favourable lines from which to lead, and we may conclude that such lines approximately represent the lines along which the natural ex- citation wave travels. Such lines in the mammalian auricle converge to a point in the neighbourhood of the angle of supe- rior vena cava and right appendix, where as you know the chief part of the sino-auricular node is situate. A specially favour- able line is that of the ta?nia terminalis. We have, therefore, * As Engelmann has shown the excitation wave radiates from a point of stimulation. The Excitation Wave in the Heart 9 a preliminary evidence that the excitation wave radiates from a central position, the region of the angle named. We take our second step. If the natural excitation wave spreads along radiating lines from the upper regions of the sulcus terminalis and we place one contact over this region and the other upon a circle of points surrounding it, we should, according to a rule which has been formulated,, obtain a series of curves of good excursion, and, if activity is always devel- oped under the central contact first, this contact should always be primarily negative to all other points. That is to say, if we VENA CAVA tf puun . VE in r vj , < v^C 4 ^?^ AR 1WTERCAVAL+ REGIOM R r APR. INFERIOR +00 ** ' l/J+'-AUR.WAll. VENA CAYA AUR.WAUL Fig. 5. A diagram, illustrating a method of examining a sheet of muscle. A central contact lies over the region giving rise to the excitation wave, the second contact is placed at outlying points successively. In these circumstances, the central contact always exhibits primary negativity. make such radiating leads, maintaining our central contact upon the point at which the excitation wave arises, a series of curves should be obtained, of which the first phases are always of a given sign; the direction of the deflections should always indicate primary negativity of the central point (Fig. 5), i.e., the first deflections should aM be upright. There is but one portion of the superficies of the mammalian auricle which exhibits these electric relations during normal contractions. If one contact is placed on the upper reaches of the sulcus terminalis and the other contact is moved along a 10 Chapter I SVC. circumference surrounding this centre, it matters not where this second contact lies, the first deflection obtained with auric- ular systole is upward in direction, indicating relative nega- tivity of the centre point. Such are the events when the centre contact lies in ap- position to the head and superfi- cial part of the s i n o - auricular node (Fig. 6). Now this experi- ment is a striking l.V.C. one, for the auric- Fig. 6. The contacts as applied to an auricle. The central contact, which is invariably rela- tively negative to outlying points when activ- ity in the auricle starts, overlies the 8. A. node. ular muscle in this neighbourhood i s thin, and the 8-A node lies in what we may regard as the centre of a muscle sheet, that is to say, a com- plete circle of points may be arranged around it. There is little or no possibility that this region of the heart receives the excitation wave from some deeper structure, for all possible paths to the node may 'be investigated. The conclusion that this centre is the centre in which the excitation wave originates is most strongly suggested. The observations upon which this proposition rests were made by Wybauw and by observation in my laboratory in conjunction with the Drs. Oppenheimer. They are observations which I have repeatedly confirmed since our original publication, and which have been recently con- firmed by Eyster and Meek, independent workers in this land. In the pig's heart, the sino-auricular node lies further up the sulcus than in the dog, and in one animal of this species I have The Excitation Wave in the Heart 11 found the point of relative negativity to be in a corresponding position. It lay, as Ivy Mackenzie subsequently snowed his- tologically, immediately over the sino-auricular node in this particular animal, as it had lain in all our dogs. Forcing a natural excitation wave. There is a second and distinct method of approaching the same subject. Suppose that we start contractions from various regions of the auricle and observe the type of curve which each i Fig. 7. Three electrocardiograms from a dog (Lead II). The last two cycles in each curve are natural heart beats. The remaining cycles are in response to stimulation over (1) the upper part of the sulcus ter- minalis, (2) left appendix, and (3) inferior cava. The natural beats are simulated when stimulation is in the region of the S.A. node. yields, using a given and fixed lead, and compare such curves with those of the normal heart beat. I have said that the shape of the curves will be controlled by the direction which the ex- 12 Chapter I citation wave takes in the muscle. If, as we stimulate the auricle to contract, we discover some region of it which yields curves which are identical with the normal, we may be sure that the natural excitation waves and those propagated from stimu- lation of the area in question follow similar paths. They can only follow similar paths if the region which we stimulate is the region from which the normal excitation waves are propa- gated. In the case of the mammalian auricle, as I have shown, there is but a single area which answers to these conditions (Fig. 7). It is the area immediately surrounding the upper reaches of the sulcus terminalis, the region which contains the S-A node. Our second evidence, therefore, accords with our first; both indicate the S-A nodal region as that in which the excitation wave has its birth. Extrinsic and intrinsic deflections. I pass to a consideration of what are termed " outlying leads," that is to say, leads in which neither contact lies over the S-A node. In leading directly from the heart muscle, the chief deflections are produced by the arrival of the excitatory process immediately beneath the contacts. The contacts are exposed to the full force of this electric discharge. Such leads .are very different from those utilised in human electrocardio- graphy, for in them the contacts are upon the limbs and not upon the heart. Curves of the excitation wave may be obtained under each condition, and for purposes both of description and of investigation, the direct and indirect effects should not be confused. Especially is this the case in leading from the heart itself. In such leads, the contacts lie on the muscle and the deflections are of two kinds. 1. There are deflections which result from the arrival of the excitation process immediately beneath the contacts; these we term intrinsic deflections. They are deflections, as you may The Excitation Wave in the Heart 13 suppose, which represent considerable electrical potentials and have considerable amplitudes. 2. There are also deflections which are yielded by the ex- citation wave, travelling in distant areas of the muscle. To these we apply the term " extrinsic deflections/' A simple example of intrinsic and extrinsic deflections is the following. Let us place two contacts upon the sulcus termi- nalis; at each beat of the auricle a large intrinsic deflection is m Hi Fig. 8. Simultaneous electrocardiograms. The upper curves from the ap- pendix, the lower curves from lead //. Showing the effect of crushing the base of the appendix and rendering the tissue under the contacts inactive. The chief or intrinsic deflection (Tn) is abolished; the ex- trinsic deflection (Esc) remains, as do the ventricular deflections (v). produced by the arrival of the excitation wave beneath the nearest contact. When the ventricle contracts, the same con- tacts pick up smaller electric discharges from the last named chamber. These extrinsic effects are records of muscle activity at a distance. But the same double effect is noticed in the auricle itself. If we lead by two contacts from the right auricular appendix for example, we obtain a curve of the form shown in Fig. 8 a. You see the usual tall spike, but it is pre- 14 Chapter I ceded by a small downward deflection. That this initial de- flection is not produced by activity in the appendix, and that the chief deflection is, can readily be demonstrated by crushing the base of the appendix. In this manner the appendix is rendered inactive, and when this is accomplished, the type of curve changes. The extrinsic effect, the small initial deflec- tion, remains, while the intrinsic effects disappear (Fig. 8&). Now this is a fundamental demonstration, for it permits us to analyse those curves which are obtained from outlying leads. All such leads give curves of composite form; consisting of a main deflection, which corresponds to the arrival of the excitation process beneath the contacts, and diminutive initial deflections which are due to the passage of other portions of the auricular muscle into the excitatory state. In considering the course of the excitation wave, as opposed to its origin, we shall focus our attention upon these chief or intrinsic deflections, for they will alone concern us. The point of primary negativity. It has been said that a single point of the auricular muscle shows negativity relative to surrounding areas when the auricle first becomes active, and it has been concluded that this is so because this area first developes negativity or activity. Re- cently we have been able to demonstrate (Lewis, Meakins and White) that such is indeed the case by a direct and most con- clusive method. We take simultaneous electrocardiograms (Fig. 9), either from two direct leads or preferably from a di- rect lead and a standard limb-lead (Lead II). By using exact methods of mensuration we have been able to reduce our cus- tomary error below a thousandth of a second and to measure the time of onset of the excitation wave, relative to P in the standard, in various regions of the auricle with great accuracy. Having searched the whole of the superficies of both auricles and the septum internally in a large number of animals, we can The Excitation Wave in the Heart 15 11 fa* O CD 16 Chapter I affirm that the first appearance of the excitation wave is over the head of the sino-auricular node and that it appears at later times in all other regions. The same observations provide this and another important evidence that the S-A nodal region originates the excitation wave. It is the only region of the auricle from which curves are obtained,, in which there are no initial deflections (Fig. 9a) ; the reason being that when the intrinsic deflection is obtained from this lead, the whole of the rest of the auricular tissue is in a state of inactivity ; while in all outlying leads the intrinsic deflection, which represents activity, is preceded by initial movements of the string (Fig. 9& and c), which repre- sent currents from the preceding activity of the S-A nodal re- gion and surrounding areas. I may sum up this the first part of my address to you, in the statement that we have abundant and conclusive evidence that the excitation wave commences in the immediate neigh- bourhood of the head of the sino-auricular node. II. THE COURSE. OF THE EXCITATION WAVE IN THE AURICLE. When we examine the intrinsic deflections in curves from outlying leads, if the contacts are arranged radially to the S-A node, the direction of the intrinsic deflection is always the same, indicating that of the two contacts the proximal always receives the excitation wave first (Fig. 10) ; we have taken many hun- dreds of such curves without noting a single exception to this rule. From the direction of the intrinsic deflection alone we may conclude that the excitation wave spreads from the S-A node in all directions radially, that it runs down the tsenia terminalis into the tip of the .right appendix, along the intra- auricular band to the tip of the left appendix, and down the septum ; that it runs into all the veins, ca.val y coronary and pul- monary, against the blood stream. And these conclusions are completely substantiated by our The Excitation Wave in the Heart 17 readings of the times at which the excitation wave reaches par- ticular points. If a series of contacts is placed upon the auricle s.v.c RTPULH.VEIN 4- 4- LFT PULM VEIN RT APP. RT AUR.V/ALL. Fig. 10. A diagram illustrating a system of " outlying " leads. A pair of contacts is arranged radially to the node in various regions. The proximal contact always receives the excitation wave first, as shown by the direction of the intrinsic deflection. in a direction radial to the 8-A node, and the times at which the excitatory process arrives in each is estimated (Fig. 11 and SUPERIOR CAVA OT SULCUS^r INFERIOR CAVA. 3. 8. 7. 6. 5. -4. 3- 2 . I. Fig. 11. A diagram illustrating leads from serial contacts. If the S.A. node lies at one end of the series, the tijne at which the excitation wave appears recedes uniformly throughout the series, starting at the nodal end. 13), a contact proximal to the S-A node is always found to receive the excitation wave before a point more distal ; and if the contacts are equidistant from each other, the times at which the excitation wave appears at the individual contacts of the series increase in a regular order. The excitation wave passes up the superior vena cava and flows along it to a point well outside the pericardium (Fig. 15) ; it ends where the heart muscle ends and the venous muscle begins. It passes down the 18 Chapter I Fig. 12. Outline of an auricle in an actual experiment; showing the ar- rangement of the muscle bands; the concentration point (C.P.) ; and the outline of the 8. A node. The diagram is accurately to scale, and illustrates the method of leading off by paired contacts and the sub- sequent orientation. Fig. 13. A scale drawing from an actual experiment; showing a number of contacts used for leads from sulcus and inferior cava. Examples of the curves are shown in Fig. 14. The Excitation Wave in the Heart 19 inferior cava to the edge of the cuff of muscle which is in places intrapericardial, in places extrapericardial (Figs. 13 and 15). Knowing the distances between our contacts and the S-A node, we are able to estimate the rates of conduction of the wave to all parts of the auricle. The average transmission times, distances and rates are given in the accompanying table. The Region. Distance in mm. Transmission Time. Transmission Rate. Number of Observations. Intercaval 15.2 .0139 1232 18 Intra aur. Band 12.9 .0126 1252 6 s. v. c 8.2 .0136 588 11 Septum (mid and low) . 31.5 .0305 1059 11 Rt. app 28.0 .0314 955 11 Rt. aur 16.0 .0206 859 7 R. Pulm. V 24.0 .0254 1121 4 I V C 31.5 .0325 998 18 Cor. Sinus 43.9 .0412 1096 5 L. Pulm. V 45.2 .0412 1118 5 L. App 44.6 .0446 996 7 Average heart rate 158.4. transmission rates are wonderfully uniform from node to all parts of the auricle; such differences as occur are readily ac- counted for by small errors of measurement, or by the arrange- ment of the muscle bands^ for it seems as if the rate of trans- mission is greatest where the muscle bands are straight. The solitary exception to the statement that the rate of transmission is uniform and approaches 1000 mm. per second is found in the superior cava; here it is lower and we are inclined to at- tribute this difference to the direction of the muscle fibres in this vein ; they are arranged for the most part obliquely across the vein, while our transmission rates have ;been estimated up and down it. We are unable to obtain evidence of hindrance to the passage of the wave from node to auricle at any point ; the 20 Chapter I ^> S2 * ^^ ^ ^ OS05 Fig. 14. Fig. 15. Fig. 14. A diagram showing outlines of the curves obtained from 5 of the leads of Fig. 13. Charted in relation to the first appearance of the excitation wave in the auricle (8.A.N. line). The intrinsic deflection gradually recedes in time as the lead is taken lower on the vein, until the edge of the muscle is reached; the intrinsic deflection is then lost. Fig. 15. Serial leads from sulcus and superior cava in another auricle. The times at which the excitation wave appeared at the several contact points are given. From the highest S.V.C. (contacts marked*) no in- trinsic deflections were obtained. The Excitation Wave in the Heart 21 rate of travel appears to be uniform, the direction of travel radial in all directions. Neither can we find any evidence of an increased rate of conduction to the A-V node, our calculated rates are the same for all parts of the auricular septum as for the rest of the auricular tissue. We have also used special methods of estimating the transmission time from node to node, by a method which I do not propose to consider in detail, and find it to be long. The excitation wave in the auricle may be likened to the spread of a fluid poured upon a flat surface, its edge ad- vances as an ever widening circle, until the whole surface is covered (Fig. 16) ; such variation as ex- ists in the rate of travel along various lines in the auricle is fully accounted for by the simple ana- tomical arrangement of the tissue. If we examine the ar- rangement of the muscle bands of any mammalian auricle, we shall agree, I think, that they are ordered upon a definite plan. Immediately below the 8-A node the fibres collect from all parts of the superficies of the right auricle in a curious fan shaped manner, to join in a knot of tissue which we term the concen- tration point (Fig. 12 C. P.). The S-A node is placed in the most advantageous position possible for a quick distribution of the contraction wave to all parts of the auricle, the fibres stream into this region of the heart from all the chief outlying regions. Fig. 16. A diagram, illustrating the spread of the excitation wave over the surface of the right auricle. The spread is almost uni- form and follows the chief muscle bands. 22 Chapter I The chief fibres of the right appendix run direct to the head of the sulcus; the tsenia runs from bottom to top of sulcus; the intra-auricular band runs from the angle across to the left appendix ; other fibres run down the intra-auricular septum. To sum up ; the excitation wave, which has its origin in the S-A node spreads immediately and at rates ranging about 1000 mm. per second along the chief muscle tracts which radi- ate from the neighbourhood of this node; it courses throughout the whole of the auricular tissue, up to its ending upon the chief veins, and courses down the septum at a similar speed to reach the A-V node, whence it is transmitted to the ven- tricle. Is it not true to say that one auricle contracts before the other ; the excitation wave appears in some portions of the right auricle before some portions of the left and vice-versa. The spread may be likened to the spread of fluid poured upon an almost flat surface. III. THE EXCITATION WAVE IN THE VENTRICLE. We have followed the course of the excitation wave from the sino-auricular node, throughout the auricle and to the auriculo- ventricular node. I do not propose to deal with the evidence for the transmission of the impulse from auricle to ventricle. We know as a result of recent investigations that it passes through the auriculo-ventricular bundle; and there is powerful evidence that it is distributed in the ventricle through that in- tricate and almost universal subendocardial network, the Pur- kin je system. We pass to a study of the excitation process in the ventricle itself. In discussing this subject I propose to take a somewhat unusual course. At a somewhat later date it is proposed to publish a full paper on this subject; the work of Dr. Roths- child and myself is still in progress but is sufficiently advanced to bring before you in the form of a preliminary communica- tion. The Excitation Wave in the Heart 23 Our observations have been conducted along lines similar to those for the investigation of the auricle.* We estimate the time of the appearance of the excitation wave, relative to R in a standard electrocardiogram, in the various areas of the musculature. The problems are more difficult than those connected with the auricle. In the last named chamber, as we have seen, the wave spreads in uniform and diverging lines. At an early stage of our observations we found that the spread in the ventricle happens in an entirely different fashion. If we examine a series of points upon a superficial band of ventricular muscle, for example, the con- spicuous fibres which sweep from the conus across the upper part of the interventricular groove and around the left border of the heart to the apex,, we immediately ascertain that the wave does not course along these bands. Fig. 18 serves as an illustration: the excitation wave appears at a series of points along the right border of this diagram at time intervals, .0241, .0231, .0198, .0150, .0146, .0187 and .0196 sec. after R. It appears almost simultaneously at all these points, although they overlie the same muscle band. We have conclusive evidence that the excitatory process takes little or no consideration of the anatomical arrangement of the mus- culature of the ventricle. If we cover the front of the heart with contacts and estimate the order of the excitation process, we constantly discover an area in the region of the anterior attachment of the wall of the right ventricle (shaded area in Fig. 18) in which the excitatory process first commences so far as the superficies of the heart are concerned. But there is this remarkable fact; there exists in this region a consid- erable area, though it is of variable extent, in which the ex- citatory process commences almost simultaneously. If we examine the underlying structures we shall find that this * With the exception that single contacts are placed on the ventricle while the second contact lies on the chest wall. 24 Chapter I regon of the is the most directly supplied by the right branch A-V bundle, and we have little doubt that the distribu- tion of the right branch to this region is responsible, in part at least, for its early and simultaneous excitation. Examining the whole superficial surface of the heart in a number of ani- The Excitation Wave in the Heart 25 mals, we find a close resemblance in the distribution from beast to beast. The superficial area which passes earliest into a state of excitation is almost always that which I have indicated, namely the portions of the conus where these join the interventricular groove. This is the portion of the wall overlying* the large anterior papillary muscle of the right ven- tricle. The rest of the^ngbt ventricle becomes active later; the latest region is the upper wall of the conus directly below the pulmonary valves ; the base of the right ventricle at its fusion with the fat in the A-V groove, and that portion which lies along the posterior interventricular groove, is almost but not quite so late. Yet although there is this almost constant order, the time differences between the onsets of activity in the several parts of the right ventricle are remarkably small. In the case of the auricle, the wave takes from start to finish 4 to 5, hundredths of a second to complete its course. In the ventricles, although these chambers are so much larger, the whole course is usually completed in dogs of the same size in less than 3 hundredths of a second. The order in the left ventricle is equally definite, though at present I shall not enter into detail. The earliest point is the vortex of the left ventricle or the extreme apex, and this region sometimes successfully rivals the right ventricle in the race; a hundredth of a second later the neighbouring points are activated. The appearance of activity over the remainder of this chamber is practically simultaneous, the time differences are usually to be measured in a few thousandths of a second. The basal attachment is generally speaking latest of all and practically coincident with the activity in the conus region. No system of spread from point to point of the muscle fibres in a definite order can be imagined which will explain this distribution. We are forced to assume that the ventricular wall is reached bv an impulse travelling along a large number 26 Chapter I of paths of distribution. These paths as we are able to show are the Purkinje paths. If we examine a series of points, such as those shown in Fig. 19 before and after section of the right branch of the A-V bundle we find clear evidence for this statement. After section of this branch, as you are aware, a con- spicuous change occurs in the form of the axial electrocardiogram; this change interferes to some ex- tent with our absolute standard of measurement, but we are able to ascertain the relative order before and after the interference Avith precision. It is found that prior to section the right A^entricle be- comes active before the left in such a series of contacts as is fig- ured ; but after section the order changes. The relation of points to each other over the left A^entricle remains unaltered ; Avhile activity in the right ventricle is materially delayed and progresses from left towards right. The Purkinje f over the right, whereas be- system is thus prOA T ed to be COn-I fore section the excitation wave appeared earliest in this region, after section it appeared latest. haA T e still to explain a great deal. Even where we take into account this branching system, we can- not fully explain the time relations over certain regions unless Ave assume that ventricular conduction is much more rapid than conduction in the auricle. To take an example: there are no free branching strands to the region of the conus ; the subendo- cardial network in this region is spread as a continuous sheet ; Fig. 19. Outline of the front of a dog's heart, upon which five contact points were investigated, before (top figures) and after (bottom figures) section of the right branch of the A-V bundle. It will be noted that over the left ventricle the order re- mains unchanged; but cerned in the distribution. But' allowing this to be the case, w^e The Excitation Wave in the Heart 27 yet conduction to the muscle beneath the pulmonary valves is extremely rapid. To meet these difficulties of explanation we have devised special experiments. It has been necessary to measure the rate of conduction through various tissue areas when an artificial excitation wave is propagated across contacts in line with each other. The natural rate of conduction in the auricle is fairly uniform and at about 1000 mm. for a second. The rate of conduction in the ventricle varies with the region examined. It is highest and approaches or surpasses 2000 mm. per second where the muscle is thinnest. It is lowest and approaches 400 mm. per second where the muscle is thickest. The reason for this variation is clear to us. The rate of con- duction through ventricular muscle is slow, the rate of conduc- tion through Purkinje substance is approximately at least 5 times as fast. When we excite the pericardial surface, the difference in the times at which the excitation wave reaches the contacts in line with the stimulation point, depends upon whether the excitation wave has time to travel through and into the Purkinje substance and along it and out again through the muscle to our contacts, before it passes directly to our contacts through the muscle alone. Evidently the thicker the tested muscle, the less likelihood is there of quick penetration. That this explanation is valid is clearly shown by two further experi- ments. If two contacts are placed opposite to each other, one on the pericardial, the other upon the endocardial surface, the natural excitation wave always reaches the internal contact first (Fig. 20). It also reaches the internal contact first, and by precisely the natural time interval, when an excitation wave is pro- voiced from the outside, provided that the point of stimulation is sufficiently far removed. Thus in Fig. 20 e represents an external and i an internal contact, and the epicardium is stim- ulated 10 mm. away. The excitation wave appears at the in- ternal contact first and at the external contact after the natural Chapter I Fig. 20. Two contacts (e external, i internal) are placed on the epi- cardium and endocardium respect- ively, and the heart wall is stimu- lated at 8, 10 mm. away. The exci- tation appears at the internal con- tact first and at a natural interval, before it appears at the external contact ; it travels therefore by way of the Pur kin je substance. interval. It has travelled therefore along the path a a a, through 8 mm. of muscle and 10 mm. of the Purkinje system before it has travelled through 10 mm. of muscle (path &). Thus it prefers to pass through 10 mm. of Purk- inje substance, rather than through 2 mm. or less of muscle. The second experiment is similar in kind. Two contacts are placed on the right ventricle (Fig. 21) and the heart is stimulated at a point in the neighbourhood of the sep- tum (n), some 10 or 15 mm. away. The interval between the arrival of the excita- tion process at p and d is relatively long. (The path taken is along c. ) But if the point of stimulation is moved 30 to 40 mm. away (/) and the experiment is re- peated, the interval is materially re- duced; in a number of such experiments it is reduced until it reaches the interval displayed % the nat- ural heart beat. In Fig. 21. A diagram of the ventricles, seen in vertical section. Two contacts, p and d, are placed on the right ventricle. The ventricle is stimulated at n and the ex- citation wave passes along the path c. The ventricle is stimulated at / and the excitation wave now appears at p and d at such times as to suggest that it travels through Purkinje tissue and bundle branches a, a, in preference to the shorter course 6, b. The Excitation Wave in the Heart 29 such instances the quicker though far longer path is over the septum and through the main divisions of the bundle (a a as op- posed to & &). Let us sum up our findings. The spread of the excitation wave in the ventricle is controlled by the Purk- inje system; it is hastened by the early branching of this sys- tem, especially in the left ventricle. The Purkinje system has a high rate of conduction as compared to ventricular muscle, and this quality also favours quick distribution. Evidently, before we may end our search, we have to inves- tigate the endocardial surface of the heart; this presents difficulties, but is in the course of completion. The excitation wave appears early inside the ventricle, and the time intervals appear to be very small ^v,; between different endo- < < > > cardial regions. We i -,. ,, ,, ,. Fig. 22. A diagram illustrating the spread believe that the earliest b of the excitation wave in the auricle region of all is the up- from a central node - The spread is along the muscle bands. per part 01 the septum on the left side, and that other regions become active according to their distance from the main distributing tracts ; but this has not been convincingly proved. Why then does the front of the right ventricle become active so long before super- ficial regions of the ventricle overlying the left papillary muscles ? For a simple reason, namely, because the muscle is thinner. We have data of a very suggestive kind which appear to show that, as Purkinje conduction is extremely rapid, the excitation process starts almost simultaneously over the whole interior of both ventricles, and that the appearance of activity upon the superficies, while partially controlled by the distance from the main Purkinje strand, is chiefly controlled by the thickness of the muscle overlying the Purkinje sub- stance. It is chiefly to this cause that we attribute the early appearance of the excitation wave over the front of the right ventricle, near its attachment, and at the vortex of the left 30 Chapter I ventricle ; for these are the thinnest points of the ventricular walls. According to our view the excitation spreads in the ven- tricle along the Purkinje system, and, appears on the surface by directly piercing the whole thickness of the wall (see Fig. 23) ; this piercing of the wall is aided by the penetration of the wall by isolated strands of the end arborisation of the Purkinje system. Fig. 23. The spread in the ventricle as it is conceived. The spread is from p, through branches of the Purkinje system ; subsequently the spread is along the endocardial network and from this at right angles through the ventricular wall. The observations which I have briefly surveyed will, I trust, take us far towards a final explanation of the normal electro.- cardiogram, for we are now in a position to state the regions which are excited when given deflections of the normal curve are inscribed; but this subject I shall defer. Our view of the distribution in the ventricle also helps us, so we believe, to understand the curious alterations of electrocardiograms met with in the hypertrophies ; for a thickened left ventricle should delay the activity of the apical musculature, and by delaying penetration should deepen and prolong S in axial leads. How- ever, this view is at present in the stage of tentative hypothesis. Finally, a word on conduction rates in various regions of the heart. We find the conduction rate to increase as we pass from : The Excitation Wave in the Heart 31 1. Ventricular muscle to 2. Auricular muscle to 3. Purkinje substance. It is to be remarked that the glycogen content of these tis- sues increases in the same order ; but more important at present is the physiological significance of these variations in activity. Distribution of the excitation wave in the auricle is expe- dited by the central position of the sino-auricular node and by a relatively high conduction rate, a relatively simple plan. The muscle of the ventricle conducts slowest because its func- tion of distribution is a minor one; on the other hand, this, the driving chamber, is provided with a special system of dis- tribution, clearly arranged to provoke almost simultaneous con- traction ; this special system is endowed with conduction powers of the highest order. THE HERTER LECTURES DELIVERED AT THE JOHNS HOPKINS HOSPITAL, BALTIMORE, OCTOBER, 1914 " CLINICAL MEDICINE AND LABORATORY METHODS " " The fourth is a Supinity, or neglect of Enquiry, even of matters whereof we doubt; rather believing than going to see." " But the mortallest enemy unto Knowledge, and that which hath done the greatest execution upon truth, hath been a peremptory adhesion unto Authority; and more especially, the establishing of our belief upon the dictates of Antiquity" " The testimonies of Antiquity, and such as pass oraculously amongst us, were not, if we consider them, always as exact, as to examine the Doc- trine they delivered. For some, and those the acutest of them, have left many things of falsity; controllable, not only by critical and collective Reason, but common and Countrey observation." SIR THOMAS BROWNE. CHAPTER II FIRST HEtRTEK LECTURE. THE METHOD OF ELECTKOCABDIOGRAPHY EXEMPLIFIED Gentlemen,, When your Committee invited me to come to your Anniver- sary meeting and did me the honour of offering me this lecture- ship, it left me to choose the subjects of my discourses. The three lectures which are to be given have been arranged under the title of " Clinical Medicine and Laboratory Methods." The choice of this title seemed to me the most fitting for the occasion, for it allows me to present my subject matter in the form of a tribute to your School. Students of the Johns Hop- kins University need no persuasion that an intimate associa- tion between the work . of wards and laboratories is essential to-day. You have been leading advocates of this policy, your institutions are living monuments to enterprise of this kind. You have indeed the right to great pride that your University should have been the youngest in the van of those promoting the study of Medicine upon the exacting lines of the scientific laboratory. That you have been pioneers is a matter of com- mon knowledge ; that you retain your position is shown by your recent innovation in Medicine, which all European schools have closely watched with interest and lively expectancy. If you are in sympathy with the observations of my collaborators and myself, and I read your invitation in that sense, you are so, if I may presume to say so, because our work has been along lines which you have always approved and encouraged. There is 35 36 Chapter II no closer bond of union between fellow-workers than the knowl- edge that the methods which they pursue are harmonious, that the trains of thought are of a kind. Laboratory methods as applied to the study of clinical medicine have come to stay; instruments and methods of precision are gradually relieving medicine of its past stigma ; they are lifting it to the plane of its sister sciences, its true and proper status. We have been too content in the past with opinion, in the future we shall rest our case upon fact ; our philosophy takes shape as it is moulded with additional and certain knowledge. To my colleagues in this field, I would say, our fight is not yet done, there lies before this generation a grand opportunity, a successful struggle for freedom. Let us go forward in a progressive spirit, cast- ing from us the fatal traditions which dog our footsteps. The history of medicine is a history darkened by the dust of faith and superstition. Our abode is still unclean; the broom has yet to sweep the house again ; let us retain it in our hands till its appointed task is done; there are many dusty corners, the cobwebs still cling thickly to the rafters. Yours is a new country; young workers in older countries look to you to lead where they may follow; they see you lead- ing where some day they aspire to follow. They send you this message, to continue to be their guide in the final emancipation of Medicine as Science. I would awaken profound distrust of authoritative utter- ances, especial distrust of suggestive but unproved doctrines; our traditional teachings teem with them; let each statement receive support to the hilt, evidence is never too complete. It has been my lot recently to examine some old established faiths in respect of cardiac hypertrophies. I do not propose to speak of them at the present time. The method has been similar to Miiller's, accurate weighing of the separate heart chambers. What the result ? Little beyond sweeping ; the destruction of one's belief in the power to gauge preponderance The Method of Electrocardiograph?/ Exemplified 37 of this or that heart chamber by bedside tests; the conviction that mechanical factors are not the sole, nay, oftentimes not the chief agents at work; a clear appreciation that the whole sub- ject must be reopened to new and more exacting investigation. It has also been my lot to join in investigating certain forms of breathlessness, and to this subject I propose to devote a later lecture. If you agree with the conclusions which I shall then draw, you will again see that it is urgently necessary for us to revise our ideas in respect of dyspnoea. So in many other directions our information is scanty or ill-founded; it is so be- cause we have been content to listen to the voices of old times, because we have failed clearly to appreciate that workers of the past were fearfully crippled by lack of means to solve the problems with which they wrestled; because in our hearts we have refused to believe in Medicine as an exact science. There is a field of clinical medicine in which progress has of recent years been considerable; so considerable that perhaps we are unable fully to grasp its significance at the present time. It is that which has refined our knowledge of movements of the heart chambers. If you took a clock to a mechanic for repairs and forbad him to remove its case, you could readily conceive his predicament ; a similar problem is presented to each of us when confronted by a patient with heart disease. The mechanism of the heart, like the mechanism of the clock, has been veiled from view; listening to its sounds, we might gauge its pulse, as a child listens with wonder and bewilderment to the ticking of a watch, or eagerly scans the circulation of its hands. Labouring under these conditions, an instrument of pre- cision has been placed at our command, an instrument which permits us to record the inner workings and brings us into direct contact with its wheels. This instrument is the string galvanometer of Einthoven. It is not possible in this lecture to cover the subject of electro- 38 Chapter 11 cardiography ; it is possible only to choose some few of the outstanding problems which have been elucidated largely by its aid. Those chosen have been chosen chiefly to illustrate method, and especially to confirm your conviction that clinical disorders may be imitated and studied in the laboratory. It is a common misconception that the study of irregularities of the heart's action ends with irregularity ; that is far from being the case. It may be unhesitatingly stated that graphic methods are slowly but surely . altering our whole conception of cardiac disease; the chapters which deal with cardiac syncope, palpita^ tion, acute dilatation, heart strain, the diagnosis of myocardial disease, and cardiac failure are to be rewritten in the light of modern observations. But we owe them other and greater debts. Graphic work has dealt as severe a blow to the prestige of anatomical pathology as any it has received of late years. Xot that I desire to deprecate this line of study; but clearly, as our prime business is with the living and not with the de- funct organism, so the pathology of the wards must take pre- cedence to that of the dead house. Graphic records are records of function, normal or pervert ; it is of pervert function that our patients complain. Graphic work sharpens our per- ceptions, it provides facts which are intensely satisfactory as a basis for argument. The records are clear messages writ by the hand of disease, permanent and authentic documents which silence dogma. The physiological electrocardiogram is as you know a direct record from the muscle of the heart, a record of the electrical changes associated with its beating. Inquire of this instru- ment the nature of the heart beat in a normal subject, it in- scribes a hieroglyphic of the form which I now show you (Fig. 24). Our first task is to learn the meaning of this strange writing; our Rosetti stone is the heart of the lower animals. If we record the movements of the separate chambers of the The Method of Electrocardiograph^ Exemplified 39 Fig. 24. Simultaneous venous, arterial and electrocardiograph} c curves, taken from a normal human subject. Illustrating the method of re- cording the movements of the several heart chambers. " a " in the venous curve, P in the electrocardiogram, represent the activity of the auricle. " c " and " v " in the venous curve, Q, R, S and T in the elec- tric curve, represent systole of the ventricle. Pig. 25. An electrocardiogram from a dog with simultaneous curves from auricular and ventricular muscle; to show how the relations of elec- trocardiographic deflections to muscular events are studied. 40 Chapter II dog's heart, and allow our galvanometer simultaneously to write its message (Fig. 25), we find it speaks of two events; it re- cords the activity of the auricles and of the ventricles. The deflection P is the representative of auricular activity, though it slightly precedes the contraction ; the deflections R, S, and T speak for the activity of the ventricles. The instrument not only signals these chief events, it tells us if the sequence of contraction in the muscle elements of a given chamber is nor- mal. The normal curve P is given by a contraction coursing along normal auricular paths only; the usual deflections R, 8 and T by a beat following physiological paths in the ventricle only. Abnormal beats of either chamber are portrayed by curves of peculiar and distinctive forms. In a given case the type of curve is controlled by the direction of contraction in the muscle, relative to the position of the contacts upon the body ; it is controlled therefore by the point at which the contraction originates. Let me illustrate these statements, which are the first grammatic rules of this new language. In the first example which I show you are two curves; the one (Fig. 26) taken from a patient who exhibited a regular coupling of the pulse beats. The electrocardiographic curves show the same coupling, and each beat of a couple consists of an auricular portion P and of a ventricular portion, R, 8 and T. It is an example of an irregularity due to what are known as auricular extrasystoles. But if you examine the curve in de- tail, you see that the second beat of each couple, the premature one, resembles the first beat of each couple in every respect ; first and second beats have followed the same muscle paths and the disturbance which gives rise to the second beat must have had its seat, if our rule holds true,, in that portion of the heart from which the first or normal beat arose. That this is so is shown by the next curve (Fig. 27). It is an experimental replica of the first, and was produced by stimulating the heart at the seat of natural impulse formation. A duplicate could be pro- The Method of Electrocardiograph^ Exemplified 41 duced in no other fashion. This is our method, to attempt to produce disturbances in the experimental heart, parallel to those which we see in the clinical heart. Our first clinical example is one in which we may locate a process of irritation in a given region of the right auricle, namely, in the immediate neighbour- hood of the sino-auricular node, the structure which forms the natural pacemaker of the heart. My second illustration s P*T p f 1 S 5 Fig. 26 and 27. Two curves showing coupled action of the heart beat, the first from a patient, the second from a dog. The coupled action in the experimental instance resulted from stimulation of the auricle in the region of the superior cava. To illustrate the method of investigat- ing the origin of irregular heart action in clinical subjects. similar (Fig. 28). Here is an electrocardiogram from a pa- tient who exhibited an intermittence of the pulse and whose electrocardiograms not only portrayed numerous beats of nor- mal outline but the curious atypical beats which give such large excursions. For comparison with this curve is one of experi- mental origin (Fig. 29) and the resemblance between the two is close. The experimental curve is written side by side with curves of mechanical shortening in auricle and ventricle, a script with which we are long familiar. The experimental irregularity was produced by stimulating the right ventricle. 42 Chapter II The disturbance is confined to the ventricle as the mechanical, records demonstrate, for the auricular rhythm throughout is undisturbed. The atypical beats which have arisen prema- turely in the right ventricle, in virtue of their abnormal origin, m m * T r Fig. 28. A clinical curve showing an irregularity of the heart's action. As, Fig. 29. A similar experimental electrocardiogram accompanied by curves of shortening of the auricular and ventricular muscle; the atypical beats were produced by stimulating the right ventricle. have pursued an abnormal course through the muscle of the ven- tricle; it. is to this that the changed character of the corre- sponding curves is due. It is in the manner illustrated that the seat of disordered heart action has been analysed. The Method of Electrocardiograph^ Exemplified 43 I show you another clinical example of a curious change in the action of the heart. The first few beats of Fig. 30 are of normal type, the auricle and ventricle are beating in their usual sequence; but as the rhythm proceeds, its rate slows a little and suddenly the auricular summits disappear. We Fig. 30. A clinical curve showing escape of the A-V node as a result of slowing of the natural rhythm. ;\J | -\\Jki ^PiilN M-^ : I >"W : i > | /t* jrf fj t joj I & * t rt { rj 1 fy . . ~~ I t. * *\! ; 17 j nt '','t^'^ 1 ' 11 - 1 1*\ I T \ rrnl T 71 Fig. 31. An experimental curve showing similar slowing of the heart and escape of the A-V node when the sino-auricular node is depressed by cooling. should possess no clue to the nature of this change had we no experimental data for comparison. The meaning of it is clearer when we study the companion curve (Fig. 31). Here we have electrocardiogram and mechanical curves, written simultaneously from the exposed heart of a dog. formally the 44 Chapter II heart beat starts in the region of the mouth of the superior cava in a structure termed the sino-auricular node (see Chapter I). If you depress the physiological activity of this struc- ture by cooling, you obtain, as Ganter and Zahn have shown, a retardation of heart rate, and before long the auricular sum- mits P are lost. They are lost, as the experimental curve shows clearly, because the contractions of auricle and ventricle are no longer in sequence but simultaneous, the auricular curve being buried and hidden in the ventricular curve. As the activity of the normal pacemaker becomes depressed by cooling, other centres become relatively more active, and the first in the race for control of the heart beat is the auriculo-ventricular node, which lies in the path between auricle and ventricle. When the upper node is cooled, the central node becomes the most active and dominates the heart's movements. Each time it produces a rhythmic impulse, this impulse travels to auricle and to ventricle simultaneously, the systoles of auricle and ven- tricle synchronise and yield this abnormal electrocardiogram. I have spoken of the A-V node ; it is the first part of a system of fibres which joins the auricles to the ventricles, the system as a whole serving as a channel of conduction for impulses passing from one chamber to the other. It is largely to work carried out in your institute by Erlanger and his collaborators that we owe our knowledge of the functions of this delicate strand of tissue, called the A-V bundle or bundle of His. The ventricle depends for its impulse to contract upon the auricle and upon the integrity of this tract. If the bundle is damaged by injury or disease, co-ordination between the two chief di- visions of the heart is disturbed. I show you a series of curves which illustrate this disorder; a clinical curve (Fig. 32), and two experimental examples. Heart-block as it is termed may be produced in a variety of ways. It has been shown to follow when the bundle is pressed upon or crushed, by Erlanger and Hirschfelder, your experimentalists. It comes when the track The Method of Electrocardiograph^ Exemplified 45 is damaged in any way, be this damage deliberate or be it through the accident of disease. It may be caused by the in- Fig. 32. A clinical instance of heart-block in. a patient who suffered from chronic myocardial disease. Fig. 33. The heart beat of a cat recovering from asphyxia. A period of 2 : 1 heart-block passes into the natural rhythm. T f* 7~ p T f> P -r f> ~r Fig. 34. Venous, arterial and electrocardiographic curves from a dog, showing heart-block as a result of stimulating the left vagus. troduction of poisons into the circulation, such for example as diphtheria toxine, digitalis or the products of asphyxia (Fig. 33). It is produced by stimulation of the vagus, more espe- 46 Chapter II cially the left nerve (Fig. 34). All these methods of produc- ing block experimentally have clinical parallels. The most important are those in which definite lesions are to be found in the bundle region. The bulk of the ventricular muscle is silent in disease; affections of the bundle or its branches tell us often of an active or chronic process in the myocardium. As you know, heart-block is responsible for one of the major forms of cardiac syncope; where a slow pulse action is accom- panied by attacks of loss of consciousness (Adams-Stokes Syn- drome). It is experiment, and experiment only, which has taught us the clinical varieties of this condition. We come to the most frequent and important disorder of the human heart beat, that so familiar to you as an accompaniment of failure of the muscle. The irregularity of the pulse which, on account of its complexity, has given rise to the term delirium cordis, was one of the last to receive adequate explanation; it has been studied since the active days of Marey, Sommerbrodt and Riegel. The first clue to its real meaning came from two laboratory workers in this land, Cushny and Edmunds; it is now definitely known to result from what is termed fibrillation of the auricles. That knowledge has been gained directly and exclusively from animal experiment, conducted side by side with clinical observations. Without such experiment we could have gathered no true conception of the events in the heart. This discovery has explained a multitude of obscure phenomena, it will continue, if I mistake not, to shed light upon the path- ology of heart disease for many years to come. When the auricles pass into fibrillation they cease to beat and their walls, standing in a position of diastole, exhibit small flickering tremulous movements, which are the expression of inco-ordinate activity. Their function of propelling blood to the ventricles is lost ; they no longer serve as reservoirs while the ventricle is contracted; the blood stagnates perpetually in them, the forma- tion of muscle clots is promoted ; heart murmurs become The Method of Elect rocardiograpliy Exemplified 47 altered; such activity as the auricle possesses is expressed in a malignant fashion, it lashes the ventricle to a quick and dis- ordered movement, exposing any weakness of the ventricular muscle, if such exists, for the muscle cries out against the in- creased strain. The arterial blood pressure sinks, venous pres- sure rises ; the onset of this condition is the most important contributory cause of cardiac failure of which we have real Fig. 35. A clinical curve from a case of mitral stenosis and muscle fail- ure, illustrating fibrillation of the auricles. Fig. 36. Venous, arterial and electrocardiographic curves from a dog in which the auricles had been forced to fibrillate by faradisation. knowledge. It was the electrocardiograph which first bore clear witness of its occurrence in the human subject. I show you two curves, clinical and experimental exainples for com- parison (Figs. 35 and 36). You will notice the irregularity of the ventricle in each, the absence of true auricular summits P, their replacement by the oscillations which characterise the condition. These oscillations are proved to arise in the auricle ; 48 Chapter II they represent the sum total of its delirious activity. The curves of fibrillation are of varied form, both in experiment and in human disease. Further examples are shown in Figs. 37 and 38. In Fig. 36 the auricular delirium was produced by faradisation of the auricles; Fig. 37 is a clinical curve; that of Fig. 38 resulted from the introduction of a poison into the Fig. 37. Spontaneous fibrillation in the human subject in "ft case erf "rheu- matic heart disease. -2T Fig. 38. Fibrillation of the auricles produced experimentally by the in- jection of glyoxyllic acid. blood stream of an animal. We are still far from a full knowl- edge of the pathology in the human subject, but the first and important steps of isolating and recognising its true meaning have been taken finally. What its isolation means to us may be grasped when its prognostic significance is appreciated, and when its almost specific reaction to drugs of the digitalis group is realised. It is from the reaction of the heart, affected in this fashion, that digitalis owes its wide reputation; it is in these cases that it grips the heart and gives the slowing of pulse rate which relieves an exhausted muscle. You will find clear instances of this affection described in Da Costa's historic treatise upon the irritable heart of soldiers ; it has since passed on numerous occasions as an instance of heart The Method of Electrocardiograph^ Exemplified 49 strain. You will see patients in whom, occurring as a tem- porary disorder, it promotes acute dilatation of the heart, and YOU will hear the term " dilatation " applied as the diagnosis in the case. It is but recently that we have appreciated that the fibrillation is the cause of the disturbance, and that the irregu- larity is not the sequel of distention of the heart. You will meet cases in which as a fleeting and recurring disorder it Fig. 39. Auricular nutter occurring in a clinical case. Fig. 40. The end of a period of flutter, produced in a dog by the injec- tion of glyoxyllic acid into the blood stream. promotes constant palpitation or even temporary loss of con- sciousness. You will meet it daily in your work as an asso- ciate and chief promoter of chronic heart failure. You will recognise it clinically because of this frequent association, be- cause it is the only common irregularity which consorts with rapid heart action, because the ventricular beating is tumultu- ous and never constant from moment to moment. The ability to recognise it is a prime asset to-day in dealing with grave cardiac affections. Our most recent acquisition is " auricular flutter " (Figs. 39 and 40). In elderly subjects a persistent and considerable acceleration of the heart's action may be found, but unlike the acceleration of fibrillation, this acceleration is associated as a general rule with regular action. In many of these patients, 50 Chapter II galvanometric curves lay bare an unsuspected and astonishing fact. While the ventricle beats regularly at from 130 to 170, the auricular rate is precisely double. That the auricles may beat at rates of 300 or 350 per minute, and that such hyper- activity may be maintained for years, would have received no credence a few years since; it is now established. A clin- ical example of flutter, as it is termed, is to be seen in Fig. Fig. 41. Venous, arterial and electroeardiographic curves from a case of auricular flutter. The pulse beats regularly at 60, the jugular curve shows little or no sign of the auricular contractions. The electrocar- diogram demonstrates a regular auricular rate of 240 per minute. 39, where the respective rates of auricle and ventricle are 228 and 114. The ventricle beats in response to each second auric- ular contraction ; nutter 'generally exhibits this associated heart- block, the ventricles fail to respond to the highest auricular rate. It may be associated with higher grades of block, whereby the ventricular rate is reduced perhaps to normal limits and further concealed. The value of our laboratory method cannot be more clearly illustrated than by clinical cases of this type. On several occasions I have examined patients when the ventricle and pulse were beating regularly at perfectly normal rates, and in whom no suspicions of the auricular rate were awak- The Method of Electrocardiograph^/ Exemplified 51 ened until the heart was submitted to this electrocardiographic test. Fig. 41 is from a case of this kind; it discloses an un- suspected auricular rate of 240 per minute; the pulse rate is 60 per minute. Kow these cases of auricular nutter, where there is extreme though regular acceleration of auricle, are not so infrequent as we at first supposed; the affection is a serious one, for even though the ventricular rate is but half the auric- ular, it is usually very fast and taxes an unhealthy or aged heart to the utmost ; moreover, there is a constant risk in many such cases that the ventricle may respond to the faster rate and that an intolerable burden may thus be imposed upon it. It is a fortunate thing that we have a sure remedy for such patients; flutter has affinities with fibrillation, for digitalis will slow the ventricle and maintain its rate within bounds in flutter as in fibrillation ; the drugs acts by increasing the pre-existing heart- block. I have seen no patient in whom this reaction could not be obtained, and in many, so I find, the reaction may be carried a step farther. If digitalis is pushed and is tolerated, the auricles pass from flutter to the higher grade of disorder, fibrillation. You might think the effect undesirable, in re- ality that is not the case. Flutter is essentially a persist- ent condition and untreated may be maintained during the rest of the patient's life. Change the mechanism by the ex- hibition of digitalis and the production of fibrillation, and, having accomplished this end, relax the drug ; the heart returns, not to flutter, but to the normal rhythm. I well remember the first case in which this reaction was clearly demonstrated. It was in a French polisher admitted to hospital with a ventricular rate of 160 ; the auricles were beating at 320 per minute (Fig. 42a). Upon digitalis the pulse fell rapidly to 80, the auricular rate persisting as before (Fig. 42&). An increase of the dose now caused the onset of fibrillation (Fig. 42c), when the drug was withdrawn the normal rhythm was restored within a short time (Fig. 42d). The man was admitted with all the classical 52 Chapter II P ' P P P - rrnr'tt*^ tHiiHiHHilliilittt^ itiiiniini.tiiuiiitn?iniiiitttttniinritinnirtitttninitiitMititiutMti-rTnninmrtnrTnn.tnHHtrnnt Fig. 42. a, 6, c and c?. Four curves from a patient who exhibited auricu- lar nutter, (a) Before treatment; the auricular rate is 320, the ventricular 160 per minute. (&) While upon digitalis; the auricular rate is still 320; the ventricle beats at 80 per minute, (c) After pushing digitalis, the auricles fibrillate; eventually, after relaxing the drug the normal rhythm is restored (d) . signs of cardiac failure, he returned to work. Some few months later the flutter returned, but being treated once more in the same fashion, it was again abolished. That is three years since and our patient is still in comfortable health and fully engaged in his trade. CHAPTER III SECOND HERTER LECTURE THE KELATIOJST OF AURICULAR SYSTOLE TO HEART SOUNDS AND MURMURS Gentlemen, The subject with which I propose to deal to-day as my second illustration of the application of laboratory method to the clin- ical case is that of the graphic registration of heart sounds. And this subject has been selected from two points of view. Eirst of all, because phonograms provide us with pictorial representations of auscultatory signs and have no inconsid- erable value in this respect for teaching purposes. A few selected phonograms accompanied by accurate descriptions bring home to the student the nature of the signs which he ob- serves, and impress the simpler lessons of acoustics in a facile and clear cut fashion. The sounds conveyed from chest by stethoscope to ear set in motion the tympanic membrane; they cause the recording instrument to vibrate in a similar fashion. There is however an important distinction between the impres- sion gained from the writing on paper as we see it and those which come to us through the more direct channels of the auditory nerves. To those who are accustomed to inscribe these records and also to listen to the beating heart, having experi- ence of its sounds, nothing is more impressive than the ability of the brain to discriminate; attention is concentrated for the moment upon sounds of one kind, perception of interfering sounds is meanwhile largely or wholly in abeyance. A delicate phonograph records all sound vibrations transmitted to it, be they of cardiac, respiratory or extrinsic origin; a short and 53 54 Chapter HI combined experience of recorder and stethoscope soon gives prominence to a fact which to a student, as he becomes clinician, rapidly recedes to the background ; the living chest is filled with a babel of tongues, the sympathetic ear heeds one voice. So it happens, when we scan our first acoustic records, that their com- plexity bewilders us, and to analyse them we confine ourselves at first to the more simple documents, and especially to those which represent in a relatively pure form the sounds which we propose to study. But the lesson is not lost; our admiration for the delicacy of the auditory mechanism is a thousandfold enhanced, and we learn that in the discrimination of pitch, tone and intensity, the physiological ear has no rival. These remarks bring me to the statement of my second object. It is to show that although the ear has this unquestioned superiority, and that although the auscultatory signs of heart disease have been minutely studied by its means and by countless workers, we have yet much to learn and much which can be learned only by the employment of mechanical aids. The chief value of the recorded heart sound is the possibility of accurately timing its occurrence in relation to the events of the cardiac cycle. It is not my purpose to consider the history of sound records, neither shall I attempt to cover a hundredth part of the whole field of fact and speculation surrounding heart sounds and mur- murs ; but I shall be content to describe in simple terms a single device, and to pass to brief descriptions of some recent observa- tions which seem to show how important the influence of the auricular pressure upon sounds and murmurs may be. In the first figure (Fig. 43) a tuning fork is represented as emitting sound; with each movement of the fork towards the right, the air in this direction becomes compressed; the tension is relieved in every direction, amongst others towards the re- cording instrument ; it travels through the atmosphere, fading as it travels, as does a ripple on the surface of water; as the fork returns from its swing, the same neighbouring air becomes 55 Relation of Auricular Systole to Heart Sounds rarefied and this rarefaction follows the wake of the condensa- tion and is transmitted through space. At a given moment, therefore, the air surrounding the fork is arranged in alternate layers of condensation (Co) and rarefaction (Ra) ; each and all Fig. 43. A diagram of a vibrating tuning fork, the sound oscillations from which are recorded by a microphone (M). The microphone con- sists of carbon plate (PI. ) and point (Pi.) and these are in circuit with a battery (B) and the primary coil of an inductoriinn. The sec- ondary coil is directly connected to the string galvanometer. are travelling along radiating lines. Our recorder contains a thin carbon plate (PI), which being sensitive to movement, oscillates ,in synchronism with the condensations and rarefac- tions as they arrive; it is the oscillation of this plate which yields the record, as it is the similar oscillations of the tympanic membrane which convey the auditory impression of sound; for the alternate layers in the air form the sound vibrations. The movements of the plate are traced by allowing it to rest against, a carbon point (Pi) and by recording the changes in resistance which occur between the two carbon surfaces as the pressures between them vary. For this purpose a constant cur- rent is transmitted from carbon to carbon and in the same cir- 56 Chapter 111 cuit a primary coil is placed. The resistance between carbon and carbon varies as succeeding phases of the sound vibrations- reach it, and so the current flowing through the circuit varies; the changes in the current are magnified by the secondary coil and pass into the sensitive string galvanometer. So each move- ment of the fork is accompanied by a movement of the string and our record is in reality a record of the fork's oscillations. Similarly in taking tracings from the chest wall, the sounds are records of the valve vibrations transmitted through the chest wall and stethoscope to the carbon plates, which form the mi- crophone, and thence to the galvanometer. Fig. 44 is a record of the movements of a tuning fork, or if you will the sound it yields, beating regularly at 50 per second. You see that the vibrations are regularly placed, and it is to this regular arrangement that the sound emitted owes its musi- cal quality. As you know, the pitch is regulated by the fre- quence. Comparable records are to be obtained from vibrating strings and from time to time the sharp edge of a broken valve. The loud and musical murmurs which are not infrequent after rupture of the aortic valves are produced in this manner; ex- amples are seen in Figs. 45 and 46. Accurate timing of sounds is best accomplished by the sim- ultaneous record of sound and electrocardiogram. The records in the accompanying figure were taken for the most part with separate galvanometers placed side by side ; in all instances the records are so arranged that points of the two curves lying on the same vertical line represent the same time instant. The onsets of first and second sounds and their relation to systole in auricle or ventricle may be estimated by a comparison of the curves, allowing a short interval in the electrocardiogram for the appearance of the excitation wave before the contraction wave. But so far as the ventricle is concerned, the most exact method in a given case is to take the onset of the recorded first and second sounds, where they are unquestionable, as the Relation of Auricular Systole to Heart Sounds 57 Fig. 44. A tuning fork record. Fig. 45. Musical to and fro murmur at the aortic cartilage. Fig. 46. A diastolic murmur of aortic origin and musical quality. Fig. 47. Record of normal apical heart sounds. 58 Chapter 111 indices of onset and offset of systole. It may be necessary when the record is complicated by murmurs to take a control record from the same case, with the object of obtaining the 1st and 2nd sound in a more uncomplicated form from a neighbouring point upon the chest wall, and then by comparing the two plates, the necessary data are obtained. The relation of the onset of the 1st and 2nd sounds to the electrocardiographic deflections is subject to some variation. The 1st sound begins from .002 to .026 seconds after the -com- mencement of R, or from .011 to .039 seconds after the com- mencement of Q, when this deflection is present. The 2nd sound may start .035 seconds before, or as late as .028 seconds after the end of T; as a rule it begins within a very short dis- tance of the end of T. As a general standard we may use R and take a point l-50th of a second after this upstroke ; it will represent the onset of systole with no greater error than 1-5 Oth of a second. Similarly, we may take the end of T as repre- senting the offset of systole and the error will be no greater than l-30th of a second. Generally speaking the natural heart sounds are complex; the oscillations are irregular in time and amplitude, vary- ing much from subject to subject. A relatively simple record from a normal heart is seen in Fig. 47 ; you will notice that the 1st sound begins as a crescendo, rapidly reaches its maximum and tails away as a diminuendo. The 2nd sound, as is usual, is abrupt in its onset, consisting as a whole of a simple diminu- endo. In the instance of the musical murmurs which I have shown you, the number of vibrations was 138 to 180 per second. The number for the natural 1st sound is much less, being 45 to 70 per second, and for the 2nd sound, 40 to 86 per second. This speaks for the valvular origin of both sounds in the main, for the frequence depends upon the length and mass of the vibrating structure and upon its state of tension. Incidentally we may compare these sound records with records of the spoken Relation of Auricular Systole to Heart Sounds 59 syllables lub-dup (Fig. 48) ; and a comparison of this kind at once demonstrates how imperfect is this phonetic representa- tion. Both lub and dup are in reality each built np by at least Fig. 48. Two records of the spoken syllables " lub-dui>." three distinct vocal acts, though in rapid speaking there is some slurring. We pass to our main topic, the influence of the auricles upon heart sounds. That auricular contractions may -ive rise to audible sounds has been suspected for a long while, that such is indeed the case was shown after dissociation of the contrac- tions in auricle and ventricle was discovered. It is now well known that in cases where the ventricle is beating slowly in response to its own inherent rhythm and where the auricular rate is still normal and therefore much faster than the ven- tricular, the long diastoles of the ventricle may not be silent; but that faint thuds may be heard at apex, epigastrium or heart base, which can only be attributed to contractions of the auricles. This explanation is clearly justified by such curves as that of Fig. 49 ; here the auricles are contracting at three times the rate of the ventricles as the simultaneous electrocardiogram demonstrates. In every diastole the auricles beat twice and on each occasion produce a faint and double sound. The first ele- ment of this double sound does not begin immediately with 60 Chapter III auricular systole, but when the latter is well advanced; its cause is not clear; that it is not due to the passage of blood to ventricle seems evident, for a similar sound oc- " curs during the o ~ end of ventricular systole where a, another auricular - contraction 'falls. Possibly it is due 3 to the actual con- | traction of the " muscle of the auri- cle and to tension -g in its walls. The second element is C/3 ~ I think attribut- ct 1 able to the cessa- s tion of flow from ^ auricle to ventricle ^ and to consequent 5; closure of the au- <; riculo - ventricular valves, as Hender- 3 son has suggested ; E for this second ele- ment falls in early auricular diastole. When a stream of water is poured through an auric- Relation of Auricular Systole to Heart Sounds r,i ulo-ventricular orifice, and this jet is abruptly broken, the valves immediately close. The sound is more intense when the auricular systole falls in early rather than in late ventricular diastole, and this is to be expected, for at such a time the ventri- cle is full and any opening of the valves must be followed by a quick return to the closed position. In heart-block, as a rule, the auricular contraction is followed by a single sound, and it is probably brought about in the manner to which reference has just been made. But if the auricular sound is audible in heart-block, why is it not in the normal heart beat ? I suggest because the auricular and ventricular systoles are too near together. Normally the end of auricular systole is terminated sharply by ventricular systole. There is no inter- systolic period. The 'swing of the A-V valves which is to be expected at the cessation of auricular contraction would coin- cide with closure and tension of these valves as a result of ven- tricular systole. Assuming this view to be correct, then if for any reason the closure of the A-V valves as a result of ventric- ular systole were delayed, we should expect double closure of the valves; the first resulting from the wake of the aurimhir systolic blood; and after a short pause a second closure result- ing from ventricular systole. It is actually the experience that when the As-Vs interval is prolonged, a double sound is often audible, for it is in these cases a fortiori that gallop rhythm appears. It is also frequently present in those curious cases in which the excitation wave appears to take an abnormal course through the ventricular walls. Gallop or canter rhythm is of two kinds ; in the commonest type the additional sound happens immediately before the natural 1st heart sound; in the second type, the additional sound lies in early or mid-diastole. A beautiful example of the first variety is seen in Fig. 50. That . the first element of the canter lies in presystole is quite clear in this record; it is equally clear that it lies toward the termina- tion of auricular svstole, the As-Vs interval being a little pro- 62 Chapter III longed. If we examine this curve in detail and focus our at- tention upon the composite sound, what strikes us most is the similarity of its two elements. The likeness is so perfect as to convince us that both elements have a common origin ; the 2nd Fig. 50. Canter rhythm at the apex beat; from a patient who presented evidence of a right bundle branch defect. element must be attributed to ventricular systole. The 1st cannot be so explained, for it begins outside the bounds of sys- tole; but both elements may be assigned to closure of the A-V valves, the first produced by the termination of auricular, the second by the onset of ventricular, systole, in the manner al- ready indicated. It is also to be remarked that in no instance as yet has a reduplication of this kind been seen where the auricles are in the state of inactivity associated with fibrilla- tion; it has always been associated with a natural sequence of contractions, but as a rule with a sequence somewhat delayed by the interposition of an intersystolic interval. Examples in which there is no delay in sequence are to be seen in Figs. 51 and 52. In these the additional sound falls with the begin- ning or height of auricular contraction and is perhaps com- - Relation of Auricular Systole to Heart Sounds 63 / 3EE / Fig. 51 Fig. 52. parable to the 1st auricular element of Fig. 49. It may be that in such cases we have to deal with hypertrophy of the auricle. In Fig. 53 the extra sound is in mid-diastole and here the height of auricular contraction falls immediately after and upon the end of the preceding ventricular systole ; in all 64 Chapter 111 probability, the sound has been produced, or at the least has been enhanced, by the auricular contraction. ,~L Fig. 53. Fig. 51, 52, and 53. Examples of canter rhythm; the extra sound accom- panying auricular contraction. 790 Fig. 54. Canter rhythm; the extra sound falling in early diastole. What appears to be wide reduplication of the second sound is seen in Fig. 54 ; here diastole is long and there is no ques- Relation of Auricular Systole to Heart Sounds 65 tion of auricular systole taking part, for the sound is far re- moved from it. Similar apparent reduplications are seen in Figs. 55 and 56, in both of which the auricles are fibrillating. '/ZQ Fig. 55 and 56. 'Canter rhythms in cases of auricular fibrillation; the extra sound being related to early diastolic events. This type of canter rhythm is very evidently of different origin to the first. It is not to be ascribed to asynchronous closure of the semilunar valves, for in all the figured instances the sounds 66 Chapter III were of maximal intensity near the apex or the canter was- confined to this region; and also because the elements stand too far apart from each other. In simple reduplication which may be ascribed to asynchronous semilunar closure, the two ele- ments are fused and are scarcely distinguishable in records. The 3rd sound (the 2nd element of the reduplication) is du& to some event occurring a little while after the A-V valves open in early diastole; it may be that these valves are set in vibra- tion by quick filling of the ventricle and their consequent clos- ure, in given cases, as Thayer and Hirschfelder have sug- gested in describing the third sound of the normal heart beat. Many of the instances which I show you are almost certainly exaggerations of this extra sound which may be heard in healthy subjects. I leave the question of canter rhythm, fully aware that the description is incomplete, but content if I have satisfied you that, in some instances at all events, auricular contraction may be responsible for it and that we have still much to learn by careful study and the use of the graphic method. Some little while since a curious change in the heart sounds was described by Dr. Griffith of Manchester in cases of com- plete heart-block. It transpires not only that the auricular sounds are audible in this disorder of the heart beat, but that the incidence of auricular contractions profoundly affects the quality and amplitude of the ventricular sounds. The variation is such that it forms a most valuable bedside test of complete heart-block when instrumental aids are not avail- able. As Griffith described it, it consists of a great increase in the loudness of the 1st heart sound when an auricular contrac- tion falls synchronously with the beginning of ventricular systole. The phenomenon is clearly to be seen in Fig. 57 and you will notice that the intensification comes when the auricular contraction slightly precedes the ventricular; if the relation- ship is reversed, as in the first cycle of this figure, the 1st sound Relation of Auricular Systole to Heart Sounds 67 tends to reduplicate. A gradual change of intensity as the auricular systole gradually moves over the commencement of ventricular systole is seen in Fig. 58. All these 1st sounds are greatly accentuated but that of the first cycle especially so. The figure should be compared with Fig. 49 which is from the same case and taken at the same sitting. The complete physical sign, as you may hear it in almost any case of total dissocia- ' T 4=5 Fig. 57. From a case of complete heart-block; showing the accentuation of the 1st sound when the auricular sj-stole overlaps the ventricular. tion, when the pulse is regular, consists of an accentuated 1st heart sound occurring in a periodic fashion and associated also with periodic reduplication of both 1st and 2nd sounds. Such variation of the sounds is very striking ; it occurs so far as I am aware in no other condition, being distinctive of A-V dissocia- tion. Mitral stenosis. For the remaining time I propose to discuss the murmurs of mitral stenosis and their relation to events in the auricle. Let us consider in the first instance the characteristic murmur of mitral stenosis which accompanies a regular heart action. 68 Chapter HI * II I s-s CS CJD .M fe g * &0 = OB s-s 2 - Relation of Auricular Systole to Heart Sounds 69 Fig. 59, 60, and 61. Examples of apical murmurs in three cases of mitral stenosis. 70 Chapter III Called presystolic by almost universal custom, it is generally believed to be presystolic in time ; yet as you are aware its actual position in the cardiac cycle has been hotly contested on many occasions. Ormerod, Barclay, Dickinson, and lastly Brockbank have held it to be in reality systolic. The final proof of its presystolic position has been supplied by graphic records. Even when it has a duration of no more than l-20th or l-30th of a second, it comes before the beginning of the 1st sound. Gairdner called it the auriculo-systolic murmur, and his suggestion that it results from auricular systole is almost certainly correct in the main; though this statement requires some amplification. In most cases of considerable stenosis where the heart's action is regular, for example in such cases as come to us in an out-patient department, the murmur usually occupies the whole diastole. This filling of diastole is due to the fact that there is generally some acceleration .of the heart and the diastole is therefore short. Many murmurs commonly called presystolic in reality occupy the whole of diastole as graphic records show quite clearly (Fig. 59). They lie in pre- systole, it is true, but also in mid- and early diastole. The term presystolic murmur properly speaking should be confined to a murmur isolated in presystole. On listening to heart sounds at the apex beat, we are too apt to time murmurs relative to the 1st sound and to neglect the relation to the 2nd heart sound. I think too that a murmur is often called presystolic, not be-" cause it is so timed, but because it has the rasping and rumbling qualities which are usually borne by such murmurs. Timing by auscultation is often a difficult or impossible task if it is to be carried out with any pretension to accuracy. At all events the fact remains that isolated presystolic murmurs are com- paratively rare ; they occur when the heart rate is slow or when the stenosis is not extreme; an example is to be seen in Fig. 62. Two murmurs of the same quality may be present, the one in early and the other in late diastole ; this condition is seen when Relation of Auricular Systole to Heart Sounds 71 the heart rate is slow and the stenosis considerable. Thus the murmurs which accompany mitral stenosis in different patients are very variable in their time relations ; they also vary greatly from cycle to cycle in the same patient and vary both in time .and quality. The meaning of such variations will be discov- ered in the sequel. The murmurs of mitral stenosis have the lowest vibration frequence of any. The frequence, as a rule, is the same, it may be a little faster, as the vibration frequence of the 1st sound in the same case. The similarity of frequence speaks for the origin of the murmur in vibration of the mitral valve. If we consider the simplest type of murmur, that which falls in presystole, we observe that it is related to auricular systole ; the murmur commences near the height of auricular contraction (Fig. 62) or starting earlier is reinforced at this time (Fig. GO, 3rd cycle, and Fig. 61). Such at any rate are the common events. JSTo one will doubt I think that the murmurs of mitral stenosis are produced by the passage of blood from auricle to ventricle through a constricted orifice. The relations of the simpler murmurs suggest that the propulsion of blood by auric- ular contraction is an important factor in their production. In some cases it is an all important factor and in these we may correctly call the murmur, as Gairdner did, auriculo-systolic. Figs. 62 and 63 were taken from a single case at a few days interval. In the first curve the murmur begins at the height -of auricular systole, and lies wholly in presystole. This curve was taken from a case susceptible to the influence of digitalis .and by administering this drug it was possible to alter the rela- tion of auricular and ventricular systole. The influence of auricular systole upon the murmurs could be studied therefore in an exact manner. After the administration of digitalis the auricular systole lay, not in presystole, but in late ventricular systole and early diastole (Fig. 63). As an association the murmur altered its position, leaving presystole and appearing 72 Chapter 111 T 'k/Ul/ytfc ffmpij Fig. 62 and 63. Two records from the apex beat in a case of mitral steno- sis, before and after the onset of partial heart-block. Relation of Auricular Systole to Heart Sounds 73 in early diastole ; as a matter of fact not in earliest diastole, but at a point in the cycle a little after the opening of the A-V valves.* The influence of auricular systole upon the murmur in this case can hardly be questioned. The appearance of a gap between murmur and 1st sound when the As-Vs interval is prolonged was first reported by Galabin ; it has been empha- sised from sounder data by Mackenzie in recent years. I would remind you too that Dr. Cohn of Xew York has reported an instance of mitral stenosis in which 2:1 heart-block devel- oped as a result of digitalis administration and that when the block appeared and the auricle was beating at twice the ven- tricular rate, two similar murmurs were audible in each dias- tole, one in mid- and the other in late diastole. I have wit- nessed the same phenomenon on several occasions and have felt the double thrill at the apex in diastole. The importance of the auricular systole in influencing these murmurs is therefore beyond doubt. Some years ago an extremely important observation was made by Mackenzie ; if you examine the earlier papers of Galabin and Fagge, you will find it foreshadowed; for these authors noted the disappearance of the murmur of mitral stenosis when the heart becomes irregular,, or its isolation in early diastole when the auricular contraction could no longer be recorded. But it is to Mackenzie's exact work that we really owe our chief knowl- edge of the behaviour of murmurs when the heart beat becomes disordered. He has spoken in the most decided manner upon, the subject, and has stated that when irregularity of the ven- tricle^ which we now know to be attributable to fibrillation of the auricle, becomes established in a case of mitral stenosis, the presystolic murmur vanishes, and its disappearance he attrib- uted to inactivity of the auricles during diastole. That Mack- * In using the word " opening " one refers, in a case of mitral stenosis, to the time of the first entry of blood from auricle to ventricle. f Ascribed by Mackenzie to " Nodal rhythm.'' 74 Chapter III enzie's statement is in the main a correct one, graphic records proclaim. I may briefly describe the events as they are known to us. The murmurs of mitral stenosis, when the auricles are fibrillating, are peculiar ; an isolated presystolic murmur is not heard; the whole diastole may be filled by murmur (Fig. 64), Fig. 64 and 65. Two apical records from a single case of mitral stenosis and auricular fibrillation, before and after treatment with digitalis. and this occurs when the heart's rate is rapid and the stenosis is great, or if the rate is slower the murmur is confined to early diastole. The commonest condition is one in which short and long diastoles are mixed; and in which the former are filled by murmurs, while in the longer ones the murmur tails away and vanishes in mid- or late diastole (Figs. 65 and 66). Relation of Auricular Systole to Heart Sounds 75 The important point to notice is that the fixed relation is to the 2nd and not to the 1st heart sound. When a case of mitral stenosis with fibrillation is first examined, the murmur generally completely fills the whole diastole (Figs. 64 and 67), or only their pillows. ^The respiratory excursion is irregular in amplitude and in rhythm ; reserve is reduced, so that the breath can be held but for a few seconds ; forced breathing is followed not by apnosa as in the normal subject but by a resumption of the previous type of breathing or even by increased ventilation. Great distress is rarely witnessed in these relatively simple cases. A special symptom complex. The facts which I have just related will be familiar to you. This simple cardiac dyspnoea, in which the blood circulating through the brain is overladen with CO 2 is not difficult to recog- nise in frank cases. Neither is the second type, to which I Chapter IV now pass, once you are acquainted with the clinical picture. 1 take first of all the most sim- ple examples. There are patients, usually elderly, who are admitted to our wards and suffer from urgent dyspnoea. The breathing is laboured; it is periodic and of the Cheyne-Stokes type (Fig. 70). The patients are not orthopnceic, they exhibit few signs of venous or liver engorgement, pressure upon the abdomen does not materi- ally increase the depth or rate of respiration (Fig. 71). The uncomplicated cases are not cyanosed. The blood is \ fully aerated and has a low l|f tension of CO 2 . There is little or no reserve. The ad- ministration of oxygen af- fords practically no relief. A conspicuous feature is the presence of nocturnal attacks of breathlessness, and these wake the patients repeatedly from slumber, are often suf- focative and last from a few minutes to half an hour or more. The heart is a little dilated; the pulse rate is al- most always increased (80- 100) and especially towards Observations Upon Dyspnoea 87 evening. The temperature is generally subnormal. The blood after removal of its CO 2 shows a considerable decrease of alka- linity, which is due to the excessive presence of non-volatile acids or acid salts. Fig. 71. A curve of respiration in a patient suffering from slight non- volatile acidosis. Pressure upon the abdomen does not increase the respirations in rate or depth. These are the almost constant clinical manifestations, but the picture is varied in a hundred ways. Add to it the symp- toms and signs of heart disease in its various forms ; add to it the symptoms and signs of renal disease and its complications, add emphysema, or cerebral arterial disease, and you are able to reconstruct the protean types in which this curious acidosis is displayed. It may be that you will declare the special symptom complex which I describe to you as ursemic, that may or may not be justified; I have deliberately avoided this term on account of its laxity. There is of course no question but that many of the cases which I have in mind are commonly termed ursemic; for the urine is of low specific gravity and contains albumen and granular casts; the blood pressure is often high; and other so-called " ursemic manifestations " frequently appear. Severe headache, twitching of the limbs, vomiting, temporary hemiplegia, convulsive seizures or aphasia may appear. Thirst and anorexia are common ; wasting and a little anaemia are fre- quent ; inflammatory affections of lung and pleura are frequent terminal complications. But what I wish to impress is that none of these last named symptoms is essential to the complex, any more than are those cardiac symptoms which I shall pres- 88 Chapter IV ently describe essential. Ursemic dyspnoea is a term which we should carefully avoid, for it presupposes that the breathless- ness is primarily of renal origin ; of this we are not certain at the present time. The malady and its varieties can only be appreciated fully if the essential features are isolated or con- stantly maintained in relief. They are those I have already enumerated, and which I now repeat, namely, dyspnoea in the absence of cyanosis or an equivalent cyanosis, accompanied by periodicity of respiration and by nocturnal seizures ; some dila- tation of the heart, rapid pulse action and a subnormal temper- i ature. Lastly, there are the characters of the alveolar air, the I * high oxygen and lovjj CO 2 content, and the signs of a non-vola- tile acid in the blood. The remaining signs and symptoms are not essential features,, but one or other, or several,, are almost always present. The un- ^ complicated case is rare. It is to this fact that the protean character of the malady is due ; it is to this fact that the symptom complex has remained hidden in the past, for it is usually obscured in greater or lesser degree. Nothing tends to hide it more than the presence of cardiac failure, and this is an extremely frequent complication. The heart may be affected in a variety of ways. Any valve lesion may be present, aortic dilatation or actual aneurysm are not uncommon. You may find all varieties of altered heart mechanism ; fibrillation of the auricles and pulsus alternans are especially frequent. Anginal pains may be present. Engorgement of the veins and liver, with or without ascites and dropsy, are the rule rather than the exception in advanced cases. These superadded phenomena mask an otherwise obvious con- dition ; engorgement of the venous system especially embarrasses the diagnosis, for it veils or hides the all important discrepancy between the breathlessness and the oxygenation of the blood. Many of these unfortunate people suffer not only from a fixed acidosis but in addition from the simple form of cardiac dyspnoea, due to lack of blood aeration. Generally speak- Observations Upon Dyspnoea 89 ing, the whole trouble of breathing is referred to the last named cause; for where the pulmonary circulation is evidently defec- tive, where in the presence of slight or moderate cyanosis, signs of aneurysm, of emphysema, or of venous engorgement, are found, the temptation to ascribe the whole breathlessness to a purely mechanical cause is too often irresistible. That the mechanical cause is not the sole cause, that often it is not even the chief cause, has been clearly shown by the blood tests. We become more and more convinced as these tests increase in number that there are very few inmates of our hospitals who suffer from really urgent and constant breathlessness, in whom a mechanical hypothesis is sufficient to explain the symptoms. You are familiar with those distressing cases, patients of mid- dle or advanced years, who in a semi-conscious state, sit in chairs in our wards, and while cyanosed and dropsical, struggle for breath during the rest of their existences. It may be that mitral stenosis, it may be that aortic disease or aneurysm are present. It may be that bronchitis and emphysema are diag- nosed. In each and all in our experience a non-volatile acidosis is a chief trouble. The more we see of the blood reactions, the more mechanical dyspnoea recedes to the background. The secret of the clinical diagnosis lies in a nice discrimination between the degree of breathlessness and the degree of cyanosis, in^a menial Comparison between these patients and those cases ol'TnTtral stenosis or^congenital heart disease in wiiicnthere is an obvTous^fackj^f blood Deration. Our tests show quite clearly that if a very breathless patient has but slight or moderate cyanosis, whether or no such patient is afflicted with emphysema, myocardial or valvular heart dis- ease, aneurysm of the aortic arch or what not, the breathlessness cannot be ascribed wholly to a mechanical cause. In the light of laboratory observation the old faiths fall away fast. Stronger and stronger becomes the conviction that death from actual but gradual asphyxia in an uncomplicated form is a rare event in 90 Chapter IV our patients, and that by far the commonest form of 'urgent breathlessness is the acidosis which I am describing to you. Go into the wards of a general hospital ; you will rarely fail to see a number of sufferers sitting in bed and in urgent need of breath ; three-fourths at least of such cases are examples of the condition now considered. Their diseases are partially described by a variety of diag- nosis; angina pectoris, aortic disease, aneurysm, mitral regur- gitation, mitral stenosis, arterial disease, chronic bronchitis, ursemia, cardiac asthma, coronary arterial disease, hydrothorax or pleurisy. In each and all of these conditions, acidosis may be found as an association, when the laboratory tests are un- dertaken. Where the breathlessness is due to non-volatile acids only, then the respiratory embarrassment is proportioned to the degree of acidity. When such patients improve the acidity is found to decline; as they lose their breathlessness, the blood reaction becomes normal. The chemical test is a sensitive lab- oratory indication of the patients' respiratory exchange. Where heart failure is added, then the breathlessness is gov- erned by two factors, first by the quantity of non-volatile acid present, and secondly by the degree of deficiency in aeration. The two combine to a common end, the creation of hyperpnoea. The most urgent dyspnoeas belong to this group. It is also to be noticed that the presence of a slight grade of relative acidity, although it may not in itself give rise to promi- nent dyspnoea, limits the reserve, so that any influence, such as exercise, holding the breath, etc., which is followed by increased ventilation in normal subjects, acts in these subjects with exag- gerated effect. The field of respiratory response is strictly limited and its bounds are easily crossed by these people. Other conditions in which non-volatile acidosis has been found. I have sketched for you the type of case where you may most Observations Upon Dyspnoea 91 readily and surely find the acidosis in question. There are other conditions in which it is known to exist. The simplest example is physiological, the dyspnoea of violent and prolonged exercise is due to such a cause ; here too there is no cyanosis and the acid responsible has proved to be lacticacid, formed in the contracting muscles. In the increased ventilation of the lungs of diabetes, the alveolar air contains more oxygen and less CO 2 than normal. The hyperpncea is not due to lack of oxygenation but to decreased blood alkalinity, owing to the presence of oxybutyric and diacetic acids. On account of this relative acidity the respiratory centre is stimulated, ventilation is increased, the CO 2 in the blood is decreased, oxygen is increased. In this manner, a partial compensation is established. But reserve is diminished. A similar condition is discovered in normal subjects at high altitudes, though the nature of the acid has not been identified as yet. In two of the patients in our own series, lactic acid was found in excess in the blood by Dr. Ryffel, but both these patients w r ere at the time moribund and we cannot regard it as the invariable or even the common male- factor ; the usual acid is again unknown., Recently we have extended our search amongst clinical cases and have found a similar acidosis in a number of conditions in which it was formerly unsuspected. These observations have not been published, but I have Mr. Barcroft's permission to speak of them. It is present in acute lobar pneumonia and is largely responsible for the dyspnoea which accompanies this con- solidation of the lung tissue. The acidosis may be of high grade, in which case the patients in our experience do not recover. Where it is originally of slighter grade, it persists over the crisis to vanish hand in hand with the breathlessness as the patient becomes convalescent. In view of these facts, we are no longer justified in attributing the whole breathlessness of pneumonia to the lung damage ; a statement which is supported by the fact that pneumococcal lesions in other parts of the body may also Ckapter IT be associated with breathlessness. We have recently found a acidosis in a case of exophthalmic goitre, where with taoe symptoms, such as vomiting and mania, breathless- fas distressing. Xot so long ago a patient was admitted to having developed an acute pneumothorax, a secondary result of chronic but almost quiescent tuberculosis. He showed dyspnoea which varied in its intensity ; the blood reaction pre- ariationsw being more on the acid side while the ; great, and more on the alkaline side while the dysp- noea was slight or ?^p^ This instance is of special interest, for with unquestionable signs of collapse in one lung, and in the absence of eheniieal tests, we should have had no hesitation in ascribing the respiratory disturbance to a mechanical cause. Yet die chief cause was not mechanical but toxic. Of cases of mitral stenosis in early years, we have examined a number : in all but one of these patients acidosis was absent. The solitary - -- :: :. M i :...:.. i priw-gnviaVi ! Ml harm Here acidosis was present in considerable degree and granular casts were discovered in the urine. Gentlemen, the observations are still at an early stage, but they are full of promise. There is in fact no branch of clinical 3y of which I know which offers greater opportunities for workers at the present time. There is a wide field for The requisite laboratory methods are at our disposal; we have but to apply them to our clinical material to reap a rich harvest of new facts. One conclusion should be emphasised. We are not justified at the present time in ascribing dyspnoea to a mechanical cause, to deficient aeration of the blood, except in the most simple forms of cardiac breathlessness, or where an evident obstruction to the respiratory passages is the only lesion in the patient. !N on-volatile acids, as opposed to CO*, appear to be an almost universal cause. There seems to me to be little doubt that aH forms of so called renal dyspnoea, many forms of ilj ujtnu , and many of the dyspnoeas which have in the Observations Upon Dyspmam past been ascribed to pressure by tumours, such as or to consolidation of the lung, collapse or emphysema of the same organ, are produced in reality mainly through the product* of altered metabolism. ;,- i At an earlier stage I described in some detail a symptssft complex in elderly subjects, where Cheyne-Stokes breathing and nocturnal breathlessness are prominent symptoms. The h* -J valescent the patient is sitting in bed, chatting or feeding may be. A nurse in charge or perhaps a neighbouring patient hears a cry or choking sound; the patient falls back on the pillows in- tensely pale, there are a few gasping respirations, a little convulsive move- ment, and the pulseless patient, rapidly becoming livid, is still. These are the symptoms which follow when fibrilla- tion develops in an experimental ani- mal; it is hardly to be doubted, consid- ering the circumstances, that the same event terminates the life of the patient. The fatal accident may happen in the untreated disease, or it may happen when any drug of the digitalis group (strophanthine, etc.) is given in excess; the same drugs given in poisonous doses to animals will induce ventricular fibril- lation. In the administration of digi- talis in cases of auricular fibrillation the period of danger is marked by the appearance of a bigeminal pulse (Fig. 76) ; upon analysis this bigeminy is found to result from extrasystoles of ventricular origin, beats which are fre- quent precursors of fibrillation in ex- periment. A few isolated instances of curves purporting to show fibrillation of the ventricles in the human subject have been published. In one of several curves recorded bv Robinson and Observations Upon Cardiac Syncope 113 Draper from moribund or dead patients, fibrillation is de- picted. Hoffman has recorded an instance of syncope in which the electrocardiograms are interpreted in the same fashion, but the analyses of these curves are open to question. The actual events in unexpected death are still in a measure uncertain; nevertheless the assumption of ventricular fibrillation is strongly supported.* Death from chloroform. Recently some remarkable observa- Fig. 77. Three electrocardiograms from a cat anaesthetised with a weak chloroform vapour. After a minute dose of adrenalin extrasystoles of ventricular origin appeared (a). These became more frequent until the heart responded entirely to new impulses of ventricular origin (6). In a short while fibrillation commenced (c). tions have been made by Levy. He has shown in a very conclu- sive manner that death during the administration of chloroform to cats is almost always due to the onset of this curious derange- ment of the heart beat and that it comes when the heart is rendered suspectible by small percentages of the vapour (Fig. 77). Levy goes further and makes out an extremely strong case for his view that the majority of chloroform fatalities in the * Dr. Halsey of New York has recently shown me a convincing example of death from fibrillation. 114 Chapter V > -J b 5 * * human subject are due to ventricular fibrilla- tion. As he points out and emphasises, most of these fatalities occur in the induction stages or at other periods of the administration w hen the saturation of the blood with chloroform is relatively low. The susceptibility of the cat's heart has recently been confirmed by Mac- William ; Levy has studied the question in such detail that, prac- tically speaking, he can produce the condition and its associated syn- cope at will. His work upon this subject is a landmark in the history of research upon death under chloroform. Death in other condi- tions. Fibrillation of the ventricles is almost certainly the terminal event in many cases of death from lightning (Jex-Blake). Patho- logical observation also teaches that it is in Observations Upon Cardiac Syncope 115 this manner that the circulation fails in embolism of a coronary artery. These experiments date from Cohnheim's researches. When a coronary artery, or often when a small branch of such a vessel is obstructed in an animal, there follows within a short space of time a series of remarkable disorders of the heart beat. First the regular rhythm is disturbed by a ventricular extrasystole, then by short runs of these beats occur- ring successively; a little later they may be so arranged as to constitute short or long paroxysms of tachycardia (Fig. 78) ; the final event is fibrillation of the ventricle and when this comes the animal dies. It is precisely the same train of events as is seen in chloroform poisoning; a gradual succession of ventricular disorders of ever increasing complexity. The relation of oblit- eration of a coronary vessel to fibrillation of the ventricles never- theless is not completely understood. It is probable that it fol- lows acute obstruction only, for it is not a rare thing to find the coronary artery almost or completely occluded by a long standing lesion in human hearts. The coronary vessels are not end-arter- ies, the anastomoses are clearly displayed by Spalteholz's method and blood is often to be found beyond a complete and old ob- struction. If you watch the muscle supplied by a coronary branch upon which a ligature is placed, you will notice that it first becomes livid and, as it loses its function, it balloons with each heart beat ; it is at this stage that irregularity of the heart is noticed, if it occurs at all; but often the livid area revives as the anastomosing vessels open up and the disorder of the heart beat vanishes. Obstruction to a small branch may or may not prove fatal in the animal ; that it may not prove fatal in man is evidenced by the appearance of fibrotic patches in the muscu- lar wall which may be attributed to arterial occlusion ; obstruc- tion of a main coronary in an animal is not necessarily fatal during the period of an experiment, though recovery is rarely seen. I would especially emphasise the possibility that certain of the cases of sudden death in heart disease are due to plug- 116 Chapter V ging of vessels supplying relatively small or deeply seated areas of muscle; such vessels are not often examined at autopsy. Accelerated heart action. The last cause of syncope which I propose to consider is acceleration of the heart's action. The normal mammalian heart has a wonderful reserve power and capacity of accommoda- tion. You may artificially increase its rate by stimulating it with serial induction shocks over a wide range of rate, without materially influencing the peripheral circulation. The effect of acceleration in the circumstances is to curtail diastole; as a consequence diastplic pressure rises and systolic pressure falls ; the mean pressure is maintained. But even in the normal heart Fig. 79. Electrocardiograms from leads / and II showing an auricular and a ventricular rate of 270 in a child. Auricular flutter. there is a limit of this accommodation and, as the rate rises, a time comes when the diastolic periods are so curtailed that filling is incomplete. The mean pressure then falls. If the heart is abnormal or its efficiency is damaged, the effects of acceleration are more speedily felt; a rise of rate, which would create no material disturbance under ordinary conditions, in these circum- stances would have profound effects. Some curious examples and contrasts have come to my notice. I recall an instance in which a regular acceleration of the heart's action to 160 and Observations Upon Cardiac Syncope 117 more per minute had been present for several years ; the patient was under my observation for several months, and this rate was constant; yet the disturbance was comparatively slight, consist- ing only of a sense of exhaustion with and after effort. Recently a child was brought to me for examination in which the ventricular rate remained at 270-290 during several hours of observation (Fig. 79) ; the curves from this child were taken while it slept or while, in a waking state, it peacefully took its food. But such rates are very exceptional, and are tolerated only by sound muscle. Where there is muscle damage a rate of 160-200 is rarely tolerated, and higher rates speedily induce signs of grave circulatory embarrassment. This embarrass- ment comes in the way I have indicated ; by a reduction of di- astole, arterial pressure is lowered and venous pressure is raised (Fisr. 80). _ # #T i*T '..fUr ^ 80. Hiirthle curve of arterial pressure and electrocardiogram. Show- ing the fall of arterial pressure which occurs when the heart's action is greatly accelerated by stimulation. Simple paroxysms of regular tachycardia are prone to pro- duce actual attacks of syncope in susceptible subjects ; giddiness during the seizures is a common manifestation (Fig. 81). These symptoms are often to be ascribed to lessened cardiac out- put and the consequent fall of arterial pressure. I show you an example in Fig. 82 where two short paroxysms of regular tachycardia (rate 200-220 per minute) are recorded; these were accompanied by giddiness, others of longer duration by severe giddiness verging on loss of consciousness; at times the same patient actually fainted. You will notice the lowering 118 Chapter V J^g 'S j & I / 02 I I Observations Upon Cardiac Syncope 119 of the pulse line, indicating reduction of the blood pressure, as each paroxysm proceeds. Several cases are upon record in which Adams-Stokes syndrome was simulated by paroxysms of this kind, for the beats of the paroxysm failed to force a suf- ficiency of blood into the arteries and consciousness during the attacks was frequently lost. Another condition in which giddiness or actual syncope is seen is paroxysmal auricular fibrillation, and the cause is the same in this malady. For the fibrillation in the auricles drives the ventricles at a greatly accelerated rate during the attack, and as a result, mean arterial pressure may be considerably reduced. -41: Fig. 83. Electrocardiograms from lead II and ///, showing auricular flut- ter. The ventricular rate is 165, the auricular rate 330. This pa- tient suffered from syncopal attacks which were proved to result from the assumption of the full auricular rate by the ventricle. There is a disorder of considerable clinical importance which has but recently been discovered. It is a condition found in adults for the most part, in which the auricles beat at extreme rates, reaching and surpassing 320 per minute. It may be taken as a general rule that in this state, which has been termed auric- ular flutter, the ventricle does not respond to the full auricular rate; it responds to alternate auricular impulses (Fig. 83), and its rate is thus halved. If the auricles beat at 320, the ventricu- lar rate is 160; the ventricular rate of 160 is usually sufficient 120 Chapter V materially to embarrass the circulation in these people; how much greater the strain when the full rate is experienced ? I question whether any adult heart, normal or abnormal, could long maintain this rate of beating; certain it is that with this heart rate, the cerebral circulation would be grossly insufficient. Now patients who are sufferers from auricular flutter and in whom there is, so to speak, a potential ventricular rate of 300 or more per minute, frequently experience syncopal attacks and it has recently been shown by the graphic method that such attacks are the result of the temporary development of the full ven- tricular rate. It should be remembered that the auricle is send- ing forth impulses at 300 per minute and that the ventricle usually refuses half these demands to contract ; now and again the full call is answered, the heart rate leaps to its fullest, arterial blood pressure sinks rapidly, the brain is insufficiently sup- plied, unconsciousness supervenes and is maintained while the ventricle gallops uncurbed. In the light of these observations, the syncopal attacks of paroxysmal tachycardia receive adequate explanation; death during such attacks unexpected death in these subjects is not very infrequent is to be explained by a prolongation of the seizures or, in certain instances, may be, to the intervention of another disorder which we have already considered, namely, fibrillation of the ventricles. Gentlemen, the facts which I have now related to you con- stitute our chief knowledge of the causes of cardiac syncope and unexpected death in heart patients. There are still evident gaps to fill; gaps which will be filled in the near future. My purpose has been not only to record our present knowledge in this single direction but to point to the trend of modern ob- servation; by example, to attempt to indicate how clear rela- tions may be established between clinical and laboratory find- ings ; to illustrate the advantages of precise methods of study ; to ask your agreement that medicine may be treated as an exact Observations Upon Cardiac Syncope 121 science, in which the simple facts of our experience may be ar- ranged and sorted out into the compartments of cause and ef- fect, in which a careful and deliberate discrimination between these facts and hypotheses may play a prominent and appro- priate part in our processes of thought ; to ask your support for the belief that the proved cause of a clinical symptom, however rare such cause may be, is of infinitely greater consequence to us than a hundred plausible suggestions whose validity is un- supported by the evidence of observation. REFERENCES Cohn and Lewis. Heart, 1912-13, IV, 7. Cohn and Lewis. Heart, 1912-13, IV, 15. Erlanger. Journ. exper. Med., 1905, VII, 1. Erlanger and Blackmann. Heart, 1909-10, I, 177. Fredericq. Arch, intern, d. Physiol., 1912, XI, 405. Gossage. Quart. Journ. of Ned., 1908-9, II, 19. Hering. Munch, med. Wochenschr., 1912., No. 14 and 15. Hill. Phil Trans. Roy. Soc., 1900, B, CXCIII, 69. Hoffmann. Heart, 1912, III, 213. Jex-Blake. Brit. med. Journ., 1913, I, 425-492. Kussmaul and Tenner. Xew Sydenham Society, 1859, 28 (trans.) Laslett. Quart. Journ. of Ned., 1908-9, II, 347. Levy. Heart, 1912-13, IV, 319 and 299. Lewis. Heart, 1909-10, I, 306. Lewis. Heart, 1909-10, I, 98. Lewis. Journ. exper. Ned., 1912, XVI, 395. Lewis. "Mechanism of the Heart Beat," 1911, 188. Mackenzie "Diseases of the Heart/' 1913, 3rd ed., Fig. 141. MacWilliam. Brit. med. Journ., 1889, I, 6. Neubiirger and Edinger. Berl Uin, Wochenschr., 1898, XXXV, 69 and 100. Rihl. Zeitschr. f. exper. Pathol u. Therap., 1905, II, 83. Robinson. Journ. of exper. Med., 1912, XVI, 291. Schiff. Lehrbuch d. Muskel u. NervenphysioL, Lahr, 1858, 108. Webster. Glasgow med. Rep., 1901, III, 413. INDEX Accelerated heart action, 116 Acidosis, 81 Adams-Stokes syndrome, 46, 109 Angina sine dolore, 102 Asystole, 102 Auricle : Origin of excitation wave in, 8 Course of excitation wave in, 16 Auricular fibrillation, 46, 62, 119 Auricular flutter, 50, 119 Auricular sounds, 59 Auriculo-systolic murmur, 70 A-V bundle, 44, 106 A-V node, 44 Bundle branch section, 26 Bundle of His, 44, 106 Digitalis, 45, 48, 51, 111 Dilatation, acute, 49, 102 Diphasic curve, 5 Dyspnoea, 82 Cardiac, 84 Mechanical, 84, 89 Nocturnal, attacks of, 85, 86 Of diabetes, 91 Of exercise, 91 Of exophthalmic goitre, 92 Of high altitude, 91 Of pneumonia, 91 Of pregnancy, 92 Periodic, 94 Relation to cyanosis, 82 Special type of, 85 "Ursemic," 88, 93 Cerebral anaemia, effects of, 109 Cheyne-Stokes breathing, 86 . Chloroform, death under, 113 Clinical medicine and laboratory methods, 35, 53, 81 Concentration point, 21 Coronary arteries: Anastomoses, 115 Plugging of, 101, 115 Da Costa, 48 Diabetes and breathlessness, 91 Diastolic Arrest, 102 Early diastolic murmur, 73 Electrocardiogram, 38 Endocardial leads, 27, 29 Excitation Wave: Conduction rates, 19, 27, 30 Course in auricle, 16 Course in ventricle, 22 Curve form governed by direction of, 6, 11 General principles of studying, 4 Origin in auricle, 8 Rate of travel, 19, 27, 30 Reversal of, 7 123 124 Index Exercise and breathlessness, 91 Extrasystoles : Auricular, 40 Ventricular, 42 Extrinsic deflections, 12 Fainting, vasomotor, 101 Favourable leads, 8 Fibrillation of auricles, 46, 62, 119 Fibrillation of ventricles, 110 Forced beats, 11 Gallop rhythm, 61 Graphic records, 38, 99 Heart-block, 44, 59, 66, 104, 107 Heart-sound recorder, 54 Heart-sounds and murmurs, 53 High altitude and breathlessness, 91 Intrinsic deflections, 12, 13 Isopotentiality, 7 Laboratory methods and clinical medicine, 35, 53, 81 " Lub-dup," 59 Mitral stenosis, 67 Murmurs of mitral stenosis, 67 Classification of, 76 During fibrillation, 73 During heart-block, 71 General theory of, 77 Musical murmurs, 56 Pace-maker : Displacement of, 43 Situation of, 8 Periodic breathlessness, 94 Pig's heart, 10 Pneumonia and breathlessness, 91 Presystolic murmur, 70 Disappearance of, 73 Primary negativity, 9, 14 Prolonged A g -F g interval, 61, 73 Purkinje distribution of excitation wave, 26, 30 Relative negativity, 5 Section of bundle branch, 26 Sino-auricular node, 10 Standstill of heart, 103 Standstill of ventricle, 104 Syncope, 46, 97 Timing of sounds, 56 Tuning fork, 54 Unexpected death, 101, 111, etc. Veins, course of excitation wave in, 16, 17 Ventricular fibrillation, 110 MEDICAL MONOGRAPHS PUBLISHED BY PAUL B. 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HOEBER'S MEDICAL MONOGRAPHS BULKLEY Compendium of Diseases of the Skin. Based on an analysis of thirty thousand consecutive cases. With a Therapeutic Formulary, by L. DUNCAN BULKLEY, A.M., M.D. Physician to the New York Skin and Cancer Hos- pital; Consulting Physician to the New York Hospital. 8vo, Cloth, xviii+286 pages $2.00 net. BULKLEY Cancer: Its Cause and Treatment. By L. DUNCAN BULKLEY, A.M., M.D. 8vo, Cloth, 224 pages $1.50 net. BULKLEY Diet and Hygiene in Diseases of the Skin. By L. DUNCAN BULKLEY, A.M., M.D. 8vo, Cloth, xvi-j-194 pages $2.00 neb. BULKLEY The Influence of the Menstrual Function on Certain Diseases of the Skin. By L. DUNCAN BULKLEY, A.M., M.D. I2mo, Cloth, 108 pages $1.50 net. BULKLEY The Relations of Diseases of the Skin to Internal Disorders: With Observations on Diet, Hygiene and General Therapeutics. By L. DUNCAN BULKLEY, A.M., M.D. i2mo, Cloth, 175 pages $1.50 net BULKLEY Principles and Application of Local Treat- ment in Diseases of the Skin. By L. 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CORBETT-SMITH, Editor of "The Journal of State Medicine" ; Lecturer in Public Health Law at the Royal Institute of Public Health. Large 8vo, Cloth, xii-|-io7 pages. .$1.00 net. CORNET Acute General Miliary Tuberculosis. By PROFESSOR DR. G. CORNET, Berlin and Reichenhall. Trans- lated by F. S. TINKER, B.A., M.B., etc. 8vo, Cloth, viii+io7 pages $1.50 net. HOEBER'S MEDICAL MONOGRAPHS CROOKSHANK Flatulence and Shock. By F. G. CROOK- SHANK, M.D., Lond., M. R. C. P. Physician (Out Patients) Hampstead General and N. W. Lond. Hospital; Assistant Physician The Belgrave Hospital for Children S.W. 8vo, Cloth, iv-f-47 pages $1.00 net. EDRIDGE-GREEN The Hunterian Lectures on Colour- Vision and Colour Blindness. Delivered before the Royal College of Surgeons of England on February 1st, and 3rd, 1911. By Professor F. W. EDRIDGE- GREEN, M.D. Durh., F.R.C.S. England. Beit Medical Research Fellow. 8vo, Cloth, x+76 pages $1.50 net. EHRLICH Experimental Researches on Specific Thera- peutics. By PROF. PAUL EHRLICH, M.D., D.Sc. Oxon. Director of the Konigliches Institut fur Experimentelle Therapie, Frankfort. The Harben Lectures for 1907 of The Royal Institute of Public Health. i6mo, Cloth, x-f95 pages $1.00 net. EIN HORN Lectures on Dietetics. By MAX EINHORN, Professor of Medicine at the New York Post-Graduate Medical School and Hospital and Visiting Physician to the German Hospital, New York. I2mo, Cloth, xvi-j-156 pages $1.00 net. ELLIOT Sclero-Corneal Trephining in the Operative Treatment of Glaucoma. By ROBERT HENRY ELLIOT, M.D., B.S. Lond., Sc.D. Edin., F.R.C.S. Eng., Etc. Lieut. Colonel I. M.S. Second Edition. 8vo, Cloth, 135 pages, 33 illustra- tions $3.00 net. EMERY Immunity and Specific Therapy. By WM. D'EsTE EMERY, M.D., B.Sc. Lond. Clinical Pathologist to King's College Hospital and Pathologist to the Children's Hospital, Paddington Green ; formerly Assistant Bacteriolo- gist to the Royal College of Physicians and Surgeons, and sometime Lecturer on Pathology and Bacteriology in the University of Birmingham. 8vo, Cloth, 448 pages, with 2 ills $3.50 net. ADOPTED BY THE U. S. ARMY GILES Anatomy and Physiology of the Female Genera- tive Organs and of Pregnancy. By ARTHUR E. GILES, M.D., B.Sc. Lond. M.R.C.P. Lond.; F.R.C.S. Ed. Gynecolo- gist to the Prince of Wales General Hospital, Tottenham, and Surgeon to the Chelsea Hospital for Women. Large 8vo, 24 pages with manikin $1.50 net. GREEFF Guide to the Microscopic Examination of the Eye. By PROFESSOR R. GREEFF. Director of the Uni- versity Ophthalmic Clinique in the Royal Charity Hospital, Berlin. With the co-operation of PROFESSOR STOCK and PRO- 3 HOEBER'S MEDICAL MONOGRAPHS FESSOR WINTERSTEINER. Translated from the third German Edition by HUGH- WALKER, M.D., M.B., CM. Ophthalmic Surgeon to the Victoria Infirmary, Glasgow. Large 8vo, Cloth, 86 pages, Illustrated $2.00 net. HARRIS Lectures on Medical Electricity to Nurses. An Illustrated Manual by J. DELPRATT HARRIS, M.D. Durh., M.R.C.S. Senior Surgeon and Honorary Medical Officer in charge of the Electrical Department, Royal Devon Hosp. I2mo, Cloth, 88 pages. Illustrated $1.00 net. HOFMANN-GARSON Remedial Gymnastics for Heart Affections. Used at Bad-Nauheim. Being a translation of "Die Gymnastik der Herzleidenden" von DR. MED. JULIUS HOFMANN und DR. MED. LUDVVIG POHLMAN. Berlin and Bad-Nauheim. By JOHN GEORGE GARSON, M.D. Edin. t etc. Physician to the Sanatoria and Bad-Nauheim, Evers- ley, Hants. With 51 full-page illustrations and diagrams. Large 8vo, Cloth, xvi-)-i28 pages $2.00 net. HOWARD The Therapeutic Value of the Potato. By HEATON C. HOWARD, L.R.C.P. Lond., M. R. C. S. Eng. 8vo, paper, vi-|-3i pages, Illustrated 500 JELLETT A Short Practice of Midwifery for Nurses. Embodying the treatment adopted in the Rotunda Hospital, Dublin. By HENRY JELLETT, B.A., M.D. (Dublin Univer- sity) F.R.C.P.I., Master Rotunda Hospital; Extern Exam- iner in Midwifery and Gynecology, Victoria University, Manchester ; Late King's Professor of Midwifery ; Univer- sity of Dublin. With six plates and 169 illustrations in the text, also an appendix, a glossary of Medical Terms, and the Regulations of the Central Midwives Board. I2mo, Cloth, xvi-f-5o8 pages $2.50 net. KENWOOD Public Health Laboratory Work. By HENRY R. KENWOOD, M.B., F.R.S. Edin., P.P.H., F.C.S., Chadwick. Professor of Hygiene and Public Health, Uni- versity of London; Medical Officer of Health and Public Analyst for the Metropolitan Borough of Stoke Newington; Examiner in Public Health to the Royal College of Phy- sicians and Surgeons, London, etc. 6th Edition, 8vo, Cloth, 418 pages. Illustrated. .. .$4.00 net. LEWERS A Practical Textbook of the Diseases of Women. By ARTHUR H. N. LEWERS, M.D. Lond. Senior Obstetric Physician to the London Hospital ; Late Exam- iner in Obstetric Medicine at the University of London ; University Scholar & Gold Medallist in Obstetric Medicine,. London University, etc. With 258 illustrations, 13 colored plates, 5 plates in black and white. 7th Edition, 8vo, Cloth, xii-f-54O pp $4.00 net^ HOEBER'S MEDICAL MONOGRAPHS LEWIS Clinical Disorders of the Heart Beat. A Hand- book for practitioners and Students. By THOMAS LEWIS, M.D., D.Sc., F.R.C.P. Assistant Physician and Lecturer in Cardiac Pathology, University College Hospital, Physician to Out-Patients, City of London Hospital for Diseases of the Chest. SECOND EDITION. 8vo, Cloth, 1 16 pages. Illustrated $2.00 net. LEWIS Lectures on the Heart. Comprising the Herter Lectures (Baltimore), a Harvey Lecture (New York) and an address to the Faculty of Medicine at McGill Univer- sity (Montreal), by THOMAS LEWIS, M.D., F.R.C.P. Phy- sician, City of London Hospital ; Assistant Physician and Lecturer in Cardiac Pathology, University College Hos- pital, London. With 83 illustrations $2.00 net. LEWIS The Mechanism of the Heart Beat. With spe- cial reference to its Clinical Pathology. By THOMAS LEWIS, M.D., D.Sc., M.R.C.P. Lecturer in Cardiac Pathology, Uni- versity College Hospital Medical School; Physician to Out- Patients, City of London Hospital for the Diseases of the Chest. Large 8vo, Cloth, 295 pages, 227 Illus $7.00 net. McCLURE A Handbook of Fevers. By J. CAMPBELL McCLURE, M.D., Glasgow. Physician to Out-Patients, The French Hospital, and Physician to the Margaret Street Hos- pital for Consumption and Diseases of the Chest, London. 8vo, Cloth, 470 pages, with charts $3.50 net. McCRUDDEN The Chemistry, Physiology and Pathol- ogy of Uric Acid, and the Physiologically Important Purin Bodies. With a discussion of the Metabolism in Gout. By FRANCIS H. MCCRUDDEN, i2mo, Paper. 318 pages $2.00 net. McKISACK Systematic-Case Taking. A Practical guide to the examination and recording of medical cases. By HENRY LAWRENCE McKisACK, M.D., M.R.C.P. Lond. Phy- sician to the Royal Victoria Hospital, Belfast. i2mo, Cloth, 166 pages $1.50 net. MACKENZIE Symptoms and their Interpretation. By JAMES MACKENZIE, M.D., LL.D., Aber. and Edin. Lecturer on Cardiac Research, London Hospital. 8vo, Cloth. Illustrated. xxii-f~3O4 pages $3.00 nel\ MACMICHAEL The Gold-Headed Cane. By WILLIAM MACMICHAEL. Reprinted from the 2nd Edition. With a Preface by SIR WILLIAM OSLER and an Introduction by DR. FRANCIS R. PACKARD. 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MURRELL What to do in Cases of Poisoning. By WILLIAM MURRELL, M.D., F.R.C.P. Senior Physician to the Westminster Hospital ; Lecturer on Clinical Medicine and joint lecturer on the principles and practice of medi- cine ; Late examiner in the Universities of Edinburgh, Glas- gow and Aberdeen, and to the Royal College of Physicians. Eleventh Edition, i6mo, Cloth, 283 pages $1.00 net. OLIVER Lead Poisoning: From the Industrial, Med- ical and Social Point of View. Lectures delivered at the Royal Institute of Public Health. By SIR THOMAS OLIVER, M.A., M.D., F.R.C.P. Consulting Physician, Royal Victoria Infirmary, and Professor of the Principles and Practice of Medicine, University of Durham College of Medicine, New- castle-upon-Tyne, Late Medical Expert, Dangerous Trades Committee; Home Office. Large I2ino, Cloth, 294 pages $2.00 net. OSLER Two Essays. By SIR WILLIAM OSLER, M.D. Regius Professor of Medicine at Oxford. Vol. i. A Way of Life. 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PEGLER Map Scheme of the Sensory Distribution of the Fifth Nerve (Trigeminus) with Its Ganglia and Connec- tions. By L. HEMINGTON PEGLER, M.D., M.R.C.S. Senior Surgeon, Metropolitan Ear, Nose and Throat Hospital, Etc. Mounted on Rollers, 4 ft. I in. x 4 ft. 8 in $7.00 net. Folded in Cloth Binder $8.00 net. RAWLING Landmarks and Surface Markings of the Hu- man Body. By L. BATHE RAWLING, M.B., B.C. (Cant) F.R.C.S. (Lond.) Surgeon with charge of Out-Patients, Late Senior Demonstrator of Anatomy at St. Bartholomew's Hospital ; Late Assistant-Surgeon to the German Hospital, Dalston; Late Hunterian Professor Royal College of Sur- geons, England, Etc. FIFTH EDITION. 8vo, Cloth, 31 plates. xii-(-96 pages of text $2.00 net. RITCHIE Auricular Flutter. By WILLIAM THOMAS RITCHIE, M.D., F.R.C.P.E., F.R.S.E. Physician to the Royal Infirmary ; Lecturer on the Practice of Medicine, School of Medicine of the Royal Colleges; Lecturer on Clinical Medicine in the University of Edinburgh. 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Translated from the German by J. DULBERG, M.D. 8vo, Cloth, 452 pages $2.50 net. HOEBER'S MEDICAL MONOGRAPHS SMITH Some Common Remedies, and Their Use in Practice. By EUSTACE SMITH, M.D. Fellow of the Royal College of Physicians ; Senior Physician to the East Lon- don Hospital for Children ; Consulting Physician to the Victoria Park Hospital for Diseases of the Chest. 8vo, Cloth, viii-|-ii2 pages $1.25 net. SQUIER and BUGBEE Manual of Cystoscopy. By J. BENTLY SQUIER, M.D. Professor of Genito-Urinary Sur- gery, New York Post-Graduate Medical School and Hos- pital, and HENRY G. BUGBEE, M.D. 8vo, Flex. Leather, xiv-(-ii7 pp., 26 colored plates. $3.00 net. ADOPTED BY THE U. S. ARMY STARK The Growth and Development of the Baby. A tabular chart, giving the result of personal observation, verified by authoritative data, as to development, weight, height, etc., during the first seven years. By MORRIS STARK, M.A., B.S., M.D. Instructor of Pediatrics, New York Post Graduate Medical School, etc. Heavy paper, 20 by 25 inches 5oc net. STEPHENSON Eye-Strain in Every-day Practice. By SIDNEY STEPHENSON, M.B., C.M. Edin., D.O. Oxon, F.R.C.S. Edin. Ophthalmic Surgeon to the Queen's Hos- pital for Children ; Editor of the Ophthalmoscope. 8vo, Cloth, x+i39 pages $1.50 net. STEPHENSON A Review of Hormone Therapy. 1913 8vo, Cloth, viii-f-!7O pages $1.00 net. Bound and interleaved edition of the famous "Hormone Number" of the "Prescriber" (Edinburgh). SWIETOCHOWSKI Mechano-Therapeutics in General Practice. By G. DE SWIETOCHOWSKI, M.D., M.R.C.S. Fel- low of the Royal Society of Medicine; Clinical Assistant, Electrical and Massage Department King's College Hosp. I2tno, Cloth, xiv+i4i pp., 31 Illustrations $1.50 net TURNER and PORTER The Skiagraphy of the Acces- sory Nasal Sinuses. By A. LOGAN TURNER, M.D., F.R.C.S.E., F.R.S.E. 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WRIGHT On Pharmaco-Therapy and Preventive In- oculation; Applied to Pneumonia in the African Native with a discourse on the Logical Methods which ought to be Employed in the Evaluation of Therapeutic Agents. By SIR ALMROTH E. WRIGHT, M.D., F.R.S. Svo, Cloth, 124 pages $i-75 net. Complete catalogue and descriptive circulars will be sent on request. DATE DUE SLIP UNIVERSITY OF CALIFORNIA MEDICAL SCHOOL LIBRARY THIS BOOK IS DUE ON THE LAST DATE STAMPED BELOW &. I SEP 12 1939 1 NOV 1 5 J946 2?n-12,'19 MEMCAL LIIBMAMY Villiam "Vatt Eerr Memorial University of California Medical School Library