Mechanism of neurogenic pulmonary edema∗

Mechanism of neurogenic pulmonary edema∗

Mechanism of Neurogenic Pulmonary Edema* ALDO A. LUISADA, M.D., F.A.C.C. Chicago, C Illinois blocking agents, the exact mechanisms remained elusi...

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Mechanism of Neurogenic

Pulmonary Edema*

ALDO A. LUISADA, M.D., F.A.C.C. Chicago,

C

Illinois

blocking agents, the exact mechanisms remained elusive. Emphasis was first placed on the carotid sinus baroreceptors,16 then on the carotid A suggestion was made body chemoreceptors’7 that central stimulation led to an increased permeability of the lung capillaries, possibly mediated by histamine or other vasoactive substances. Other studies demonstrated the effectiveness of sympatholytic drugs in forms of pulmonary edema caused by ingestion of ammonium chloride (Koenig and Koenig18), trauma to the chest (Daniel and Cate*g), pulmonary embolism (Laurent et al., *O Singer et a1.2L), and even experimental coarctation of the aorta (SarnoV2t). More recently Kov&h and co-workersz3*** perfused the head of a dog from the trunk of a Large doses of epinephrine and saline donor. injected into the trunk of the donor caused less severe edema in the lungs of this animal than in those of the recipient, whose heart and lungs were not reached by the drug. A rise of left atria1 pressure was ascribed to “left ventricular failure” of unexplained origin. FollowEpinephrine-Induced Pulmonary Edema:

LINICAL observation of the frequency of pulmonary edema in trauma to the skull,1-3 cerebrovascular accidents* and neurological conditions,3 and the fact that morphine is more effective than digitalis in the clinical treatment of attacks of pulmonary edema led to studies of “neurogenic” pulmonary edema by various experimental methods. EXPERIMENTAL STUDIBS Pharmacologic studies5 s6 demonstrated that morphine, phenobarbital, chloral hydrate and various other narcotics and sedatives were effective in the treatment of experimental pulmonary edema induced in the rabbit by the intravenous injection of adrenalin (a combination of epinephrine and norepinephrine). Subsequent experiments’,s showed that high pressure perfusion of the “isolated” dog head Howalso induced severe pulmonary edema. ever, the demonstration that hidden venous channels still permitted drainage from the head to the trunk led me to discount these results. Jarisch et al.9 described a form of pulmonary edema caused by intracisternal injection of Subsequent studies with this meveratrine. thod,lOp’l as well as with intracisternal injection of thrombin and fibrinogen,12 showed that paroxysmal systemic hypertension preceded pulmonary edema. This seemed at first to shift the emphasis from the central nervous system to the left ventricle. However, a new concept was soon advocated: that of redistribution of blood causing active congestion and edema of the lungs.13-15 Luisada and Sarnoff16 employed rapid intracarotid infusions of saline toward the brain and obtained pulmonary edema with volumes of fluid which had little effect when injected intraWhile the role of the central nervous venously. system seemed established by the preventive effect of hypnotics, sedatives and ganglionic

ing this study, the author and his co-workers25l26 tried injecting epinephrine in blood into a carotid artery toward the brain, a simplified technic, compared and the same doses of epinephrine The and blood injected into a peripheral vein. most striking result noted was a tremendous rise of left ventricular diastolic pressure to levels of This rise, which was accom50 to 80 mm. Hg. panied by marked dilatation of the heart, might be considered related to left ventricular failure. However, the following facts do not support (1) This rise occurs rapidly, such contention: often within one or two minutes; in the first period of these experiments, this rise is reversible; (2) a large dose of ouabain does not det This study has necessarily led to a re-evaluation the original work of Welch.27

of

* From the Division of Cardiovascular Research, The Chicago Medical School, Chicago, Ill. This study was made during the tenure of Training Grants HE-5002 and HE-5182, as well as Research Grant HE-09527 of the National Heart Institute, U. S. Public Health Service. 56

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crease such a rise; (3) the first derivative (dp!dt) of left ventricular pressure (an index of cardiac contractility) shows a sharp increase of the early-systolic wave, which persists nearly to the end; and (4) a similar or greater rise of left ventricular systolic pressure follows the injection of methoxamine while left ventricular diastolic pressure rises less than in standard experiments and no pulmonary edema occurs. The final accepted interpretation was (a) the systolic and diastolic overloads of the heart represented a favoring element; (b) the effect of epinephrine on the left ventricular wall caused a rise of diastolic pressure which was transmitted to the pulmonary capillaries; and (c) brain stimulation potentiated the effect of epinephrine both in its peripheral and cardiac effects. Veratrine-Induced Pulmonary Edema: Following these experiments, and a similar one in rabbits,27 another study was conducted in animals in which brain stimulation was obtained by means The of an intracisternal injection of veratrine.27 same sequence of events was noted : paroxysmal hypertension, increase of the first derivative of left ventricular pressure, and rise of left ventricular diastolic pressure followed by pulmonary These results parallel those obtained by edema. the previous method and are significant because no exogenous epinephrine was employed and no increase of total blood volume was involved. Thus, they are the most similar to the sequence of events in clinical conditions with irritation of brain centers. THEORIES OF PULMONARY EDEMA The oldest theory, that of Welch,27 attributed pulmonary edema caused by aortic obstruction to acute left ventricular failure. However, he failed to take into account changes in the peripheral circulation and in the circulation of the brain. These were considered more fully by Sarnoff.22 Teissier28 attributed pulmonary edema of hypertensive patients to a neurogenic, sudden dilatation of the pulmonary vessels but failed to demonstrate such a mechanism. Sarnoff’3-15 explained “neurogenic” pulmonary edema as due to sympathetic stimulation, peripheral vasoconstriction, massive displacement of blood from the periphery to the heart and pulmonary bed, and finally “relative heart failure.” For this reason, he suggested the term neurohemodynamicpulmonary edema. Factors in Neurogenic Pulmonary Edema: Our finding of an apparent shift in left ventricular diastolic compliance or response seems once VOLUME

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more to change the emphasis from the periphery to the center and may lead to the impression that we have gone full circle. However, three elements seem to be essential in this “neuro(1) periphgenie” type of pulmonary edema: eral vasoconstriction leading to a systolic ovcrload of the left ventricle; (2) mobilization of the blood toward the right heart and lungs causing a diastolic overload of the left ventricle; and (3) inadequate relaxation or response of the left ventricle causing an inordinate rise of the left ventricular diastolic pressure, and followed by a rise of left atria1 and pulmonary capillary pressures. The importance of the first two factors is cow firmed by the fact that veratrine-induced pulmonary edema fails to appear in animals if their spinal cord is cut.zg The importance of the third factor seems obvious: In no experiment of our series did pulmonary edema occur unless left ventricular end-diastolic pressure rose above 35 mm. Hg and persisted at that level for several Therefore, pulmonary edema followminutes. ing injury or irritation of the brain is related to a “cardiovascular storm” with special overburden of the heart and with characteristic abnormalities of cardiac function. Thejinal determinant of the edema is a rise of pulmonary capillary pressure caused by the abnormal relaxation of the left ventricle. If the left ventricle is damaged, actual left ventricular failure may occur during the sequence of events. If the heart is normal, “failure” in the accepted sense of the term cannot be considered present. SU~~MARY

The mechanism of paroxysmal puln~onary edema following brain injury or irritation is discussed after a review of older and recent experimental studies. It is concluded that both a systolic and a diastolic overload of the left ventricle, connected with sympathetic stirnulation, are necessary elements. However, a recently described phenomenon, i.e., inadequate left ventricular relaxation caused by the same adrenal-sympathetic mechanism, seems to play an essential role by rapidly elevating the pressure in the pulmonary capillaries. REFERENCES et mort par oedtme pulmonaire aigc chez les bless& crania-enchphaliques. (Relation de ces faits aux rccherches recentes sur les fonctions des capsules surrtnales.) Presse mid., 26: 108, 1918.

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Hypertension

2. ANTONINI, A.

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BIANCALANI, il.

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Luisada nei traumatizzati de1 crania. Arch. antrop. trim., 47: 747, 1927. GERNEZ, C. and MARCHANDISE, C. Les oed&nes aigus du poumon d’origine nerveuse. Gar. d. hGp., 106: 483, 1933. WEISMAN,S. J. Edema and congestion of the lungs resulting from intracranial hemorrhage. &r&y, 6: 722, 1939. LUISADA, .4. A. Neue Untersuchungen fiber die Wirkung des Morphiums auf Blutgef%se, besanders Lungengefssse. Arch. exper. Path. u. Pharmakol., 132: 296, 1928. LUISADA,A. A. Beitrag zur Pathogenese und Therapie des Lungenoedems und des Asthma cardiale. Arch. rxper. Path. IL. Pharmakol., 132: 313, 1928. LUISADA, .4. .\. Ipertensione encefalica ed edema polmonare sperimentale di natura riflessa. Boll. Sot. ital. biol. sper., 5 : 528, 1930. LUISADA, A. A. I fattori nervosi dell’edema polmonare acute. In: Frugoni, C. L’Edema Polmonare Acute, p. 164. Roma, 1930. Pozzi. JARISCH, A., RICHTER, H. and THOMA, H. Zentrogenes Lungenoedem. Klin. Wchnschr., 18: 1440, 1939. ARAVANIS, c. et al. Pulmonary reflexes in pulmonary edema? Am. J. Physiol., 189: 132, 1957. JACONO, _4., KAPLAN, M. and LUISADA, A. A. Relative mitral insufficiency as a factor of paroxysmal pulmonary edema. Cardiologia, 39: 1, 1961. CAMERON,G. R. and DE, S. N. Experimental pulmonary oedema of nervous origin. J. Path. GY Bact., 61: 375, 1949. SARNOFF, S. J. and SARNOFF, L. C. Neurohemodynamics of pulmonary edema. I. Automatic influence on pulmonary vascular pressures and the acute pulmonary edema state. Dis. Chest, 22: 685, 1952. SARNOFF,S. J. and SARNOFF, L. C. Neurohemodynamics of pulmonary edema. II. The role of sympathetic pathways in the elevation of pulmonary and systemic vascular pressures following the intracisternal injection of fibrin. Circulation, 6: 51, 1952. SARNOFF,S. J., GOODALE,W. T. and SARNOFF,L.C. Graded reduction of arterial pressure in man by means of a thiophanium derivative (Ro-2-2222). Preliminary observations on its effect in acute pulmonary edema. Circulation, 6: 63, 1952. LUISADA, .\. -4. and SARNOFF, S. J. Paroxysmal mclnarc

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pulmonary edema consequent to stimulation of cardiovascular receptors. Am. Heart J., 31: 270, 1946. LUISADA, A. A. and CONTRO,S. Experimental pulmonary edema following rapid carotid infusion: Mechanism and therapy. Circulation Res., 1 : 179, 1953. KOENIG, H., and KOENIG, R. Studies on the pathogenesis of ammonium pulmonary edema. Am. J. Physiol., 158: 1, 1949. DANIEL, R. A4., JR. and GATE, W. R., JR. “Wet lung”-an experimental study. I. The effects of trauma and hypoxia. Ann. Surg., 127: 836, 1948. LAURENT,D., LARRAIN, G., SINGER,D., PICK, R. and KATZ, L. N. Mechanisms causing bilateral pulmonary edema following unilobar miliary embolization as revealed by the action of certain pharmacological agents. Am. J. Physiol., 191: 431, 1957. SINGER,D., SALTZMAN,P. W., RIVERA-ESTRADA, C., PICK, R. and KATZ, L. N. Hemodynamic alterations following miliary pulmonary embolization in relation to the pathogenesis of the consequent diffuse edema. Am. J. Physiol., 191: 437, 1957. SARNOFF, S. J. Some physiological considerations in the genesis of acute pulmonary edema. In: Pulmonary Circulation, p. 273. Edited by ADAMS, W. R. and VEITH, I. New York, 1959. Grune 8r Stratton. Kovbcrr, A. G., R~HEIM, P. S., IRANYI, M., KISS, S. and ANTAL, J. Effect of the isolated perfusion of the head on the development of ischaemic and hemorrhagic shock. .4cta Physiol. Acad. SC. Hung., 14: 231, 1958. KOVACH, A. G. B. Neurohaemodynamische Zusammenhaenge bei der Entstehung des Lungenoedems. Allerg. Asthma, 10: 338, 1964. LUISADA,A. A., WORTHEN, M. and PLACIK, B. Left ventricular function in pulmonary edema induced by central stimulation (Abstr.). Fed. Proc., 25: 693, 1966. WORTHEN, M., PLACIK, B., .ARGANO,B., MACCANON, D. M. and LUISADA, .4. A. The cardiovascular mechanism of “neurogenic” pulmonary edema. Am. J. Physiol., in press. WELCH, W. H. Zur Pathologie des Lungenoedems. Virchows Arch. path. Anat., 72: 375, 1878. TEISSIER,J. De I’otdeme aigu du poumon. Compt. rend. XIII Congr?s Int. med., 4: 190, 1900.

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