The Factors of the Respiratory Rhythm and the Regula- tion of Respiration. BY W. Y. COWL, M. D. REPRINTED FROM Neto York ittetocal ^Journal for September 6, 1890. Reprinted from the New York Medical Journal for September 6, 1890. THE FACTORS OF THE RESPIRATORY RHYTHM AND THE REGULATION OF RESPIRATION. By W. Y. COWL, M. D. In an article entitled The Self-regulation of Respiration, read before the American Physiological Society in New York, December 28, 1889, and published in the issue of this Journal for January 18, 1890, Dr. S. J. Meltzer, of this city, brings forward a new theory of respiratory rhythm, or, more precisely, a revival, under a new hypothesis, of the idea of the peripheral incitation of the inspiration in ordi- nary respiration, which for several reasons-but chiefly be- cause of a disregard therein of the mass of facts that show a central origin for inspiration, and already furnish indeed sufficient and simple explanation of the respiratory rhythm -deserves further attention. Instead, namely, of referring the impulse to inspiration to the respiratory center, as is usual at the present time,* he supposes an incitation of this center by the vagus to occasion each inspiratory effort, and in the following lines, which I regret to have to repeat, he gives the only refer- * Flint, Text-book of Physiology, New York, 1888. 2 THE FACTORS OF THE RESPIRATORY RHYTHM ence in his paper to the facts that are acknowledged to show the non-pulmonic incitation of inspiration.* "For the production of inspiration, Gad (1) seeks the cause in a center in which a constant inspiratory stimulus resides. Thus the inspiration is said to start from the cen- ter, and the inhibition of this inspiration is to be effected by reflex from the lungs. Hence the inspiratory nerve fibers which undoubtedly exist in the vagus find no application in Gad's theory, and this alone speaks sufficiently against this hypothesis." But to give an idea of the general contents of Dr. Meltzer's paper. After briefly stating the results of a series of electrical stimulations of the vagus largely stronger than those used by other observers in this field, and accepting the theory (2) of the induction of expiration by the inspiratory expansion of the lung, and the excitation thereby of pulmonary vagus fibers reflex-inhibitory of inspiration, the author puts forth the supposition, upon the basis of his experiments, that in- spiration arises by a similarly and in fact simultaneously effected excitation of pulmonary vagus fibers reflex-incita- tory of the inspiration, the excitation of the respiratory cen- ter by which, at first hidden under the predominating inhi- bition, outlasts the same and causes then a new inspira- tion. In the research itself he obtained, upon using weak or medium strong electrical excitation, like previous experi- menters, a varied effect upon the respiration-namely, as stated, of an inspiratory or of an expiratory character, while upon using very strong stimulation he found the effect uni- formly expiratory, consisting " partly in passive, partly in active expirations." The course of these expirations-in fact, their number * Hermann, Lehrbuch der Physiologic, Berlin, 1889. AND THE REGULATION OF RESPIRATION. 3 and frequency, if repeated during any one stimulation of the nerve-is not stated ; but in another place it is left to be inferred that, at least in the main, there was an arrest of respiration-namely : " But we can also conclude, wher- ever we find after an expiratory arrest an inspiratory after- effect, that inspiratory fibers are present in the trunk and have been likewise stimulated in a latent manner. But, as we have demonstrated in all animals under strong stimula- tion, such an inspiratory after-effect following an expiratory inhibition, we may conclude that both kinds of nerves exist in the vagus of all animals." In the case of his stimulations of the vagus the author was able to exclude the occurrence of a coexcitation of the u perior laryngeal nerve in that, as he had previously shown (3), such excitation always produces a succession of swallowing acts, which were absent in his experiments, and he therefore used stronger currents than previous observers without fear that the recorded effects were due to such co- excitation. The direct ground adduced by Dr. Meltzer for his new and ingenious hypothesis, above given, is not, then, the im- mediate effects of these strong excitations of the vagus dur- ing the time of the same, but the character of the respiration after their cessation-namely, a notably increased inspira- tory activity over that before the excitation, which the au- thor assumes to be a specific effect of such excitation of the so-called inspiratory fibers in question, outlasting the ef- fects of the excitation of the inhibitory fibers. He also draws an analogy between his experiments and those of Head (4) upon the intact animal, wherein a prolonged in- sufflation of the lungs occasioned an inhibition of respira- tory effort during the time of the same, and a marked inspi- ratory effect after its cessation. In bringing forward this hypothesis, the author makes 4 THE FACTORS OF THE RESPIRATORY RHYTHM no mention, on the one hand, of the assumptions concern- ing such experimentation upon the vagus, which form a pre- requisite to this use of its results, nor does he, on the other, bring evidence to show that this inspiratory after-effect is not dyspnoea from non-aeration of blood coursing through the respiratory center, such as indeed is to be awaited upon arresting respiration in expiration. The conclusions, tacit or expressed, from simple electri- cal excitation of the vagus, which are necessary to form a hypothesis thereon concerning the ordinary respiration, are the following-namely, first, that the fibers of the vagus, the excitation of which causes the changes in respiration, are pulmonary fibers and not sensory fibers from the lower part of the larynx (deriving its sensibility in part from the inferior laryngeal nerve [5]), the trachea, oesophagus, stom- ach, or intestine, not to include the bronchi; and, secondly, that they are fibers which exercise their function in ordinary breathing, and not fibers either from the alveolar walls, the pulmonary pleura, or the bronchioles or bronchi, which merely come into play under extraordinary circumstances of the respiration-e. g., in coughing. . That extraordinary circumstances do call forth special action in a reflex manner is shown quite conclusively by one experiment. Berns (6) under Bonders, and M. Rosenthal (7) under Gad, have induced dyspnoeic breathing immediately by the first of a series of inhalations or by a single inhalation of carbonic-acid gas. In the latter's experiments the gas was purified and the gas-holder so arranged that, upon the first inspiration after opening the communication with the trachea, the gas was inhaled. Hydrogen respired in the same way produced only a secondary, i. e., a later-ap- pearing dyspnoea, dependent upon deficient arterialization of the blood. A secondary dyspnoea alone was produced AND THE REGULATION OF RESPIRATION. 5 by the carbonic acid when the vagi were previously cut. The immediate dyspnoea excited then is of peripheral origin. That the vagus libers, the terminations of which become excited in this instance, are pulmonary, is open to a certain slight doubt, which is lent strength by the known excitant action of carbonic acid on the dermal surface (9), for it is impossible to ascertain what part if any of the immediate dyspnoea is due to excitation of the sensory nerve libers dis- tributed to the lower part of the trachea, below the point at which the tracheal cannula may be introduced. That this portion of the respiratory tract is much less sensitive than the pulmonary parenchyma, however, is to be inferred from an experiment respecting such excitation of the tra- cheal surface, directly to be mentioned. Other facts indicating the existence of special nervous provision for extraordinary circumstances of the respiration are that the inhalation of chloroform (through a tracheal cannula) causes at once inspiratory dyspnoea, as found by Knoll (5), who also passed the vapor through the length of the trachea alone without effect upon the respiration, like- wise that vapor of ammonia causes immediate expiration, and, furthermore, the peculiarity noted by Head, that, after interrupting the impulses coursing through the vagi by the method of Gad (by local freezing of the nerves), at the be- ginning of their resumption of power, upon thawing, an insufflation of the lungs will cause an inspiratory effort of the diaphragm, instead of an expiratory effort as in the in- tact animal. But, in addition to the doubts above expressed, which arise in the present state of knowledge concerning the va- gus, whenever the effects upon the respiration of simple electrical excitation of the nerve be boldly referred to its pulmonary fibers, and indeed obtrude themselves when the 6 THE FACTORS OF THE RESPIRATORY RHYTHM assumption be made that these fibers thus act continually in ordinary respiration, there are positive reasons which re- enforce them. First, the expiratory effect, with stoppage of respiration, upon electrical excitation of other nerves than the vagus, or indeed upon natural excitation of their endings, and the marked increase in the inspiratory activity thereafter. Evi- dence of such is to be found in the graphic tracings of the respiration upon stimulation, notably of the splanchnic and infra-orbital nerves, published by Knoll (10), who also calls attention to the signs in the tracheotomized animal of crying efforts occasioned by strong excitation, and gives tracings of the respiration, showing it to be very much in- creased and remarkably regular. Again, the fact observed by the same author that strong excitation of the inferior laryngeal nerve causes expiratory effects (5), while excitation in the same manner of the va- gus beyond this branch-namely, in the chest-produced, as a rule, inspiratory effects. Thus we perceive that, by ex- citation of the vagus in the neck, there is a probability, when obtaining expiratory effects, that they come from the excitation of the sensory fibers of the recurrent laryngeal nerve, and not from the pulmonary branches of the vagus. As previously noted, Dr. Meltzer does not refer to vitiation of the blood as a possible cause of the dyspnoea after the arrest of respiration during his excitations of the vagus, although such is to be expected, either upon simple stoppage of the respiration, or especially when the arrest occurs in expiration, for dyspnoea appears more quickly and strongly after a cessation of breathing when the chest is contracted than when expanded and full of air-a fact, however, which, if, according to the theory, the inspiration be excited wholly, nay, or even partially, by expansion of the chest, is certainly difficult to explain. AND THE REGULATION OF RESPIRATION. 7 The sensitiveness, on the other hand, of the respiratory center to changes in the constitution of the blood, which was long since indubitably shown under various condi- tions by the researches of Rosenthal (11), Pfliiger and Doh- men (12), and others, is particularly well demonstrated by Fredericq (13), who causes the blood to flow to the brain through only a single artery in each of two rabbits, where- by, in their quiet state, as shown by Gad, though in each both vertebrals and one carotid be occluded, no changes in respiration or general blood-pressure are occasioned, and thereupon, by means of crossed cannulas, so connects the free vessels that each animal serves the brain of the other with blood. Upon then partly obstructing the trachea in one animal, increased breathing appears in the other, while diminished breathing is to be observed in the one supplied with insufficient air. That the cause of the changes in respiration here does not lie in the decrease and increase, respectively, in the amount of oxygen inspired, but in the variation from the normal amount of carbonic acid in the blood circulating through the respiratory center of each animal, is to be concluded from the researches especially of Gad and M. Rosenthal (7), Miescher (14), Kempner (15), and others. The delicate reaction of the respiratory center to a change in the constitution of the blood in this experiment, together with the many current facts showing the influence of nervous impressions reflected upon this center, convey an idea of its importance for the regulation of the respira- tion under various circumstances of the individual. Two observations of Gad (1) and Sig. Mayer (16) show, furthermore, the change in the excitability of the respira- tory center which is effected by considerable changes in the blood-supply. The former observer, on diminishing the flow of blood to the brain for a time and then restoring the 8 THE FACTORS OF THE RESPIRATORY RHYTHM current to its previous amount, observed a stoppage of res- piration. The latter noted the same on occasioning a pause in the heart's action. We have in these experiments a demonstration of the two ground factors in the above-mentioned regulation- namely, the excitability of the spino-bulbar respiratory cen- ter, and the constantly present excitant of the same, as well as a proof of the variability of each of these factors whereby this regulation becomes effected. In respect of the experiments of Head, cited by Dr. Meltzer in support of his theory, it is to be noted that the former, without expressly stating what he does regard as the causation of the results obtained by him, refers to the after-effect upon the action of the diaphragm of his pro- longed insufflations of the lungs, in the following words, the here Italicized portions of which alone concern us in this connection : If the lungs are inflated, the expiratory pause produced by the inflation is finally broken by an inspiratory contraction, al- though the lungs are still dilated. This contraction is strong, of comparatively short duration, and traces a curve with an ex- tremely sharp crest. But if the lungs are allowed to return to the normal volume just before this interrupting inspiration would normally have made its appearance, the breathing under- goes a very different modification. At the moment of collapse the inspiratory muscles contract strongly, and produce a strong, flat-topped curve. This con- traction is of about the same strength as the interrupting in- spiration, but exceeds it greatly in duration. Thus sudden re- turn of the lungs to the normal volume after an inflation of considerable duration produces a strong and long inspiratory contraction. It might be objected that both the interrupting in- spiration and the strong inspiratory effect which follows collapse after an inflation were due to the dyspnoea which must neces- sarily result during such a long pause in the breathing. How- ever, I think that this explanation will scarcely suffice to explain AND THE REGULATION OF RESPIRATION. 9 either phenomenon ; for, provided the inflations are of'the same strength, the pause is broken at almost exactly the same moment, whether oxygen, air, or hydrogen be used to inflate the lungs. It is true that the strength of the interrupting contraction is generally greatest when the lungs have been inflated with hydro- gen, but the time of its appearance is the same with all three gases under otherwise similar conditions. Again, the fact that the animal is breathing oxygen during and after the inflation does not diminish the strength of the inspiratory contraction, which is produced by the sudden return of the lungs to their normal volume after the inflation. Indeed, it is rather favorable than otherwise to its appearance, for, if the animal is dyspnoeic, this inspiratory contraction is of much shorter duration and is much more difficult to produce than when the ungs have been inflated with air or oxygen. It will be noticed in the above that the author, with- out leaving the question an open one, does not distinctly hold these inspirations, during or after prolonged insuffla- tions of the lungs, to be due to central (direct) or to pe- ripheral (reflex) incitation ; namely, to vitiated blood in the medulla, or to excitation of the vagus in the lungs; but it is evident that the latter is his view. This conclusion does not seem to me to follow, how- ever, from the simple circumstance stated, that the inter- rupting inspiratory effort was stronger on the use of hydro- gen than of air or oxygen. Exception may also be taken here to the author's use of the word dyspnoea, whereby he wrests it from its univer- sal clear and symptomatic meaning of increased respiratory effort with want of air, and devotes it to a condition of the respiratory center, due to vitiation of blood, for the reason, namely, that neither of these definitions includes the other; for we may have, on the one hand, as already detailed, a peripherally arising dyspnoea, and on the other, as in the experiments of Gad and of Sig. Mayer, already cited, a 10 THE FACTORS OF THE RESPIRATORY RHYTHM vitiation of the blood with diminished rather than increased breathing; or, as in the author's case, a diminished respiratory effort with increasing vitiation of the blood, until finally the inhibition of the respiration is broken through by the increased excitation of the center; or, again, a stoppage of the breathing after a dyspnoeic patient draws the first long breath or two upon a tracheotomy, or the same when, after a severe haemorrhage, a transfusion is quickly made ; and yet in all these cases the center contain vitiated blood and tissue fluid, the condition of which has only begun to be- come normal. The difficulties, moreover, to which such a conception of dyspnoea are apt to lead is illustrated in the last sen- tence of the quotation, in which the animal is spoken of as "dyspnoeic," when in reality it is apnoeic (17). That the above-mentioned experiment, as given to us, is, furthermore, of altogether too complicated a nature to be more than food for controversy, or better, perhaps, for further investigation, is indicated by the following considerations, as well as by the description itself: 1. It has been shown, especially by the above-cited ex- periments of Gad and M. Rosenthal, which covered the use of both gases concerned, that dyspnoea unmistakably appears upon a slight increase of the carbonic acid in the inspired air, while a much greater corresponding decrease of oxygen in an atmosphere breathed is requisite for a similar effect; in fact, they consider that in respiration from a limited air space the dyspnoea is in reality occa- sioned by the carbonic acid. 2. In the above-cited experiments of Head, the condi- tions for the diffusion of carbonic acid from the blood into the pulmonary alveoli were apparently the same in all three cases. 3. By reason of the quietude of the animal, which, in AND THE REGULATION OF RESPIRATION. 11 the first place, narcotized, in the second made no respira- tory effort, the general consumption of oxygen was un- doubtedly small; the vitiation of the blood in general was, therefore, reduced to a minimum from the beginning of the experiment on. 4. As the respiratory center had ceased its respiratory activity, we may assume both its call for oxygen and the vitiation of the blood and tissue fluid within it to have been abnormal-to have been abnormally small. 5. In that the insufflations with hydrogen, commencing during normal respiration, were superimposed upon the residual plus the reserve atmospheric air then in the chest, there was merely less oxygen available therein than when air or oxygen was injected. 6. By their considerable duration (some twenty sec- onds), and the continually lessening haematosis, especially in the case of the hydrogen insufflations, the excitability of the respiratory center would by this of itself be reduced- would not, therefore, respond so quickly or so well (1, 16). That this was the case is to be seen from the last sentence of the quotation, which seems to contradict the previous statement concerning the effect of hydrogen. 7. Where less oxygen is furnished to the organism, less carbonic acid is formed (15). 8. The data given are insufficient for estimating the two variable factors at the center-namely, its excitability, and the amount of excitant offered to it. As indicated at the beginning of this paper, an inhibi- tory function of the pulmonary vagus in ordinary respira- tion has been established and without recourse to excita- tion of the nerve stem-namely, the power of cutting off inspiration and inducing expiration, which was maintained in the first part of the theory of Hering and Breuer. 12 THE FACTORS OF THE RESPIRATORY RHYTHM This fact was rendered probable by the experiments of these observers (2), who noted the effect on the respiratory efforts of pulmonary insufflations in the intact animal and the absence of such effect after the vagus was cut. The conclusive proof of the same was brought by Gad (1), who, by using chloral instead of opium as a narcotic, by a means of precisely and continuously registering the changes in the volume of the lungs with inspiration and expiration (18), but chiefly by the employment of a new and trustworthy method of suddenly interrupting the nervous impulses coursing through the vagus without exciting the nerve thereby-namely, by locally freezing it-was enabled to observe, so soon as this latter was done, that the inspira- tions were deepened and their frequency reduced, just as is found some time after cutting the vagi, and also that the respiration was carried on with a much greater distention of the chest, while a new pause, relative or absolute, ap- peared at the end of inspiration, and the normal one at the end of expiration in ordinary quiet respiration disappeared, so that the tracing of the latter appeared inversed and magnified from the moment on when both nerves were frozen through, although the animal often breathed less air thereafter than before. From this alteration of the type of respiration it is evi- dent that a restraining, an inhibitory influence has been re- moved ; for, as above said, not only were the individual inspirations now deeper, but the inspiratory muscles con- tinued each time in a state of contraction after the inflow of air had ceased, while the expirations were cut short by a new inspiration, so that altogether the mean expansion of the chest remained by a considerable amount above its for- mer level. We are also furnished, however, by the above experi- ment with the presumption of the sufficiency of the direct AND THE REGULATION OF RESPIRATION. 13 action of the respiratory center in inciting inspiration, for the respiratory activity upon eliminating the influence of the vagi, instead of decreasing, has markedly increased. We find, moreover, in the following experiments of Flint (19), to which we would call especial attention by reason of their obvious incompatibility with the theory of Dr. Meltzer, a further evidence of the sufficiency of the action of the res- piratory center for the incitation of ordinary respiration. This observer noted in an animal abundantly and regularly supplied with air by a bellows, and which in consequence thereof had ceased respiratory effort, that the latter would begin upon letting arterial blood, and that the same would occur whether the vagi were intact or cut. The conclusion of the author therefrom-that the incitation to inspiration did not flow from the lungs-was the first emancipation from the confusion that seems to have been stamped upon the subject by the various memoirs of Marshall Hall (20). The complement to this was furnished by Rosenthal (11a), who showed, by cutting the various cerebral and sensory paths to the medulla oblongata, that respiration was not a reflex act. Hermann and Escher (21), by occluding the veins lead- ing from the brain and cervical cord, showed that it was merely lack of circulation and not the emptiness of the blood-vessels by which, in Rosenthal's researches on this point, the dyspnoea was caused, and that therefore the con- clusion of the latter-that occlusion of the cerebral arteries acted by disturbing the tissue changes in the center-was justified. As pointed out by Gad, the pause following normal quiet expiration indicates that the inhibitory influence from the vagus, which cuts off the inspiration, overlasts the lat- ter. The existence of this pause at the end of expiration and the absence of such at the end of normal inspiration are adduced by him, in addition to the presumable suffi- 14 THE FACTORS OF THE RESPIRATORY RHYTHM ciency of the central incitation to inspiration, against the second part of the theory of Hering and Breuer, according to which the inspiration is incited by reflex from the dimin- ishing lung, just as expiration is induced by inhibitory re- flex from the expanding lung. As this view still remains undemonstrated, notwithstand- ing extended researches directed to the same (4), we may regard the causation of the respiratory rhythm in the fol- lowing manner, substantially as formulated by Gad, who divides it into three factors, namely : 1. To incite inspiration : The constant presence in the respiratory center of an excitant, probably carbonic acid. 2. To occasion expiration: The lowering of the excita- bility of the center below the point of .response to the amount of excitant present through mechanical excitation of the vagus in the lung in inspiration. 3. For the continuance of expiration: A persistence of this effect until the excitability of the center has again become sufficiently great to determine reaction to the ex- citant. Upon this basis a regulation of the respiration-namely, of the depth and frequency of the respiratory efforts and of the mean distention of the chest, according to the position, condition, and activity of the individual-would depend (1) upon the constituency of the blood furnished to the respira- tory center, and (2) upon the nervous impulses of various kinds which, reflected upon the respiratory center, raise or diminish its excitability, the latter acting to supplement the former, just as at birth a cold shock assists the stoppage of the placental circulation in occasioning the first respiratory efforts. With reference to the constant influence of the vagus upon respiration, which we have already noted in the re- searches of Gad on the normally breathing animal, the AND THE REGULATION OF RESPIRATION. 15 following experiment by Hering and Breuer (2), which demonstrated the presence of. such an influence under the conditions specified and showed it to be independent of the motions of the lungs, concerns us respecting the theory of Dr. Meltzer at this point. Upon sending a constant, even current of air through the thereby distended and multiply- punctured lungs, the rhythmic respiratory efforts continue, and they at once diminish in frequency upon cutting the vagi, just as in the normally breathing animal. Recently it has been found by Loewy (22) that, by ren- dering one lung airless, impulses cease to flow therefrom to the respiratory center through the vagus, which was shown by cutting the vagus of the other lung, when the respira- tion changes, just as after section of both vagi in the nor- mal animal, while section of the nerve on the side of the atelectatic lung causes no change in the respiration; and it has been confirmed by inflating the airless lung, when, if its vagus be intact, the former frequency, and we may allow ourselves to believe also the former type of respiration, is restored. These experiments, as well as the simple pulmonary in- sufflations of Hering and Breuer and of Head, have been considered to show that it is the expansion of the lung that excites the fibers inhibitory of inspiration in the vagus, and Dr. Meltzer has founded his theory of respiratory rhythm, as before stated, on this idea. Without going further into the question in this place, I wish, however, to call attention to the fact that this is only an inference ; for in the experiments of the above- named observers there was, besides expansion, also pressure present, and, in fact, considerable pressure, the influence of which, if it have an influence, was not excluded or con- sidered by them. The researches of Loewy, in the absence of such exclu- 16 THE FACTORS OF THE RESPIRATORY RHYTHM sion, simply show that the constant normal inhibitory in- fluence of the vagus on the respiration may be due to the state of expansion of the lungs, or to their intermittent active expansions, or to the intermittent pressure or rise of pressure in the alveoli, or to some two or all of these. But another supposition in this theory deserves atten- tion, in that it could have been readily avoided by leaving the question an open one-namely, the assumption of two kinds of pulmonary fibers in the vagus for ordinary respira- tion ; the one for inspiration, the other for inhibition of the same; for it is possible that, by reason of the nature of their connections with the central ganglia, or of their end- ings in the lungs, one set of fibers suffices for all functional purposes, so that one degree or kind of excitation effects ordinary incitations or inhibitions ; other degrees or kinds of excitation, extraordinary incitations or inhibitions. This is an alternative, mentioned indeed by Hering and Breuer in connection with their own experiments, and were still more worthy of regard in building upon the effects of arti- ficial excitation of the nerve stem. In conclusion, it remains only to note that the communi- cation of Dr. Meltzer is restricted to his explanation of the respiratory rhythm, and does not concern itself with the regulation of respiration; indeed, the question that very naturally suggests itself-namely, what self-regulation of the respiration can, under any normal circumstances, be exerted alone by an expanding lung, which by one and the same process excites both inhibiters and exciters of the respiration-is not even alluded to. 1. Gad. Die Regulirung der normalen Athmung. Du Bois- Reymond's Archiv, 1880, p. 1. 2. Hering and Breuer. Die Selbststeuerung der Athmung References. AND THE REGULATION OF RESPIRATION. 17 durch denNervus Vagus. Berichte d. Alcad. d. Wissenschaften zu Wien, 1868, II. Abthl., Band 58. 3. Kronecker und Meltzer. Ueber den Scbluckact und die Rolle der Oardia bei demselben. Du Bois-Reymond's Archiv, 1881, p. 465. 4. Head. On the Regulation of Respiration. Journal of Physiology, 1869, vol. x, p. 1. 5. Knoll. Athmung bei Erregung der Vaguszweige. Ber. Alcad. Wiss. Wien, 1883, Band 88, III. Abthl. 6. Berns. Over den invloed van verschillende Gassen op de Adembevveging. Onderzoolcingen gedaan in het Physiol. Labor, der Utrechtsche Hoogschool, 1870, 2°, Reeks III. 7. M. Rosenthal. Ueber die Form der Kohlensaure- und Sauerstoff-dyspnoe. Du Bois-Reymond's Archiv, 1886, p. 248. 8. Gad. Ueber automatische und reflectorische Athemcen- tren. Verhandlungen der physiolog. Gesellschaft zu Berlin. Du Bois-Reymond's Archiv, 1886. 9. Goldscheider. Ueber der Einwirkung der Kohlensaure auf die sensiblen Nerven der Haut. Verh. physiol. Gesellsch. zu Berlin. Du Bois-Reymond's Archiv, 1887, p. 575. 10. Knoll. Athmung bei Erregung sensibler Nerven. Ber. Wiener Alcad., 1885, Band 92, III. Abthl. 11. Rosenthal. Die Athembewegungenund ihre Beziehungen zum Nervus Vagus, Berlin, 1862. Ila. Rosenthal. Studien uber Athembewegungen. Zwei- ten Artikel. Du Bois-Reymond's Archiv, 1865, p. 192. 12. Dohmen. .Untersuchungen uber den Einfluss der die Blutgase auf die Athembewegung ausiiben. Unters. aus dem physiol. Labor, in Bonn, 1875. 13. Fredericq. Proc6d6 operatoire nouveau pour l'6tude physiologique des organes tboraciques. Bulletin de Vacad. roy. d. Belgique, 3 S6rie, t. 13, N. 4, p. 417. 14. Miescber-Rusch. Bemerkungen zur Lehre von den Ath- embewegungen. Du Bois-Reymond's Archiv, 1885, p. 355. 15. Kempner. Neue Versuche iiber den Einfluss des Sauer- stoff gehaltes der Einathmungsluft auf dem der Oxydationspro- cesse in thierischen Organismus. Du Bois-Reymond's Archiv, 1884, p. 396. 18 THE RESPIRATORY RHYTHM. 16. See Langendorff. Ueber die automatische Thatigkeit des Athmungs-centrums. Du Bois-Reymond's Archiv, 1888, p. 283. 17. Gad. Ueber Apnoe, Wurzburg, 1880. Gad und Wegele. Ueber die centrale Natur reflectorischer Athmungshemmung, Wurzburg, 1882. 18. Gad. Ueber einen neuen Pneumatographen. Verb, physiol. Ges. Berlin. Du Bois-Reymond's Archiv, 1879, p. 181. 19. Flint. Experimental Researches on Points connected with Respiration. Amer. Jour, of the Akd. Sciences, New Se- ries, 42, 1861, vol. ii, p. 341. 20. Marshall Hall. Memoirs on the Nervous System, Lon- don, 1837. 21. Hermann und Escher. Ueber die Krampfe bei Circula- tionsstdrungen im Gehirn. Pfluger's Archiv d. Physiologic, Band 3, p. 3. 22. A. Loewy. Ueber den Tonus des Lungen-vagus. Pflii- ger's Archiv, 1888, Band 42, p. 273. W A REASONS WHY Physicians Should Subscribe roR The New York Medical Journal, Edited by FRANK P. FOSTER, M. D.,1 Published by D. APPLETON & CO., 1, 3, & 5 Bond St. x, BECAUSE : It is the LEADING JOURNAL of America, and contains more reading-matter than any other journal of its class. 2. BECAUSE: It is the exponent of the most advanced scientific medical thought. 3. BECAUSE: Its contributors are among the most learned medical men of this country. 4. 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