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CLINICAL PROGRESS

Acute Pulmonary Edema

Pathology, Physiology and Clinical ManagementBy A. A. LuISADA, M.D. AND L. CARDI, M.D.

Acute pulmonary edema may be associated with the most varied clinical conditions includingcardiovascular, renal, cerebral, and pulmonary diseases, trauma to the skull or chest, infections,and shock. Many drugs and physical means have been employed in the treatment of this syn-

drome. Two main clinical types of pulmonary edema may be differentiated because of the differenteffect of therapy in each of them. Antifoaming therapy, a purely symptomatic method of treat-ment, tends to break a vicious circle and may be lifesaving. It should be employed initially whilethe patient is being examined and drugs or other remedies are being selected for possible addi-tional treatment.

NO BETTER definition of edema of thelungs can be given than that ofLaennecl (1834): "Edema of the lung

is the infiltration of serum into the substanceof this organ, in such degree as evidently todiminish its permeability to the air, in respira-tion." While edema of the lungs is initiallysimilar to edema of other organs, the struc-tures surrounding the capillaries are so thinthat an immediate outpouring of fluid intothe alveolar cavities* occurs. In this respect,pulmonary "edema" is followed by pulmonary"exudation."The term "pulmonary edema" carries with

it different associations to different specialists:to the pediatrician, acute glomerulonephritisor rheumatic carditis; to the surgeon, thoracicor abdominal intervention; to the neurologist,cerebrovascular accident or trauma to the skull;to the cardiologist, hypertension, coronary oc-clusion or mitral stenosis.

ETIOLOGY

Contrary to a widely accepted view, acutepulmonary edema can be encountered in a greatvariety of conditions, as shown by necropsy

From the Division of Cardiology of The ChicagoMedical School and Mount Sinai Hospital, Chicago,Ill. This study was done under a Teaching Grant ofthe National Heart Institute, United States PublicHealth Service, Bethesda, Md.

* To a more limited extent, fluid also appears inthe pleural cavities.,

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findings (table 1). The frequency of pulmonaryedema in the various diseases is indicated intable 2. A more detailed study of the variousconditions which may be associated with acutepulmonary edema is presented in table 3.A large number of clinical cases succumb

without pulmonary edema; this disorder, there-fore, is not a "terminal" or "agonal" phe-nomenon to be considered as the necessaryprecursor of death.A brief review of the most common causes of

pulmonary edema in clinical cases follows.(1) Pulmonary Edema and Arterial Hyper-

tension. This type of pulmonary edema was inthe past most common' but is now seen lessfrequently, partly on account of more effectivetreatment of various clinical conditions, andpartly because other types tend to predominate.Chronic nephritis with uremia is frequentlyaccompanied by episodes of edema of the lungs.In certain cases, moderate nitrogen retentionmay be the only evidence of renal insufficiencyand there may be little or no acidosis. All otherforms of hypertension, including essential hy-pertension and that of coarctation of the aorta,may present pulmonary edema. Cases withmalignant hypertension have these paroxysmalattacks more commonly than others.

(2) Pulmonary Edema and Coronary HeartDisease. The observation that severe coronaryocclusion is frequently accompanied by pulmo-nary edema has led to the belief that minorcoronary episodes may also contribute to these

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TABLE 1-Main Necropsy Findings in 100 UnselectedCases of Pulmonary Edema (from Cameron2)

Pathology No. of Cases

Severe coronary disease .............. 34Congestive failure ................... 32Carcinoma of various organs (carcinoma

of lungs = 15 cases; obstruction ofpulmonic veins = 11 cases) .......... 27

Bronchopneumonia. .................. 23Hypertensive heart disease ........... 18Massive pulmonary embolism ......... 10Cerebral hemorrhage................. 9Cerebral tumor...................... 7Tuberculosis .......................... 6Liver cirrhosis ....................... 6Fractured skull ....................... 3Multiple fractures (excluding skull). . 2

attacks. However, no certain proof has beenpresented, and the mechanism of productionof the edema might be somewhat different fromthat in hypertensive patients. Cardiogenicshock is more frequently associated with pulmo-nary edema than other types of shock. Pro-tracted forms are common in coronary heartpatients.

(3) Pulmonary Edema and Cerebral Diseases.The occurrence of pulmonary edema in cases

of meningitis, encephalitis, or brain tumor isrelatively common, in children as well as adults.Cerebrovascular attacks, including hemor-rhage, embolism, or thrombosis, and sub-arachnoid hemorrhage, as well as trauma to theskull, are frequently followed by pulmonaryedema. Undoubtedly, coronary lesions and pre-

existing hypertension may be contributingfactors in certain cases. However, in others,no evidence of such lesion or disorder can bedemonstrated clinically following recovery, or

at autopsy.(4) Pulmonary Edema and Pulmonary Heart

Disease. Contrary to current opinion, this as-

sociation is far from rare. Pulmonary edemamay follow pulmonary embolism. Occlusion ofa stem of the pulmonary artery causes increasedflow in the other, and this may favor highcapillary pressure in one lung. Even occlusionof smaller branches may cause diffuse, bilateraledema, a fact which has led to numerous

speculations. In chronic cor pulmonale withright ventricular hypertrophy and pulmonary

hypertension, acute pulmonary edema may de-velop. This is particularly true in the formscausing no destruction of capillaries and nopulmonary ischemia.

It is likely that vascular obstruction or de-struction of a number of vascular districts (fi-brosis, emphysema) favors pulmonary edemaof other areas and districts. It is known thatone-half of the pulmonary vessels can carrythe entire flow of the lesser circulation withoutany increase in pressure. However, this is ob-tained through distention of the normal vesselswhich, in itself, predisposes to edema. When-ever an increase of venous return takes placein such patients, the already distended (nor-mal) vascular districts are taxed beyond physi-ologic limits and transudation is likely to occur.In addition, sudden pulmonary edema was ob-served in cases with deformity of the chest(pulmonocardiac failure of Chapman, Dill andGraybiel23). It is self-understood that, when-ever other causes of pulmonary edema arepresent, this condition may develop in casesof chronic cor pulmonale like in others. Thisparticularly applies to systemic hypertensionand coronary heart disease. Anoxia would favorthe edema; narrowing of arterioles would de-crease its severity, at least in the involveddistricts.

(5) Pulmonary Edema in Trauma to theChest. This syndrome, called by surgeons"traumatic wet lung," has been the object ofconsiderable speculation and is of particularinterest because of its spreading from thedamaged to the intact areas of the lungs.

TABLE 2.-Frequency of Pulmonary Edema in 500 Au-topsies of Special Conditions (from Cameron2)

Total No. ShowingPathology No. of Pulmonary

Cases Edema

Hypertensive heart disease (ex-cluding chronic nephritis) ... 94 81 (86%)

Chronic nephritis ............ 50 37 (74%)Coronary occlusion ........... 66 45 (68%)Cerebral hemorrhage......... 66 44 (67%)Mitral stenosis ............. 84 55 (65%)Fractured skull ............. 38 24 (63%)Multiple fractures (excluding

skull) . ................ 28 17 (61%)Pulmonary embolism ............ 74 23 (31%)

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ACUTE PULMONARY EDEMA

TABLE 3.-Clinical Conditions Associated with Acute Pulmonary Edema

(A) Cardiovascular dis-ease

(B) Diseases or lesions ofthe central nervoussystem

(C) Diseases or lesions ofrespiratory system

(D) Allergy

(E) Following stimulationof hollow viscera

(F) Surgical and obstetri-cal cases

(G) Toxic

(H) Miscellaneous

1-Syphilitic heart disease (aortic insufficiency; aortitis; aortic aneurysm)2-Rheumatic heart disease (acute rheumatic carditis; mitral insufficiency; mitral

stenosis; aortic insufficiency; aortic stenosis)3-Coronary heart disease (severe, acute coronary occlusion; minor occlusion plus

extensive ischemia or fibrosis of the myocardium)4-Hypertensive heart disease (pheochromocytoma, essential hypertension; acute

glomerulonephritis; hypertensive nephropathies, especially if there is uremia;toxemia of pregnancy)

5-Congenital heart disease (coarctation of the aorta; atrial or ventricular septaldefect, patent ductus; Eisenmenger complex; Lutembacher syndrome)

6-Acute or chronic pulmonary heart disease (pulmonary embolism; chronic corpulmonale)

7-Shock (including that caused by exposure to x-ray radiation)8-Congestive failure1-Trauma to the skull2-Subarachnoid hemorrhage3-Cerebrovascular attack (hemorrhage, thrombosis, embolism, abscess or tumor)4-Encephalitis, meningitis, poliomyelitis, tetanus1-Pneumonia, bronchopneumonia (especially influenzal)2-Drowning, strangulation, asphyxia, respiratory obstruction (edema of the

glottis, bronchial asthma, foreign bodies)3-Inhalation of irritant or toxic gases (including those used in warfare); respiratory

burns4-Following rapid thoracentesis5-Following trauma to the chest6-Following lobectomyAngioneurotic edema; serum sickness; following injection of gold preparations; fol-

lowing inhalation of penicillin aerosol.1-Distention of esophagus, stomach, or gall bladder.2-Following too rapid emptying of distended bladder or ascites.1-During pregnancy or after labor (especially, but not only, in cases with rheu-

matic heart disease, eclampsia, or toxemia)2-Following transfusions or infusions (especially, but not only, in cardiac or

anemic patients)3-Following surgical manipulation of stellate gangliaFollowing use or overdose of thiourea derivatives, iodides, muscarine, eserine,

prostigmine, opium, methyl salicylate, acetic and butyric ether, phenylcar-bamide.

Thyroid crises. Beriberi. Insulin shock. Burns.

(6) Pulmonary Edema in Mitral Stenosis.The occurrence of pulmonary edema in caseswith a persistent block proximal to the leftventricle contradicted the established theorywhich attributed these episodes to acute leftventricular failure. It is only in recent yearsthat an adequate dynamic explanation has beenfound. Patients with mitral stenosis occasion-ally cough up large amounts of pure blood.This syndrome, called "pulmonary apoplexy,"is closely related to pulmonary edema and hasa similar, though not identical, mechanism.

(7) Pulmonary Edema and Infections. It hasbeen clearly established that pulmonary edemaand pneumonia may be closely interrelated.

Pneumonia may predispose to pulmonaryedema and vice versa; furthermore, they maysimulate each other. Many other febrile diseasesmay be complicated by pulmonary edema,partly through inflammatory lesion of theheart, lungs, or brain, and partly throughoverload of the circulation caused by thera-peutic intravenous infusions. Unexplainededema of the lungs may also develop duringthe chill phase of a febrile reaction.110

(8) Pulmonary Edema and Shock. Shock isfrequently associated with pulmonary edema.It is not known whether shock itself causespulmonary edema or whether both shock andpulmonary edema result from a common cause.

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Since cardiogenic shock is frequently associatedwith pulmonary edema and the latter dis-appears when shock is alleviated, the vascularmechanism of shock is probably of funda-mental importance.

THE CLINICAL EPISODE

An attack of pulmonary edema may occurat any time of day or night. Precordial oppres-sion or pain, restlessness, weakness, and dry,non-productive cough may precede the attack.If this occurs at night, a nightmare frequentlyprecedes the paroxysm. Respiration becomesdifficult and labored and is usually accelerated.The patient sits up in bed and may lean for-ward. Within a few minutes, gurgling soundscan be heard, and the patient repeatedly emitsa white, yellowish or pink frothy sputum. Thismay vary from a few bubbles to enormousamounts (as much as 2000 to 3000 cc. of foamwithin one to two hours). Cold, clammy ex-tremities, paroxysms of suffocation and vomit-ing may occur. The pulse and blood pressurediffer in the two main types of attacks asfollows:

(1) In most cases connected with coronaryocclusion, pulmonary embolism or allergicshock, the pulse is rapid and small (and maybe irregular), and the blood pressure dropsgradually, sometimes reaching shock level.Some cases of rheumatic mitral lesion alsoexhibit a drop in blood pressure.

(2) Other cases, particularly those withhypertensive or syphilitic heart disease or thosewith a cardiovascular accident, present a full

FIG. 1. X-ray film of the chest during pulmonaryedema.

pulse and a blood pressure either equal to orhigher than the previous level.

Physical examination reveals a high, tym-panic percussion note over the lung fields andinnumerable moist rales over the entire chest,which arise in the small bronchi, and gurglingsounds created by the foam in the trachea.X-ray of the chest reveals extensive shadows

in both lung fields (fig. 1).The temperature is usually normal during

the attack except with inflammatory edema,but may rise soon afterwards because of re-absorption of altered proteins from thelungs.The sputum has a chemical composition

similar to the fluid of angioneurotic edema orallergic coryza, and to the inflammatory effu-sions of large serosal cavities. This is true,not only of clinical episodes,4 but also of experi-mentally induced attacks.4'

Catheterization of the right heart has revealedthat pulmonary arterial pressure is severelyincreased and that pulmonary "capillary'"pressure rises to 32 to 54 mm. Hg during theattack."7' 47

EXPERIMENTAL PULMONARY EDEMA

Experimental pulmonary edema has beenobtained by using a great variety of meth-ods.

(1) Acute left ventricular strain has beenobtained by ligation of the aortic arch in therabbit,7 but this procedure is far from beingconstantly successful, especially if the chestis open,8' and cannot be duplicated in thedog.2" Acute right ventricular strain has teenprovoked by inducing pulmonary em-bolism."3, 72

(2) Acute ventricular damage was obtainedby reducing the left ventricular chamber7 10and by necrosis of either the left'1 12 or theright12 ventricular walls.

(3) Acute obstruction of the pulmonary veinswas tried in animals,6' 9 but, was not particu-larly successful.

(4) A complex mechanism involving thecardiovascular and nervous systems leads topulmonary edema following the intravenousinjection of epinephrinel4'-6 or l-norepineph-rine.'7 This procedure is consistently successful

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in the rabbit, guinea pig and rat, but not inthe dog or cat. A similar mechanism seems tooccur in hypoglycemia.73

(5) Trauma to the chest'8 and limited pul-monary embolism72 are of particular interestbecause they cause bilateral pulmonary edemain the dog.

(6) Enormous doses of intravenous infu-sions'9-22 or rapid intracarotid infusion of some-what smaller doses of saline or plasma are suc-cessful in producing pulmonary edema in therabbit,23 cat3 or dog.' 22

(7) Direct irritation of the bronchial treeis obtained by inhalation of toxic gases,26-24or intrabronchial injection of hypertonicsolutions.3

(8) Toxic pulmonary edema follows theinjection of methyl salicylate,27 muscarine28 29or alloxan,56 or the ingestion of thioureaderivatives30' 31 or ammonium chloride.32-34

(9) Cerebral damage or dysfunction has beenobtained through occlusion of the carotidarteries in the rabbit,35' 36 trauma to the brainin the dog,37' 38, 39 destruction of the hypo-thalamus in the rat40' 41 or the intracisternalinjection of veratrin42 or fibrinogen plusthrombin43 44 in the rat, rabbit or dog.

(10) A combination of stress applied to theleft ventricle (aortic insufficiency) plus in-travenous epinephrine or central nervous systemstimulation was successfully employed in the

dog.45 A similar result was obtained by aorticinsufficiency plus unilateral nephrectomy andcontralateral narrowing of the renal artery.7

PATHOGENESIS

The mechanism of production of pulmonaryedema has been explained in different ways.Most writers have attempted to evolve onetheory which might apply to all causes ofpulmonary edema. It is the feeling of theauthors that this is not feasible and that differ-ent mechanisms should be advocated.The oldest theory, advanced by Cohnheim19

and Welch7 in 1878, postulates acute leftventricular failure causing a rise of pulmonaryvenous pressure and then pulmonary edema(fig. 2A). This theory met with wide accept-ance and is even now currently invoked.Several objections can be raised:

(1) Many clinical cases of pulmonary edemahave a normal left ventricle and the initialsequence of events involves either the centralnervous system or the lungs. Some cases havesevere mitral stenosis or cor pulmonale andthe right ventricle is the cardiac chamberunder strain.

(2) Many clinical cases with acute leftventricular failure die in shock (cardiogenicshock) without pulmonary edema. This isprobably due to the fact that pulmonary capil-lary pressure rises only if there is good venous

A a

FIG. 2. Scheme of mechanism of pulmonary edema according to three theories. (A) Left ventricu-lar failure (passive congestion). (B) Pulmonary vasodilatation (active congestion). (C) Peripheralconstriction with pulmonary congestion.

LPr. = periphery.

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return to the right heart with a strongly activeright ventricle.A second theory was advocated by Teissier46

in 1900. Disregarding cardiac elements, heconsidered pulmonary edema as due to anactive, sudden dilatation of the pulmonaryvessels (fig. 2B). Even though this theory couldnot be accepted, the importance of reflexchanges of the pulmonary vessels has beenemphasized by one of the authors (A.A.L.)and his co-workers,3. 48 49 as well as by Cameronand Kuo.43 The following experimental dataseem to confirm the importance of these reflexesin the production of pulmonary edema, eventhough they may also be interpreted accordingto other theories.

(1) Bilateral stellectomy is effective inpreventing pulmonary edema caused by in-travenous epinephrine in the rabbit.48

(2) Rapid infusions produce different resultsdepending upon whether they are givenintravenously or injected into the carotidarteries. Denervation of the carotid sinus areaprevents this type of pulmonary edema.49 5

(3) Anesthetics, sedatives and sympatho-lytic agents are more effective in preventingmost types of pulmonary edema than vaso-dilators.63Another theory was advocated by Peserico3

in 1930 and revived by Sarnoff44 in 1952.This "neurohemodynamic pulmonary edema"emphasizes the massive displacement of bloodfrom the greater to the lesser circulation caused bystrong sympathetic stimulation (fig. 2C).

Three elements should be considered ofimportance in the production of pulmonaryedema.

(1) High Pressure in the Pulmonary Capil-laries. This is usually the result of forcefulcardiac dynamics. A sudden displacementof blood from the greater to the lesser circula-tion may favor the edema, especially in thepresence of decreased reserve of the leftventricle or mitral block. Severe peripheralvasoconstriction may be caused by epinephrine(anger, fright, exposure to cold), angiotonin(renal ischemia), or vasomotor stimulation(central lesions, reflex stimulation). Thisvasoconstriction causes increased arterial re-

sistance resulting in left ventricular strainon the one hand, and increase of venous returnto the right heart on the other. This tends,therefore, to produce a high pulmonary capil-lary pressure through a dual mechanism.High pulmonary arterial pressures are usu-

ally found in experimental pulmonary edemaand were also observed in clinical cases throughcatheterization.57 However, only a few suchcases have been studied so far. Pulmonaryedema, induced by inhalation of phosgene,fails to show pulmonary hypertension51 andseems to have a different mechanism. It istheoretically sound to assume that pulmonarycapillary pressures above 25 mm. Hg wouldlead to a transudation of plasma. However,much higher capillary pressures are requiredfor causing pulmonary edema in animals,whereas pressures of 30 to 40 mm. Hg are notunusual in mitral patients without evidenceof edema. Mitral patients experience a riseof pulmonary "capillary" pressure from 25 to30 mm. Hg to 32 to 54 mm. Hg during anattack of edema. It is interesting to note thatsimilar pressure increases are observed ineither mitral patients or hypertensive pa-tients in failure, during exercise tests withoutthe appearance of edema.47 Even though it ispossible that minimal edema is quickly drainedvia the lymphatic vessels, it seems likely thatother protective elements are also involved.A close relationship exists between humoral

and mechanical elements. This is well illus-trated by the observation that histamine exertsa more powerful constrictive effect on thevenules than on the arterioles of the lungs.62Thus histamine, by causing a marked increaseof pulmonary capillary pressure, may be oneof the contributing elements of pulmonaryedema.

(2) Increased Permeability of the PulmonaryCapillaries. This is favored by increased pul-monary flow (leading to dilatation of thecapillaries), allergy, poisons, anoxia, dyspnea(suction effect), chronic heart failure, inhala-tion of toxic gases. Speculations on whethercapillary permeability may be altered bynerve impulses without concomitant changesof capillary pressure have not, as yet, beensupported by conclusive evidence. There are,

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however, suggestive experiments, includingthe production of pulmonary edema withoutpulmonary hypertension through faradic stimu-lation of the stellate ganglion.4The part played by specific substances in

increasing permeability has been the objectof several investigations. The histamine contentof certain organs, especially of the lungs,58 isincreased after an injection of epinephrine.58 59

Large amounts of this substance are liberatedduring experimental pulmonary edema.58' 60Corticotropin (ACTH) decreases the mortalityof animals from experimental pulmonaryedema,52, 80 and this has led to speculation thatadrenal cortical hormones also play some rolein the mechanism of the attack.53' 80 This effectof corticotropin explains why different "stressreactions" inhibit pulmonary edema in ani-mals.52' 53, 80 The unexplained effect of splenicsubstances in favoring pulmonary edema ofthe rabbit80' 105-107 might be interpreted asbeing due to increased permeability of thepulmonary capillaries caused by substanceswhich are either formed by or are stored inthe spleen.

(3) Decreased Osmotic Pressure of the Blood.This occurs after prolonged saline infusions,in lipoid nephrosis, starvation or liver diseases.The effect of this factor is widespread. There-fore, either pulmonary edema is part of adiffuse anasarca or is favored by other edema-togenic factors.

A comprehensive work on pulmonary edemaof 25 years ago3 divided the factors of pul-monary edema into mechanical, neurogenic,and humoral. It is now possible to modify thisview by recognizing that most elements areinterrelated: chemical and endocrine productsmay cause vasoconstriction and changes ofpermeability; blood pressure changes may causereflex release of hormones or chemicals; andneurogenic elements may act either through thevasomotor system or through hormones. More-over, the part played by the various factorsis different according to the various causesand associated elements of pulmonary edema.Among the conclusions reached by experi-

mental workers, the following have a specialimportance:

Extreme stimulation of the brain or the carotidbody leads to direct or reflex stimulation of thesympathetic system, followed by severe vaso-constriction. This leads to increased peripheralresistance with increased loading of the leftventricle; displacement of a large mass ofblood from the arterioles, capillaries, and bloodreservoirs towards the veins; increased venousreturn; and, finally, filling of the blood vesselsof the lungs with a large quantity of blood.In other words, this stimulation causes anincreased output of the right ventricle, and, atthe same time, increased difficulty in theemptying of the left ventricle. This mechanismassumes great importance if there is leftventricular strain, and even more so if there isleft ventricular failure. Whether or not it issufficient to cause pulmonary edema with anintact heart is still open to question.The possible role of vascular phenomena of

the lesser circulation in favoring pulmonaryedema is still speculative. It is known thatarteriolar constriction in the lungs is presentin many clinical conditions associated withhigh pulmonary arterial pressure and preventsan excessive increase in pulmonary capillarypressure. Any relaxation of these arteries wouldfavor flooding of the capillary bed and edema.Some of the possible causes of loss of arteriolartonus, such as reflex vasodilation, direct effectof hormones, and direct effect of anoxia, stillrequire investigation.Anoxia causes a direct dilatation of the

pulmonary vessels and a reflex (carotid body)increase of cardiac output.55 The combination ofthese two elements strongly favors pulmonaryedema.The following considerations attempt to

explain the various clinical forms of pulmonaryedema.

(1) Pulmonary Edema Following MassiveMyocardial Infarction. When the power of theleft ventricle is suddenly decreased, there occursa marked increase of left atrial and pulmonarycapillary pressures. However, the latter persistsonly if adequate venous return is maintained.Therefore, a severe (but not too severe) lesionof the ventricle is the most effective. A periph-eral mechanism initiated by cerebral ischemia,carotid-sinus hypotension or carotid-body

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hypoxia, may contribute to the disturbanceby causing peripheral vasoconstriction. Theaccumulation of blood in the lungs is, therefore,very probably due to both a cardiac and avascular mechanism. The peripheral effects ofserotonin, liberated in the area of infarct,are still speculative.

(2) Pulmonary Edema of Patients withHypertension, Aortic Insufficiency or AorticStenosis; of Cases with Minor Coronary At-tacks; and Following Transfusion in Surgical,Obstetrical, Anemic or Cardiac Cases. Leftventricular strain is followed by increase ofleft atrial and pulmonary venous pressures.Excitement, exposure to cold, fear of deathor exertion, cause sympathetic stimulation andredistribution of the blood with its accumula-tion in the lungs, favoring thereby acute pul-monary edema. The increased peripheralresistance may transform ventricular straininto ventricular failure. Or else, transfusionsor infusions, by directly increasing the volumeof blood in the lungs and lowering osmoticpressure, further favor the edema.

(3) Pulmonary Edema of Nephritic Patients,Especially if Uremic. A mechanism similar tothat of (2) can be postulated. Retention ofmetabolites increasing capillary permeability(nephritis) or decreased osmotic pressure ofthe blood (nephrosis) may be among thefavoring causes.

(4) Pulmonary Edema Following Traumato the Skull or Lesion of the Central NervousSystem. In this type, there is severe centralsympathetic stimulation. This causes vaso-constriction and increased resistance placing asevere load on the left ventricle; it also leadsto redistribution of the blood and its accumula-tion in the lungs. While these elements favorpulmonary edema, other factors should alsobe taken into consideration such as dilatationof pulmonary vessels and liberation of sub-stances increasing capillary permeability (hista-mine, hyaluronidase, etc.).

(5) Mitral Stenosis. The outflow of bloodfrom the lungs is impeded by the mitral block,even during rest. Sympathetic stimulationcaused by excitement, exertion, exposure tocold, anger or fright leads to: (a) tachycardia,with shorter diastole and impaired emptying

of the left atrium; and (b) rasoconstriction,with redistribution of the blood and its ac-cumulation in the lungs. The effect of themitral block is proportionally increased bygreater venous return to the heart.

(6) Exposure to Toxic Gases. Here the mostimportant effect seems to be damage to thecapillary endothelium followed by liberation ofsubstances increasing capillary permeability.The role of reflexes arising in the mucosa ofthe respiratory passages is still to be evaluated.These reflexes and the effect of anoxia havespecial importance in cases of strangulation,asphyxia or drowning.

CLINICAL TYPES OF PULMONARY EDEMAWhile different signs have led to the recog-

nition of various clinical pictures of pulmonaryedema, duration of the episode allows divisionas follows: (1) fulminating (5 to 10 minutes);(2) acute (10 to 60 minutes) and (3) pro-tracted (1 to 36 hours).However, the attention of one of the writers

was called several years ago to the fact thattwo groups deserve separation because of thedifferent effect that treatment exerts on theclinical picture and on the final course.

Patients of the first group, which seems tobe the most numerous, present evidence ofincreased blood pressure,6' rapid circulation,increased cardiac output" and extreme risein pulmonary arterial pressure.57 This groupincludes cases with hypertensive heart disease;syphilitic or rheumatic heart disease with iso-lated aortic insufficiency; some of the cases withcerebrovascular accidents, mitral insufficiencyor minor coronary episodes; and patientstreated with too abundant venous infusions ortransfusions. It is apparent that any methodwhich succeeds in decreasing venous returnto the right heart will be most effective in thistype of edema.

Patients of the second group, less numerousbut tending to increase, present either nochange or a drop of blood pressure,6' decreasedcardiac output and a more moderate rise inpulmonary arterial pressure (some cases mayeven have a normal pulmonary arterial pres-sure). This group includes cases with massivemyocardial infarct, some of the cases with

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TABLE 4. Pharmacologic Treatment of Pulmonary Edema

Indication

Coronary occlu-

sion, CVA at-tacks

Hypertension, cor-

onary occlusion,mitral stenosis

Barbiturates, chloral See above

Mercurial diuretics See above

Ouabain, Digitoxin

Sympatholytics,

spinal anesthesiaAminophyllinAntihistaminics

Heparin*

Hypertension,CVA attacks

See above

See aboveAll cases

All cases

Contraindication

Other cases

Shock, allergy, toxicgases, pregnancy,

drowning, CVA attacks

See aboveSee above

Mitral stenosis. Massivemyocardial infarction.Toxic gases, drowning.

Shock, toxic gases,

drowningSee above

Mechanism of effect

Blocks vagus (increased heart rate helpsif there is severe bradyeardia)

Slower respiration, decreased metabo-lism, decreased reflexes, decreasedvenous return (probable), decreasedperipheral resistance

See aboveDecreased venous return and venous

pressure

Increased dynamics of both ventricles(mostly the right if the left is dam-aged or there is mitral obstruction)

Peripheral vasodilatation with shift ofblood from lungs toward periphery

See above (moderate effect)Prevention of histaminic effect on capil-

lary wall, possible central sedationDecreased permeability of capillary wall

* So far, only experimental pulmonary edema.

severe mitral or aortic block, some cases

following inhalation of toxic gases, some

cases of cerebrovascular accidents andsome cases with toxic, rheumatic or bacterialmyocarditis. While a reduction in venous returnmay be useful in these cases, it also carrieswith it the danger of precipitating shock.

THERAPY

The multiple etiologies and the variousmechanisms, which may be involved in pul-monary edema, have led to the employment ofa multiplicity of drugs and physical measures.

Unfortunately, tradition on the one hand anderroneous concepts on the other have pre-

vented, so far, a rational approach. Althoughlittle agreement exists between differentgroups of physicians, each group treats allcases of pulmonary edema in a similar manner.

Table 4 summarizes the various drugs;table 5, the physical or physicochemicalmethods of treatment.

Drug Therapy

Morphine. The empirical use of opiates isold. The value of morphine was demonstratedin various types of experimental pulmonaryedema.8, 16, 32, 63 Morphine terminates most ofthe mild and some of the severe clinical attacks.However, the best results are obtained in

TABLE 5.-Physical or Physicochemical Treatment of Pulmonary Edema

Treatment

Hot bathVenesection, application oftourniquets

Oxygen inhalationPressure respiration

Alcohol vapor or aerosol

Silicone aerosol

Indication

HypertensionHypertension,

mitral stenosisAll cases

Most cases

Most cases

Inhalation of toxicgases

Contraindication

Other cases

Shock

Inhalati(gases

on of toxic

Mechanism of Effect

Vasodilation, decreased venous returnDecreased venous pressure and venous

returnDecreased anoxiaResistance to transudation, decreasedvenous return

Changes of surface tension, decreasedfoaming, decreased anoxia, mildsedation

Changes of surface tension, decreasedfoaming, decreased anoxia

Drug

Atropine

Morphine

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cases with hypertension, uremia or mitralstenosis. The untoward effect of morphine incerebral accidents or lesions and in chroniccor pulmonale, may contraindicate or limit itsuse in such cases. The deleterious effect ofmorphine on the fetus may indicate the needfor a cautious use of this drug in attacks oc-curring during pregnancy. Even in cases ofcoronary occlusion, large doses of morphinemay favor the onset of shock.The mechanism of action of morphine is not

completely known. This drug depresses therespiratory center and decreases the suctioneffect of dyspnea (which in turn may decreasethe edema). In pharmacologic doses, mor-phine causes no apparent changes of cardio-vascular dynamics,6 and the pulmonary vesselsare affected only by extremely large doses.64Pulmonary arterial pressures of cardiac pa-tients, studied by catheterization, decreasedin 26 out of 34 cases, but increased in the othereight.65 It is, therefore, difficult to foreseewhether the effect of morphine will be bene-ficial. Alleviation of anxiety and interruptionof harmful reflexes may be a useful action ofmorphine, especially in coronary patients.Vomiting may be deleterious and even dan-gerous. Morphine decreases the basal meta-bolic rate; this should decrease the work ofthe heart and lower the venous pressure.However, it may take some time for this effectto become apparent.Morphine is usually administered sub-

cutaneously, in doses of 10 to 15 mg. It maybe given intravenously, as shown by one of theauthors (A.A.L.) in 1928.66 Intravenous ad-ministration is followed by more rapid effects,but causes nausea more frequently.

Atropine. Atropine was used empirically inEngland for a long time before any publicationdescribed its beneficial effect in pulmonaryedema.67 It is likely that the well-known"drying" effect of atropine on secretions andthe results obtained in bronchial asthma(which originally was not clearly separatedfrom other syndromes) were responsible for itsbeing prescribed in pulmonary edema.

Atropine was found either mildly beneficial'6or harmful63 in intact animals and only slightlybeneficial in tracheotomized animals,50 when

pulmonary edema was induced by means ofepinephrine or rapid intracarotid infusion.Atropine does not improve pulmonary edemacaused by ingestion of ammonium chlorideswhile it is beneficial in pulmonary edemacaused by the central nervous system lesions.39The latter effect seems due to prevention ofextreme bradyeardia, one of the possiblefactors of pulmonary congestion. The clinicaluse of atropine should be limited to neurologicconditions with bradyeardia and to some casesof coronary occlusion, also presenting brady-cardia. In the other cases, tachycardia, causedby atropine, and vagal inhibition in generalmay be detrimental. Bronchodilation causedby atropine has been considered either harm-ful68 or useful69 according to different theories.For the above reasons, Demerol, a drug withboth an atropine-like and a morphine-like ac-tion, should not be preferred to morphine,except in cases with a definite indication forthe use of atropine.

Barbiturates-Chloral. Barbiturates and chlo-ral hydrate have been shown to be ofvalue in experimental pulmonary edema.'6Their intravenous administration in man wasattempted long ago66 and their value in severalcases of pulmonary edema has been shownsince 1930.3, 74 However, these drugs may beineffective and, in certain cases, one cannotescape the impression that the deep sedationproduced by them hastens the patient's demise.Venous return is decreased by chloral andbarbiturates, and it is only logical to avoiduse of these drugs in patients of the secondgroup, those in danger of shock.

Aminophyllin. This drug is a mild vaso-dilator, a bronchodilator, and a stimulant ofthe respiratory center. The first action is usefulthough inadequate, the second is of doubtfulutility (see atropine) and the third is definitelydetrimental.'6 For these reasons, aminophyllinshould not be used in the emergency treatmentof the attack. The routine use of aminophyllin,practised in certain hospitals, cannot berecommended.

Papaverine. Intravenous injection of papa-verine in association with other drugs has beenadvocated by one of the authors (A.A.L.) since1930.3 74 Papaverine is a smooth muscle

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relaxant and a vasodilator. Its usual dose is10 mg. intravenously. Possible objections toits use are: (1) if the patient belongs to group 1(high output), papaverine is too mild a vaso-dilator to be effective; (2) if the patient belongsto group 2 (low output), even a moderatedecrease of venous return can be dangerous.Amyl Nitrite. This drug is used empirically

by inhalation in some hospitals. It is veryprobable that its powerful vasodilator effectmay be useful in certain hypertensive patients,in spite of its extremely short duration ofaction. However, since this drug may dilatethe pulmonary vessels, the authors do notrecommend it, even in cases of group 1. As faras patients of group 2 are concerned, the useof amyl nitrite presents the same dangers asthat of other vasodilators.

Mercurial Diuretics. Mercurial diureticsare injected intravenously in pulmonaryedema in many hospitals. Empirical use ofthese agents undoubtedly rested on the hopeof rapid dehydration of the patient obtainedthrough promotion of diuresis. This action,however, would hardly be adequate andtimely for improving the circulation duringthe attack. Another property of the mer-curials was subsequently described, whencardiac catheterization revealed that Novuritcauses an important drop of pressure in theright atrium and ventricle within 20 to 30minutes.70 This drop in pressure is still unex-plained and may be due to venous constrictiondecreasing venous return. This effect shouldbe considered useful in patients of group 1(high output) but unwanted and possiblydangerous in patients of group 2 (low output).

Sympatholytics. Drugs inhibiting or pre-venting stimulation of the sympathetic systemhave been considered helpful following demon-stration that bilateral stellectomy was usefulin preventing pulmonary edema in man'03 aswell as in experimental animals,48' 18 and alsothat spinal anesthesia produced similar bene-ficial effects in man.76 In animals, sympatho-lytic drugs have been shown to favorablyaffect the course of the edema caused byintravenous epinephrine,'7 7 rapid intracarotidinfusion of saline,50 ingestion of ammoniumchloride,32' 33 pulmonary embolism72 or intra-

cisternal injection of fibrin.44 7 Scanty clinicalreports75 78 seem to indicate beneficial effect inman. Like all hypotensive drugs, sympatho-lytics (Dibenamine, Hydergine) and ganglionicblocking agents (Arfonad, tetraethylammo-nium chloride) may induce shock in patientsof group 2. Disadvantages of these drugs aretheir lasting action and the difficulty of counter-acting their effect, whenever this proves to beharmful.

Digitalis Glycosides-Ouabain. According tothe theory of left ventricular failure, attacks ofpulmonary edema are caused by an acuteweakening of the left ventricle. Therefore,intravenous administration of drugs stimu-lating the myocardium, like strophanthin(or ouabain), was advocated since the earlytwenties89 in the emergency treatment ofthese attacks. More recently, intravenousDigitoxin or lanatoside C were substituted forstrophanthin and in many hospitals intra-venous Digitoxin has become part of theroutine therapy. A recent study"2 advocatessmall doses of ouabain (0.05 to 0.2 mg.) in thetreatment of cardiogenic shock with pulmonaryedema.

This therapeutic concept presupposes: (1)that the left ventricle can still be stimulatedalthough this may not be possible when theventricular wall is damaged by recent coronaryocclusion or prolonged and severe coronaryinsufficiency and (2), that the right ventricleis not unduly stimulated by the drug, so thatno further rise of pulmonary arterial pressurewill take place. It is interesting to note that,according to many authors, digitalis glycosideshave their greatest effect whenever the myo-cardium is functionally under stress while notstructurally damaged. This seems to applymore to the right than the left ventricle duringan attack of pulmonary edema because theright ventricle is under stress on account ofacute pulmonary hypertension and is seldomdamaged to the extent of the left.

Digitalis glycosides rapidly lower venouspressure; however, this effect is mainly due toimproved function of the myocardium. There-fore, and purely on theoretic grounds,digitalis and ouabain should be useful afterthe attack in hypertensive patients even though

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POW SMT

v4 10 20 30

FIG. 3. Pressure of the pulmonary artery aatrium during cardiac catheterization in awith mitral stenosis. Injection of 1.2 mg. of Ivia the catheter was followed by pulmonaryMorphine and venesection terminated thE(from Lenegre and Sc6bat57).

these drugs might be detrimental durattack in cases of myocardial infaiA special case should be made for I

with mitral stenosis. In these patienhigh pressure of the pulmonary capillcaused by high right ventricular outpupresence of mitral obstruction. t Rapitalization can increase the severityedema, if performed during an attacmay even precipitate pulmonary edem2creasing right ventricular output while 1flow from the lungs is impeded by theblock.11' A striking demonstration iQ(fig. 3). Injection of 1.2 mg. of Digitoipatient with mitral stenosis during cathtion was rapidly followed by pulmonarytension and pulmonary edema. Morphivenesection lowered pulmonary pressithis was followed by cessation of foai

Antihistaminics. The concept thattion of histamine was the final event piedema of the lung has been advancedof the authors (A.A.L.) and co-worke1930. This concept seemed to be corro

by subsequent studies60 but is still far frombeing conclusively demonstrated.

Antihistaminics (Phenergan) seemed to givePressure good results in experimental81 82 and clinical83Pulm.A. pulmonary edema. However, the former effect

has not been confirmed.84 Depression of thecentral nervous system caused by these syn-thetic drugs may contribute to the results ob-tained.

Pressure If the main action of the antihistaminicsRt.A.

is at the site of liberation of histamin, it isj likely to be exerted within the walls of the

pulmonary capillaries (fig. 4).and right Heparin. Heparin was found beneficial inpatient experimental pulmonary edema 50, 80 Clinical

)igitoxin reports are still unavailable. As this drug isy edema. known to decrease capillary permeabilitye attack and the other anticoagulants do not share

its beneficial action in pulmonary edema,50the effect of heparin is probably due to local

ing the action on the capillary wall.

ration.* Corticotropin (ACTH). Corticotropin has)atients been found beneficial in acute pulmonaryits, the edema of rabbits.53' 80 Considering that itslaries is effect was obtained after four days of treat-t in the ment, this drug might be considered in theid digi-of the

lk, andby in-

the out-3mitrals givenxin in aLeteriza-r hyper-ine andare andming.libera-

recedingby one

irs since)borated

BleeigAccaM

AdrwenolYticS

* Experiments testing intravenous digitalis in pul-monary edema are being done in this laboratory.

t In certain cases, vasoconstriction of the pulmo-nary arterioles prevents an excessive rise of pressurein the capillaries of the lungs.

bywpatholiticsAtropin

FIG. 4. Site of action of the most used drugs

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prevention of the clinical attacks, but not intheir therapy.

Physical, Physicochemical and Surgical Treat-ment of Pulmonary Edema

Several physical or physicochemical pro-

cedures have been used. Some are effectiveand should be considered in certain cases.

A hot bath (Sitzbath) has been used em-

pirically and may be of help by causing periph-eral vasodilatation. It is particularly indicatedin patients with hypertension or aortic in-sufficiency.

Venesection or application of tourniquetsis an old procedure. It is extremely effectivein patients with arterial hypertension or

aortic insufficiency and in certain cases ofmitral stenosis with high venous pressure. Asthe main result is decreased venous return,venesection is contraindicated in patients ofgroup 2 because it may induce shock. Thegeneral procedure is withdrawal of 500 to600 cc. of blood from an antecubital vein bymeans of a 15 gage needle or after cutting thevein with a scalpel. If the tourniquet procedureis used, these bindings are applied to the fourlimbs with a moderate pressure; each is re-

leased and reapplied every 20 to 30 minutesin order to avoid venous thrombosis.

Oxygen was used at first only in cases withpronounced cyanosis. As anoxia may occur inpulmonary edema either as a primary or as a

secondary factor, the use of oxygen is rational.Moreover, clinical improvement follows itsuse in certain cases. It is unfortunate that foamin the bronchioles prevents oxygen from reach-ing many of the alveoli. Oxygen is usuallyadministered in the form of 100 per centoxygen with a humidifier in order to preventdrying of the mucosae. As oxygen in highconcentrations is irritant, its administrationshould be interrupted by periods of normalair breathing.

Pressure respiration has been advocatedin the treatment of pulmonary edema. Thetheoretic basis of this method is that theincreased pressure in the broncho-alveolarsystem counteracts the high pulmonary capil-lary pressure and decreases transudation.

Following animal experimentation, Barachand associates85 suggested breathing againsta positive pressure of 3 to 6 cm. water. Thisprocedure produced useful results in severalclinical cases and seemed particularly in-dicated in pulmonary edema due to gas poison-ing.86

It has been shown that positive pressurerespiration, by increasing intrapleural pres-sure, decreases venous return.104 This pro-cedure, which may be useful in patients ofgroup 1, presents some danger in patients ofgroup 2, where impending shock might beprecipitated.*

Spinal anesthesia was tried by Sarnoff andFarr76 with encouraging results in clinicalcases of protracted pulmonary edema whichwere refractory to other therapy. The intensivevasodilatation which follows spinal anesthesiadecreases venous return to the right heartand lowers pulmonary arterial pressure. It islikely that the mechanism of action and thecontraindications of this technic are similarto those of sympatholytic drugs (page 123).

Stellate block has proved useful in experi-mental pulmonary edema, when tried by aco-worker of the author.48 Clinical use of thismethod was made in 1952 by Pierach andStotz.103 They blocked the right stellateganglion with procaine in eight clinical casesof pulmonary edema with hypertensive,coronary or rheumatic heart disease. Excellentresults were reported. The authors state thatonly the right ganglion should be blockedwhile block of the left would increase pul-monary congestion. Explanation of the mecha-nism of action is only tentative.

Antifoaming TherapyPulmonary edema, whatever the initial

cause, starts a vicious circle of events whichtends to prolong the attack. This cycle is based

* While positive pressure obtained by an expirationvalve definitely decreases venous return, positivepressure respiration with modern apparatus seemsto increase intra-alveolar pressure only for an

extremely brief time. If this is confirmed, the lattermethod might be applied to any case of pulmonaryedema without danger.

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on high pulmonary capillary pressure, transu-dation and accumulation of fluid in the alveoli,foaming and local anoxia, which in turn leadsto more transudation, more foaming and more

anoxia. While any procedure tending to lowerpulmonary capillary pressure is undoubtedlythe most effective in patients of group 1, theseprocedures are either poorly effective or

acually dangerous in patients of group 2.Since 1950 we have tried a new approach,

that of attempting to break the cycle byacting on the foaming process itself. It was

shown long ago87 that large amounts of fluidmay be present in the air passages with littledanger to life; as soon as the surface tension ofthe fluid reaches a critical point, foamingstarts. This leads to extremely severe effects,partly through the enormous increase involume (foam) and partly through modifica-tion of the normal alveolar function which isbased upon surface tension effects betweenhumid alveolar surface and air.88

Since impairment of the normal gas ex-

changes of the lungs is followed by anoxiawhich in turn causes increased permeability ofthe capillaries,69 the foaming process in itselfmay be responsible for the continuation of theattack and may be a cause of death. If a

modification of the surface tension of the foamis brought about, the bubbles burst and thefluid composing the thin separating layers thenoccupies a much smaller volume.

Antifoaming or defoaming agents (ether,octyl alcohol, capryl alcohol and ethyl alcohol)were tested by one of us in the form of vapors

or aerosols in four different types of experi-mental pulmonary edema.90' 91 While the use

of long chain alcohols did not seem to improvethe outcome, ether had a mildly beneficialaction and ethyl alcohol (ethanol) producedexcellent results. The inhalation of oxygen

with a high concentration of ethyl alcoholvapor was followed by a decreased mortality,a lower lung-body index and the easy expec-

toration of fluid. The systemic effect of alcoholwas slight, both on account of its being only a

mild sedative and vasodilator, and because ofpoor absorption. This was shown by theobservation that beneficial effects of alcoholby other routes were obtained only when

administered ii doses which induced deepanesthesia.11

Experimental studies have also been made byothers with silicone in ether92 or in water;93' 111

both were found beneficial. We have recentlycompared several antifoaming agents includingsilicone mixtures.94 Three agents were definitelybeneficial: 10 per cent silicone in water, freonand ethyl alcohol. Since freon may presentsome dangers if administered for long periods,only alcohol and silicone were considered forclinical use. While alcohol yields superiorresults in experimental pulmoi ary edemainduced by adrenalin, it has a moderatelyirritant effect oil the bronchial mucosa. Thisshould favor the use of aerosol solutions ofsilicone in forms of pulmonary edema causedby lung irritants (chlorine, etc.). Experimentsin this direction seem to confirm this view-point.95' 108, 114 The effectiveness of silicone aero-sol tends to support the opinion that the utilityof alcohol vapor is not due to systemic effect,but rather to its effect oin surface tension ofthe foam.

Several studies with antifoaining agents inclinical cases of pulmonary edema have beenreported. At first, the tolerance for alcohol andthe best method of administration were studiedill normal volunteers as well as ill cardiacpatients without pulmonary edema.96 19 Twomethods which gave excellent results are: (1)Use of a face mask and a 20 to 30 per (entalcohol solution. This technic is especiallysuited for comatose patients. (2) Use of anasal catheter and a 95 per cent alcohol solu-tion. This method is to be preferred in ( onsciollspatients.

In both methods, the alcohol is placed ill theusual humidifier bottle, connected to all oxy-gen tank. The oxygen flow is kept at 2 to 3liters per minute for the first few minutes.Then, when the patient's mucosae becomeadapted to the irritant gas (local ainestlhesia?),the flow rate is gradually stepped up until,after 10 to 12 minutes, it reaches 9 or 10 litersper minute, and is maintained at such level.*

* It should be emphasized that prolonged alcoholvapor treatment should be done only by alternatingperiods of inhalation (30 to 40 minutes) and periodsof rest (10 to 15 minutes) during which the patient is

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By means of this technic, alcohol vapor was

administered to 14 patients during 17 severe

or extremely severe attacks of pulmonaryedema. In 14 of the attacks, previous conven-

tional therapy had failed; in the other three,alcohol was the only therapy used. Whenoxygen-alcohol vapor was administered, theresults were dramatically favorable in 10 ofthe attacks and definitely helpful in the other 4.

It was noted that patients with severe

attacks responded most dramatically and thatthose with attacks of shorter duration had a

more rapid recovery following alcohol vapor

inhalation. Usually, subjective relief precededobjective improvement, so that the patientfelt completely recovered even though some

chest rales were still audible.The beneficial effects of alcohol vapor were

also noted by Goldmann and Primiano in one

obstetrical case,97 by Gootnick and co-workers98in two cases (one of them in shock) and byWeyl in seven surgical cases.'02 A furtherreport summarized the results of alcoholtherapy in 50 attacks99 (table 6).Another method was tried by Sadove,'09

12 per cent alcohol aerosol by face mask. Hisresults were equally good.

The following abridged case reports illustratethe efficacy of this method of treatment.

Case 1. A 50 year old white female with hyper-tensive cardiovascular disease was semicomatose andunimproved one hour and a half following the onsetof acute pulmonary edema of 4 plus severity.Oxygen bubbling through 95 per cent alcohol was

administered via nasal catheter and dramatic im-provement ensued. Forty-five minutes after ther-apy was begun, improvement was 4 plus subjec-tively and objectively. Therapy was discontinuedafter two hours and 15 minutes. No other treat-ment for acute pulmonary edema was given beforeor after the inhalation. The patient was later dis-charged to the Cardiac Clinic.

Case 2. A 65 year old, white female with acutepulmonary edema of 3 plus severity and of threehours duration was admitted to the hospital fortreatment. Oxygen by mask for 30 minutes failedto induce improvement and no other treatment hadbeen given. Thirty minutes after the inhalation ofoxygen-alcohol vapor via nasal catheter was started,

breathing air or oxygen. This prevents excessive ab-sorption of alcohol which might lead to unwantedsystemic effects.

TABLE 6.-Results of Alcohol-Oxygen Vapor Therapyin Clinical Cases of Pulmonary Edema*

Mode of Therapy

Alcohol-oxygenvapor only

A.O.V. given afterfailure of otherprocedures

Possible contribu-tory action ofother proce-

dures

All methods

AttacksTreated

3

92

Total 14

115

Total 17

36

Total 9

17203

Total 40

Degree ofSeverity

+++

++

+++

Degree ofImprovement

+++

++

+++

* From Goldmann and Luisada99Severity of attacks graded as follows: +++ +

very severe, +++ severe, ++ moderate.Improvement graded as follows: ++++ com-

plete or almost complete, +++ good, ++ fair.

improvement was marked subjectively and objec-tively. Toleration of the vapor was good. After 45minutes, treatment was discontinued. A diagnosis ofhypertensive cardiovascular disease, class III, withleft ventricular hypertrophy, was established. Afterconvalescence, the patient was discharged to theCardiac Clinic.

Case 3. A 65 year old white female with coronaryheart disease and calcific aortic stenosis sufferedfrom a posterior myocardial infarction and developedshock and acute pulmonary edema of 4 plus se-verity. Morphine sulfate 15 mg., atropine sulfate1.2 mg. and Desoxyn 10 mg., were administeredintravenously. Notwithstanding these measures,her blood pressure dropped to 70/60 mm. Hg.Ninety minutes later, the patient was considered tobe agonal and oxygen-alcohol vapor was administeredby mask. Toleration was good. Improvement wasgradual and progressive, being 4 plus subjectivelyand objectively at the end of six and one halfhours. After eight and one half hours, alcohol ther-apy was discontinued. The patient was dischargedfour weeks later.

Case 4.102 A 61 year old patient was sufferingfrom pyloric obstruction and was scheduled for

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gastric resection. Past history revealed exertionaldyspnea and bilateral intermittent claudicationafter walking two blocks. An electrocardiogramshowed low voltage and diphasic T in aVL. Induc-tion of anesthesia and intubation were uneventful.Balanced anesthesia with circle absorption tech-nique was used and respiration was assisted. Pulseand blood pressure were satisfactory (blood pres-sure, 140/80; pulse, 100) and color was good. Onepint of blood was given in one and one-half hours.After the peritoneum was closed, only 50 per centnitrous oxide oxygen was administered. At the endof the three-hour operation, cyanosis was noted.The pulse was 140; blood pressure 100/60. Suddenappearance of foam from the mouth then occurredand gurgling and bubbling sounds were heard. Im-mediate inhalation of oxygen-alcohol vapor wasinstituted by mask and, within 20 minutes, thepulmonary edema had subsided, the chest soundedclear, the color was pink, and the patient seemedimproved. An electrocardiogram showed changes inaVL, T, and V4 through V6. Subsequent tracingsshowed definite evidence of an acute anterior wallinfarct. The patient made an uneventful recoveryand left the hospital six weeks later in good condi-tion.

Case 5.97 A 43 year old Negro woman was ad-mitted to the hospital because of hypertensioncomplicating pregnancy. Hypertension had beennoted during two earlier pregnancies; however, nointerim examinations had been performed. Physicalexamination revealed an obese woman with bloodpressure of 230/140, pulse 84, temperature 98.6 F.,and respiration 20. The size of the uterus was con-sistent with a nine month gestation.

While lying supine following the examination,the patient became severely dyspneic and cyanotic,and developed acute pulmonary edema of thegreatest severity, with continuous emission ofcopious amounts of pink, frothy fluid from the noseand mouth. The patient's head was elevated andpositive pressure oxygen by mask was instituted.Successively, morphine sulfate 30 mg., amino-phyllin 0.5 Gm., atropine sulfate 0.5 mg., sodiumamytal 0.5 Gm. and Digalen (1 cat unit) wereadministered intravenously within 15 minutes fromthe onset of the attack. Forty minutes after thesemeasures were completed, the patient was deliriousand frothy sputum was still being emitted in copi-ous quantities from the mouth.

Administration of alcohol vapor was then startedvia face mask. It was necessary to remove the maskfrequently to permit removal of collected foam.Improvement was prompt, dramatic and progres-sive. Within 15 minutes, the foam became moreliquid in character and expectoration was moreeffective. At the end of 30 minutes, the patient wasable to sit up and speak clearly, although withsome effort. Bubbling sounds and crepitant pul-

monary rales on auscultation were now markedlyreduced. At this point, alcohol vapor was givenand treatment was discontinued. Approximatelyseven hours later, the patient spontaneously de-livered a female infant who required trachealcatheterization and oxygen.

Protracted pulmonary edema often startssuddenly but has a protracted course and isless likely to be a crucial issue for the prog-nosis. Ten such cases, all of them in poor orterminal state, were submitted to alcoholvapor therapy, in spite of the fact that nonewas considered likely to survive.99 Seven casesimproved but the improvement was slowerand less marked than in the acute attacks. Itwas good in three, moderate in two and mini-mal in two. The following case is an example.

Case 6. A 65 year old white male with coronaryheart disease and congestive failure gradually andprogressively developed pulmonary edema of 3 plusseverity (over a period of 15 hours). Oxygen vianasal tube, morphine sulfate 15 mg. hypodermically,aminophyllin 0.25 Gm. and 3 units of Digalenintravenously, were given without noticeable im-provement. Oxygen-alcohol vapor was started vianasal catheter and improvement was 3 plus objec-tively 20 minutes later. After 40 minutes of alcoholvapor treatment, improvement was so well estab-lished that this therapy was discontinued. Thepatient died suddenly on the following morning.Autopsy revealed a recent anteroseptal infarction,marked left ventricular hypertrophy and absence offroth in the tracheo-bronchial tree.

Following these reports, alcohol vaportreatment of pulmonary edema was insti-tuted in various hospitals. It is unfortunatethat, although the results are usually describedas good, no other accurate clinical reportshave been published.The good results of another antifoaming

agent, 2-ethyl-hexanol, was stressed by Reichand associates,'00' 101 following its use in 14unselected cases. One-half of the patientsshowed a good response. Other antifoamingagents are being tested by various investigatorsincluding Sadove.109

MANAGEMENT

Treatment of the Attack

At present, the directions for managementof the attack are still tentative (table 7).

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Further studies onl the mechanismn of action ofthe various drugs and physical proceduresused in the different clinical types of pul-monary edemna are necessary.

Atntifoaming therapy is compatible with anyother dr1g or physical treatment. Therefore,it is the viewpoint of the authors that all casesof pulmonary edema should be immediatelytreated with an antifoaming agent. Ill cases ofpulmonary edema due to inhalation of toxicgases, silicone aerosol may prove to be theagent of choice. While the patient is under-going inhalation treatment, a thoroughexamination of the causes leading to the attackshould be made and their effects on the patientnoted (pulse, blood pressure, electrocardio-grami). After this routine examination, whichmay take from 20 to 30 minutes, and if theattack has not subsided, other proceduresshould be instituted.

Cases of pulmonary edema, associated withhypertension or aortic insufficiency, stenosis orcoarctation, should receive 15 mg. of morphineand may also receive an intravenous injectionof a mercurial diuiretic. Sympathollytic drugsmay be given but other hypotensive agents(such as nitroglycerine, papaverine), having ashorter action, may be preferred.

Cases with myocardial infarct and bloodpressure above 100 or above 120, if there washypertension prior to the attack, should alsoreceive 15 mg. of morphine; 0.5 mg. of atropinemay he administered if there is marked brady-cardia. il~ercutrial diuretics may be given, butin small dose (1 cc. intravenously). If the bloodpressure drops below 100 mm. Hg, the dose ofmorphine should be not more than 10 mg.,

and no inercurial may be given. The samerationale applies to cases of rheumatic heartdisease and mitral stenosis.

Patients with cerebrovascular accidentsshould not receive morphine. They may begiven atropine, mercurials and, possibly,chloral hydrate by rectum or intravenously.

Morphine should be given only ill smalldoses (5 mg.) to patients who have inhaledtoxic gases.

Spinal anesthesia or right stellate block shouldl)e used only in cases of cerebrovascular acci-eents or hypertensive heart disease with pro-

tracted edema, which is refractory to treat-ment, and thenr only if blood pressure is high.

V"enesection occasionally may be a life-saving procedure. It should be employed onlyin cases of hypertension, cerebrovascularaccidents, mitral stenosis or aortic insufficiencyhaving high venous pressure or vrisible venousengorgement. Its use in other cases is morequestionable, even in the presence of venousengorgement. As an example, in patients withmyocardial infarct and systemic venous coll-gestion, venesection may precipitate shock.

Pressure respiration has, in general, a favor-able effect in pulmonary edema. However,patients with cerebrovascular accidents anddepression of the respiratory center mayrespond poorly to this treatment.

PROPHYLAXISIt should be kept in minid that transfiusions

of blood and infusions of plasma or salinestrongly favor pulmonary edema. Failure toconsider this fact is responsible for manyepisodes of edema in medical and surgicalwards. 1Moderation and wisdom in the ad-ministration of intravenous fluids may preventmany attacks, not! only in cases with coronaryor rheumatic heart diseases or aneemia, but alsoin patients whose myocaidium is less efficientbecause of anesthesia, surgical intervent ionor infection.

Prevention of pulmonary edema in hyper-tensiv'e patients (can be obtained in two ways:(1) by decreasing the load placed upon theleft ventricle (salt poor diet, hypotensivedrugs, sympathectomy, sedation); or (2), bystimulating the myocardium (digitalis glyco-sides). Both methods are extensively used.This may account for the impression that oc-currence of pulmonary edeIna in these patientsis less frequent than formerly.

Prevention of pulmonary edemia in patientswith coronary or cerebrovascular diseases ismore difficult: prevention of the arterioscleroticprocess would be the answer. Central sedation,especially at night, may prolong the life of thesepatients.

Prevention of pulmonary edema in r h(eu-matic heart disease is based on avoidance ofexcessive physical work, on salt restriction,

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use of diuretics and digitalization. Mitralvalvotomy is effective in preventing attacksof pulmonary edema of patients with mitralblock. In acute rheumatic fever, adrenocorticalextracts are the best treatment, whenever themyocardium is severely damaged. The sametreatment may be lifesaving in rheumaticheart disease with silent rheumatic carditis.Most of the other forms of pulmonary edema

are caused by unpredictable and often un-avoidable events. The incidence of pulmonaryedema in these cases will be reduced followingimprovement of working conditions (decreasedexposure to toxic material), improvement ofmedical technics (slow removal of serosal fluids,moderation in the administration of intrave-nous fluids, rational anesthesia) and improvedtherapy of infections, including those involvingthe heart or the nervous system.

SUMMARY

Acute edema of the lungs is the infiltration ofserum into the interstitial pulmonary tissue,followed by exudation into the alveolar cavities,frothing and expectoration of foam.Acute pulmonary edema is encountered in a

great variety of conditions including cardio-vascular, renal, cerebral and pulmonarydiseases, trauma to the skull or the chest,infections and shock.Pulmonary edema may be fulminating,

acute or protracted. Two clinical types can berecognized, that associated with a full pulse, ahigh blood pressure and a high output (group1), and that associated with severe bloodpressure drop, low output and tendencytoward shock (group 2).

Experimental pulmonary edema can beproduced by a great variety of methods.These range from damage to the heart or brainto ventricular strain; from trauma to the skullor chest to pulmonary embolization; fromoverload of the circulation to inhalation oftoxic gases or administration of poisons.The mechanism of production of pulmonary

edema is still somewhat obscure. Three mainfactors seem of paramount importance: highpressure in the pulmonary capillaries, in-creased permeability of these capillaries, anddecreased osmotic pressure of the blood. While

strong sympathetic stimulation is one of themost common factors leading to displacementof a large mass of blood from the periphery tothe lungs, the roles played by vascular phe-nomena in the lungs, secretion of endocrineglands and locally elaborated humoral agentsare still under discussion.

Special aspects of the treatment of pul-monary edema in mitral stenosis, in massivemyocardial infarct and in exposure to toxicgases are discussed.Therapy of pulmonary edema is based on

the use of drugs and physicochemical means.Among the most successful drugs are morphine,mercurial diuretics and sympatholytics, whileoxygen therapy, pressure respiration andvenesection may also be useful. Most of theabove drugs and physical procedures tend todecrease venous return and cardiac output;therefore, while helpful in patients of group 1,they may induce shock in patients of group 2.

Digitalization during the attack is con-sidered of questionable value, particularly incases of myocardial infarct, mitral stenosisor exposure to toxic gases. It may be useful inthe prevention of the attacks.Antifoaming therapy is a purely sympto-

matic treatment which tends to break a self-perpetuating cycle by modifying the surfacetension of the froth, thus reducing its volume.This procedure has been shown to he ofdefinite value and should be used routinely asthe first remedy, even preliminary to a briefstudy of the case. Drug therapy and otherphysical measures should be employed later,after an evaluation of the clinical picture, and,especially, if antifoaming therapy fails toterminate the attack.

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postoperative period. Illinois State AM. J. 108:265, 1955.

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A. A. LUISADA and L. CARDIAcute Pulmonary Edema: Pathology, Physiology and Clinical Management

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