The pathophysiology of pulmonary congestion

The Pathophysiology

of Pulmonary

Congestion

By BERNARDF. SCHFBINER, JR., GERALD W. MURPHY, DAVID H. KRAMER, PRAVIN M. SHAH, HERBERT J. MARX, AND PAUL N.Yu

T

HE TERM PULMONARY CONGESTION has had different meanings and interpretations, depending upon the physician’s viewpoint. To the family physician, internist, or surgeon, it is characterized clinically by dyspnea on effort, orthopnea, paroxysmal dyspnea pulmonary rales, and/or bronchoconstriction, and, at times, pleural effusion. This syndrome is seen frequently in patients with valvular or myocardial disease. In pediatric practice, tachypnea may be the only symptom, while signs of pulmonary congestion may be minimal clinically but readily demonstrable radiographically. The radiologist’s view of pulmonary congestion may include “pulmonary vascular engorgement” associated with significant left-to-right intracardiac Aunts ( Fig. 1) ; “pulmonary congestion,” a fan-like increase in “pulmonary vascular markings,” is seen in left ventricular failure complicating acute myocardial infarction or hypertensive heart disease (Fig. 2). Similar findings of “pulmonary congestion” may be observed in advanced aortic or mitral valve disease (Fig. 3). However, in addition to the increase in pulmonary vascular markings, a change in the distribution of pulmonary blood flow is quite characteristic (Figs. 4 and 5). Thus, pulmonary arteries and veins in the lower lobes are narrowed, while those in the upper lobes are distended (Figs. 4 and 5). Furthermore, Kerley B lines characteristic of interstitial edema may be present in the lower lung fields. The pathologist’s criteria for pulmonary congestion include the finding of firm lungs of increased weight which, upon sectioning, reveal induration with fluid easily expressed from the exposed surface. Tight microscopy discloses an incrrase in alveolar proteinaceous material as well as in fluid associated with From the Cardiology Unit, Department of Medicine, University of Rochester School of Medicine and Dentistry, and the Medical Clinics of Strong Memom’al Hospital, Rochester, N. Y. Supported in part by USPHS Grants HE-03966 and HE-5500. Contract PH 43-68-1331 from the National Heart and Lung Institute, Clinical Re.search Center Grant RR-00044 from the Division of Research Facilities and Resources, National Institutes of Health, and by the Genesee Valley Heart Association, the Hochstetter Fund, and the Ernest L. Woodward Fund, BERNARD F. SCHRFXNER, M.D.: Professor of n4edicine, Cardiology Unit, University of Rochester School of Medicine and Strong Memorial Hospital, Rochester, N.Y. GERALD \V. MURPHY, M.D.: Associate Professor of Medicine, Cardiology Unit, University of Rochester School of Medicine and Strong Memorial Hospital, Rochester, N.Y. DAVICY H. KRAMER, M.D.: Assistant Professor of Medicine, Cardiology Unit, University of Rochester School of Medicine and Strong Memorial Hospital, Rochester, N.Y. PRAWN M. SHAH, M.D.: Associate Professor of Medicine, Cardiology Unit, University of Rochester School of Medicine and Strong Memorial Hospital, Rochester, N.Y. HERBERT J. MARX, M.D.: Assistant Professor of Medicine, Cardiology Unit, Llniversity of Rochester School of Medicine and Strong Memorial Hospital, Rochester, N.Y. PAUL N. Yu, M.D.: Professor of Medicine, Cardiology Unit, University of Rochester School of Medicine and Strong Memorial Hospital, Rochester, N.Y. PXKXESS

IN CARDIOVASCULAR

DISEASES,

VOL.

XIV,

No.

1 (JULY),

1971

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55

ScHREI,h;ER 14X AL.

Fig. l.-Posterioanterior chest roentgenogram in patient with lat-ge left-to-right shunt resulting from atria1 septal defect. Note cardiomegaly, prominence of the main pulmonary artery, and diffuse pulmonaw vascular engorgement. distortion of the interstitial spaces. If the pulmonary congestion has been acute as that observed in acute myocardial infarction, the walls of pulmonary blood vessels may appear to be nearly normal. On the other hand, if the process has been chronic as seen in mitral valve disease, medial hypertrophy and intimal proliferation of the pulmonary arteries and veins are conspicuous, particularly in the lower lobes of the lungs. Electron microscopic examination may reveal edema in the interstitial space, which is bounded by basement membranes of capillary endothelium and alveolar epithelium, or in spaces where basement layers arc separated by gaps containing extension of fibroblasts. In this discusion, we shall attempt to define and characterize pulmonary abnormalities resulting from valvular and primary myocardial heart disease which serve as prototypes of pulmonary congestion. Before doing so, however, it would be appropriate to review briefly certain features of the anatomy and physiology of the pulmonary circulation, These include the pulmonary capillary-alveolar interface, pulmonary lymphatics, pulmonary capillary bed, and the distribution of pulmonary blood flow, NORMAL

Pulmonary Capillary-Alveolar

PULMONARY

CIRCULATION

Interface

Since the primary function of the lung is gas exchange, the structure of the

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Fig. 2.-Posterioanterior chest roentgenogram in patient with long-standing hypertensive cardiovascular disease in acute left ventricular failure. Cardiomegaly is present, but main pulmonary artery segment is not enlarged. Lungs show diffusely increased pulmonary vascular markings, but upper Iobe pulmonary veins are not unusually prominent. Both lung fields have hazy, glassy appearance suggesting both marked interstitial and alveolar edema. interface is most important. Electron microscopy has delineated the variety of cells present as u-e11 as the intimate relationship between capillary endothelium, alveolar epithelium, and the interstitial space (Fig. 6). The alveolar capillary membranes is composed in part of central portions of endothelial cells containing nuclei and, in part, of continuous cytoplasmic extensions which originate from the former. Two modes of communication exist between the blood plasma and the tissue spaces. One consists of numerous pinocytotic vesicles within the capillary membrane which are capable of taking up small protein molecules from the p1asma.l The other is located at intercellular junctions where the “seal” is not tight. This site is responsible for greater transfer of small proteins than can be be accomplished by the pinocytotic vesicles.1 The epithelia1 cells composing the alvelar wail have a similar structure, consisting of both central nucleated cell bodies and long cytoplasmic extensions. The organelles are confined to the perinuclear cytoplasma. Since cytoplasmic extensions of both endothelial and epithelial cells cover a large area and are devoid of metabolically active structures, they are vulnerable to injury. For example, several investigators have shown that the

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Fig. X-Posterioranterior chest roentgenogram in patient with severe mih-al stenosis and pulmonary congestion. Moderate cardiomegaly and marked prominence of the main pulmonary artery segment are evident. Vascular markings to upper lobes are increased, while those to lower lobes are inconspicuous. A double shadow suggesting left atria1 enlargement is faintly discernible. primary event in oxygen toxicity occurs in the squamous portion of endothelial cells.2-4 A second type of cell lining alveoli, the granular pneumocyte, is interspersed among the squamous cells. This cell is devoid of squamous extensions, is very active metabolically, contains the osmiophilic laminated bodies, and is reor removal’ of surfactant. The presence of an sponsible for the production”,” ultrathin layer of surfactant on the alveolar membrane, which has recently been demonstrated by Weibel and Gil, is believed to be an important mechanism for maintaining alveolar architecture.” The interstitium of the lung is of varying composition. Over large areas, it consists only of the basement membranes of endothelium and epithelium, some of which are fused. In other regions, the two basement membranes are separated by projections of connective tissue fibrils or firoblasts. The interstitial space is continuous and is anchored by fibers extending from central structures, such as bronchioles and pulmonary arteries, to the more peripheral pleura and interlobular septa. The course of fluid draining from these spaces is along alveolar walls until the lymphatic capillaries around axial structures or those in the pleura and septa are reached.

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Fig. 4.-Anterioposterior pulmonary arterial angiogram obtained in same patient whose plain film is shown in Fig. 3. Note marked enlargement of main pulmonary arteries with disproportionate perfusion of upper lobe arteries with contrast material compared to lower lobe arteries.

The regions of the interstitial space appear to behave differently in response to experimental interventions leading to edema formation. The areas of closely opposed basement membranes do not readily accumulate fluid as a result of experimental acute pulmonary edema. However, fluid accumulation in the other regions of the interstitial space is cmitr readily demonstrated.D Pulmonary Lymphatics Abundant lymphatic channels are found wherever there is loose connective tissue. Axial lymphatic flow, which ultimately enters the venous circulation, is aided by the ever-changing tensions of the flexible connective tissue framework which accompany the cyclic changes in lung volume. Tobin has demonstrated the presence of lymphatics accompanying small branches of both pulmonary arteries and veins.l” In the hilar regions, the lymphatics are relatively thick-walled and resemble the thoracic duct. Although drainage is usually centripedal, it has been shown that lymphatics in the pleura are capable of providing collateral pathways to

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Fig. 5.-Venous phase of pulmonary angiogram shown in Fig. 4. Veins draining upper lobes are filled with contrast, while those from lower lobes scarcely fill. Note moderate left atria1 enlargement. carry lymph around local sites of obstruction within pulmonary segments to other points of entry into the main lymphatic channels leading into the mediastinum.1u The functional significance of the lymphatic system has not been clearly delineated. It would appear that in normal man and in experimental animals the fluid and other plasma constituents which leave the pulmonary capillaries must be matched by equal lymphatic drainage to insure maintenance of “dry” pulmonary tissues. The importance of the lymphatic system in the genesisof experimental pulmonary edema has been assessedby a number of workers.11-14Their collective results may be summarized as follows: ( 1) an increase in pulmonary lymph flow accompanies pulmonary edema, but the increase in flow may be delayed

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CONGESTION

Fig. 6.-Electron photomicrograph obtained from dog lung after three hours of red blood barbituate anesthesia. Alveolar space (A); p u 1monary capillaries containing cells (C); capillary endothelial cell nucleus (END): Al veolar epithelial cell nucleus (EP); Fused squamous extensions of both endothelial and epithelial cells (1); Area where squamous extensions of both cell types are separated bv connective tissue fibrils and edema (2).

vis a vis duration of left atria1 presure elevation and may be of relatively small magnitude when the latter is less than 25 mm Hg. (2) In acute experiments, lymph flow increases three to four times when the mean left atria1 pressure exceeds 25 mm Hg. (3) In chronic experiments, lymphatic flow does not increase when mean left atria1 pressure remains below 25 mm Mg. Pulmonary Capillary Bed It has been traditionally held that the mean pulmonary capillary pressure in normal subjects is less than 12 mm Hg. Since the colloid osmotic pressure of the plasma

is slightly

less than

30 mm

Hg,

a wide

pressure

gradient

exists

which prevents net transfer of fluid from the intravascular to the interstitial and alveolar compartments within the lung. If the Starling concept of equilibrium is applied to the pulmonary capillary memebrane at heart level, then the interstitial fluid presure in man should be approximately -16 mm Hg. This is derived by adding the pulmonary capillary pressure (8 mm Hg) to the colloid osmotic presure in the interstitial fluid (6 mm Hg-assumed to be equal to that of the puImonary lymph), amII by subtracting the colloid pres-

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sure of plasma (30 mm Hg, ie, 8 + 6 - 30 = -16 mm Hg. This value is consonant with estimates of interstitial pressure made in viva in the dog by Levine, I5 Mayer,l” and their respective associates. This negative pressure may be important in keeping the interstitial spaces at a minimal volume, thereby helping to maintain relative dryness in the lung. It probably also serves to exert a suction effect on the alveolus which could play a role in absorption of fluid by the interstitium. It is pertinent to define more precisely the magnitude of pulmonary capillary pressure. Although it is normally less than 12 mm Hg when recorded by cardiac catheterization in the supine position, it may vary widely in the upright posture because of gravitational effects. Indeed, at the lung bases in the upright position the pulmonary capillary pressure approximates 20 mm Hg.le In contrast, toward the lung apices the pulmonary capillary pressure may be only 34 mm Hg. Thus, there is a marked range of pulmonary capillary pressures due to hydrostatic factors which may be almost as important in determining pulmonary capillary pressure as the driving pressure derived from right ventricular systole. With vigorous exercise in the upright position, the most pronounced changes in the vascular pressure would be expected to occur at the bases of the lung, where a pulmonary capillary pressure of 30 mm Hg may be expected.18 Assuming that the interstitial pressure did not change, the capillary hydrostatic pressure could lead to fluid extravasation into the interstitial space in the basal areas. In pathological conditions in which the mean left atria1 pressure is chronically elevated such as in primary myocardial disease or mitral valve disease, the effective capillary pressure may exceed the effective plasma colloid osmotic pressure and enhance transudation of fluid from the capillary bed to the interstitial space. Distribution

of Pulmonary

Blood Flow

In the normal lung, there is a wide variation in the distribution of pulmonary blood flow as well as of ventilation, XXX For example, in the upright posture the lower lobes are better perfused than the upper lobes. During mild exercise, these differences tend to decrease, so that perfusion of the upper lobes increases to a greater extent than that to the lower lobes.?l In pathological conditions such as mitral stenosis or left ventricular failure, regional perfusion is grossly abnormal. In the upright posture, perfusion is redistributed into the upper lobes with under-perfusion of the lower lobes.‘“~z’-‘5 Furthermore, Heath and Hicken have shown that in the presence of left atria1 hypertension there is enlargement of perivascular spacesz6 PRESSURE

VOLUME

RELATIONSHIPS

IN MAN

IN PHYSIOLQCICAL

AND

PATHOLOGICAL

STATES

Resting hemodynamic data from I5 “normal” patients studied in our laboratory over the past ten years have been reported previous1yz7 and are in agreement with the experience of other investigators.2”-36 Left ventricular enddiastolic pressure is less than I3 mm Hg. Since in normal subjects the left

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ventricular diastolic, left atria1 mean, and the pulmonary venous pressures are almost identical, the pulmonary capillary pressure must be of the same order of magnitude. The driving pressure providing left ventricular inflow and diastolic pressure is derived from the right ventricle which normally operates at a systolic pressure less than 30 mm Hg and a diastolic pressure less than 5 mm Hg. The normal pulmonary arterial, systolic, diastolic, and mean pressure are, respectively, less than 30, 12, and 20 mm Hg. Pulmonary blood flow, which is normally equal to the systemic cardiac output, averages about 3.4 liter/min/sqm (range, 2.74.5 liter/min/sqm). It should be pointed out that in a normal subject the aforementioned pressures remain within a relatively narrow range despite a two-to threeflold increase in pulmonary blood flow during supine exercise.‘1-33J7 Th e maintenance of normal pressures in the face of increased flow is probably due to recruitment of previously closed pulmonary vascular channels,“” as well as to the distensibility characteristics of the pulmonary vascular bed. Measurements of pulmonary blood volume (PBV) in patients with normal hemodynamics studied in our laboratory averaged 271 ml/sqm (SEM 2 lo).” Similar values have been obtained by a number of other workers.3G’3”.“9-1’ Pulmonary capillary blood volume ( V, ) , determined by the single-breath carbon monoxide method at two levels of inspired oxygen tension, averaged 54 ml/sqm.‘7 The method of Chinard and associates has been applied to the determination of another volume, namely, the pulmonary extravascular volume or lung water (PEV) .4z This method depends upon indicator-dilution principles and the fact that tritiated water (THO) after injection into the pulmonary artery permeates the pulmonary capillary extravascular space during its initial passage through the pulmonary vascular bed. The determination is made by the simultaneous injection of THO and a nondiffusible indicator such as radioiodinated human serum albumin (RISA) into the pulmonary artery (PA) with sequential sampling of blood from a brachial artery (B,4) at intervals of 1 to 2 WC. PEV is calculated as follows:

where CI = cardiac index in ml/sq m/set, TM Tl10 (IJA-n,,, mean transit time in seconds of tritiated water from pulmonary artery to brachial artery, and TM,,,, = mean transit time in seconds of RIS_4 from pulmonary artery to (PA-B .\, brachial artery. As shown in this formula, the difference between the mean transit times in seconds of THO and RISA multiplied by the cardiac index per second gives the value of PEV. The indicator-dilution method is limited and measures only 60% of the actual extravascular volume, as determined directly by desiccating the lungs in experimental animals;‘3 nevertheless, it provides useful information concerning clinical pulmonary congestion. Determinations of the various volume components within the pulmonary circulation are of importance, since they add a capacitance parameter in the assessment of pulmonary congestion not provided by measurements of pressure and flow alone. However, it must be stressed that these determinations provide only gross information for the entire pulmonary vascular bed and do

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MITRAL STENOSIS

i A ii

A : CLASS 1,II (33) 8 = CLASS III (871 C : CLASS IV,lS)

40 C

Fig. 7.-Relationship between pulmonary vascular distending pressure (Pn) and pulmonary blood volume (PBV) in 287 pa- 2 tients with valvular heart 2 disease.ClassI, II, II, IV refer to functional

classifi-

cation basedupon criteria of the New York Heart Association.

B

20

MITRAL REGURGITATION A : CLASS 1‘11 121) 8 : CLASS III (39)

A

C = CLASS IV (2)

0

LLL

40 AORTIC STENOSIS

qQ20

,

,

,

i

i

yE::(”

i 40 AORTIC REGURGITATION 20o

,

,

200

,

il

250 300 PBV (ml/M*)

;~:~:::;;:‘,~:

350

not compartmentalize the various volumes into pulmonary arterial or pulmonary venous components. Likewise, they do not differentiate between events of regional significance, such as those occurring in upper and lower lobes of the lung. Notwithstanding the limitations, they contribute pertinent data concerning pathogenetic mechanisms which we believe are important in considering the phenomenon of pulmonary congestion. The data analyzed from our own laboratory concerning the pressure-volume relationship in human pulmonary vascular bed may be summarized as follows: Volume

Measurements at Rest

The resting values for PBV and pulmonary vascular distending pressure (PI>)* in 287 patients with valvular heart disease are depicted in Fig. 7. Among Class I and II patients with mitral valve disease or aortic stenosis, the PBV was normal and P,, only slightly increased in the presence of mitra1 stenosis. Among Class III patients, the PBV was increased considerably, while P, was elevated, particularly among patients with mitral valve disease. In *P/D = PAm + LAm/ left artrial mean pressure.

where

PAm = pulmonary

artery mean pressure and LAm

=

PATHOPHYSIOLOGY

40

OF

1

PULMONARY

CONGESTION

c

Q?

67

CARDIOMYOPATHY

L

20

ISCHEMICHEARTDISEASE B : CLASS Ill

Fig. 8.-Myocardial disease.Symbolsand abbreviations as in Fig. 7.

(141

0 200

250

300

350

PB','(ml/M2)

contrast, in the 10 Class IV patients, the average PBV was reduced below the normal range and PI, markedly elevated. Values for PBV in patients with aortic regurgitation (Classes I, II, III) were slightly elevated.“+ In 106 of these patients, 62 with mitral valve disease and 44 with predominant aortic valve disease, pulmonary capillary volume (V,) was also determined. In general, the changes in V, paralleled the changes in PBV.45 The relationship between PBV and PD in patients with varying degrees of disability associated with cardiomyopathy is depicted in Fig. 8, top. The changes in PBV and P, with increasing functional disability are quite similar to those observed in patients with mitral valve disease. All nine patients in Class IV had normal or low PBV values, while the average P, was markedly elevated. Data obtained in 25 patients with ischemic heart disease are shown in Fig. 8, bottom. Although the numerical functional classification of these patients is similar to that in other groups, the pulmonary vascular pressure-volume relationship is quite dtierent, since angina pectoris, not exertional dyspnea, is the predominant symptom. Those in Class I and II had low normal PBV, but normal values for PO. In Class III patients, both PA and LA pressures were still normal, but the PBV was increased. In the three patients of Class IV, both P,, and PBV were elevated.“.J” When the data from all groups of patients are compared, certain generalizations can be made. In Class I and II patients, there is little or no left atria1 hypertension, and the PBV is usually normal. As disability increases to Class III, left atria1 hypertension is usually present and probably accounts for the obser\,ed increase in PBV due to recruitment of previously closed vascular channels or to distension of existing ones. However, as the pathological process continues, there is a progressive restriction of the pulmonary vascular bed, both from within and without, which more than offsets the distending effects of left atria1 hypertension. As a result, the PBV returns to normal or even below normal values, while the distending pressure continues to rise. These findings strongly suggest alteration in the pressure-volume relation-

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RESTING VALUES q OFPATIENTS IN i’! HEARTFAILURE t’

50 Fig. 9.-Relationship between pulmonary vascular distending pressure (P,,) and pulmonary blood volume (PBV) in response to supine exercise. Resting values are depicted by open symbols, exercise by closed symbols. The patients exercised were all in Class I, II, or III. Insert depicts resting values in 23 patients in Class IV. The dashed Iine represents a hypothetical pressurevolume curve for these patients.

NORMAL MITRAL STENOSIS MITRAL REGURGITATION AORTIC STENOSIS AORTIC REGURGITATION MYOGIRMAL DISEASE I I

260

250

I

300

I

3’50

1

4bo

PBV (ml/M2) ships with

a marked

reduction

in pulmonary

vascular

compliance.

Supporting

evidence was provided by observations in seven patients with chronic pulmonary disease, thromboembolic hypertension or “idiopathic” pulmonary hypertension. In each instance, the PBV, which averaged 209 ml/sqm, was found to be low-normal or distinctly reduced, and yet the pulmonary arterial pressure was significantly elevated.?; Response to Physiological Interventions Supine Exercise (Fig. 9): In normal subjects, exercise resulted in a significant increase in PBV accompanied by only a’ minimal increase in Pn. The values obtained in patients with aortic regurgitation were shifted slightly upward as compared to the response in normal subjects. In marked contrast, when disease patients with mitral valve disease, aortic stenosis, or myocardial (principally cardiomyopathy) were exercised, the increase in PBV was accompanied

by a disproportionate

increase

in left atria1

and pulmonary

artery

mean pressure and, hence, an increase in P,,. The slopes of these curves were much steeper than those found in normal subjects or in patients with aortic regurgitation.27r47,48 At&l Tachypacing: In patients with normal hemodynamics, those with mild aortic value disease, and those with compensated primary myocardial disease, atria1 tachypacing with an increase of the heart rate of 30-40 b/min over the control rate resulted in a fall in left ventricular end-diastolic, left accompanied by a modest decrease atrial, and pulmonary arterial pressures, in PBV and little or no change in cardiac index, These findings suggested a modest augmentation in left ventricular performance accompanied by a pas-

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sive decline in PBV. The slope of the curve for these patients with heart disease is somewhat steeper than that for patients with normal hemodynamics. In sharp contrast was the response of patients with mitral stenosis, in whom tachypacing caused a marked rise in PD, accompanied by a considerable increase in PBV. The magnitude of the pressure and volume changes was similar to that induced by supine exercise, but the change occurred without change in ventilation or increase in cardiac index. kg Reponse to Transfusion and Phlebotomy: The effect in two normal subjects and seven patients of autotransfusion of 300 to 400 ml of titrated whole blood removed from each individual 2-3 days prior to study is illustrated in Fig. 10A. The increase in pulmonary vascular pressures was minimal in two normal subjects, but it was of significant and potentially serious magnitude in the patients with valvular heart disease. Indeed, in three of the patients with mitral stenosis, the left atria1 mean pressure reached 26, 30, and 30 mm Hg, respectively. However, the average increase in PBV was only 30 ml/sqm in each group. These findings confirm the potential hazard of precipitating acute pulmonary edema by rapid intravascular infusions in such patients. In the converse procedure, graded phlebotomy up to 400 ml was also carried out in ten patients-two with normal hemodynamics and four each with mitral valve or aortic valve disease (Fig. 10B). Pulmonary artery, left atrial, and P,, pressures all declined progressively. As would be expected from the transfusion studies, these changes were of least magnitude in the two normal subjects and greatest in the patients with mitral valve disease. The average decrease in PBV was in general also in the neighborhood of 30 ml in each group. It is of interest that removal of as little as 200 ml of blood from patients with valvular heart disease frequently reduced elevated LAm, PAm and PII. An additional phlebotomy of 200 ml reduced LAm and PAm to normal in some instances. Thus, in patients with valvular heart disease, particularly mitral stenosis, a modest reduction in total blood volume and in PBV, which may be difficult to demonstrate because of the limitations of the technique, may greatly improve the pressure volume relationships in the pulmonary vascular bed and cause a disproportionately large fall in pulmonary vascular pressure.?’ CONCEPTS OF PRESSURE VOLUME RELATIONSHIPS IN CONGESTIVE HEART AND IN PULMONARY EDEMA

FAILURE

In the past, the pathogenesis of pulmonary congestion in patients with chronic congestive heart failure has been frequently attributed to an increase in PBV.““-Si Others have stressed that the decline in vital capacity and in total lung capacity has been due to an enlarged PBV with vascular encroachment on the alveoli and displacement of air.55-“7A number of these hypotheses have been based upon clinical and radiological evaluation and assessmentof “central blood volume” (CBV). The CBV includes, in addition to the PBV, left heart volume, components of the systemic arterial volume and, in some instances, variable portions of right heart volume. It has been known for sometime that in patients with severe mitral stenosisor left ventricular failure, measurements of CBV have been inconsistent.SR-‘i’

70

Fig. lO.-Pulmonary vascular distending pressure desponse to autotransfusion (A) and phlebotomy (B).

SCHREINER

i

:

ET

AL.

1 CONTROL

CONTROL

TRANSFUSION 0

NORMALSUEJECTS

n

AORTIC

VALVE

DISEASE

0

MITRAL

VALVE

DISEASE

PHLEBOTOMY

In the light of these divergent observations, Ebert suggested that the true PBV may be normal in congestive heart failure because of altered pressurevolume characteristics of the pulmonary vascular bed.63 Vamauskas and colleagues confirmed the concept that the pulmonary circulation in congestive heart failure is dominated by pressure elevation rather than by an increase in PBV. Furthermore, they suggested that high pulmonary capillary pressure caused transudation of fluid into alveoli and interstitium, especially in the dependent portions of the lung.6’ The synthesis of these observations into a concept of the pathophysiology of pulmonary congestion derived further impetus from the observations of Samoff and Berglund, who constructed pressure-volume curves for the isolated canine lung. 65 They observed that in the initial portion of the curve, over a relatively large change in volume, pressures changed little. However, in a given curve, as volume was increased further, pressure quickly began to rise so that a smal1 increment in volume resulted in a disproportionate increase these pressure-volume relationships were derived in in pressure. Although reverse, i.e., the preparation was volume-loaded at high intravascular pressure

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and then aliquots of volume withdrawn, the same general characteristics appeared to apply when volume was augmented from an initial low pressure. It appeared to us that in patients with advanced heart disease and chronic pulmonary congestion, the normally flat pressure-volume curve was shifted upward and became progressively steeper with respect to the volume axis. Ultimately, in patients of Class IV the PBV may be normal or only slightly increased, but the pulmonary vascular distending pressure is markedly elevated. In this situation, a further small increment in PBV would result in a very marked increase in PD. The lines of evidence may be summarized as follows: Exercise, atria1 tachypacing, autotransfusion, and phlebotomy result in only minimal changes in P, in patients with normal hemodynamics. These findings, taken together, suggest that the normal lung is operating on a relatively flat initial portion of its pressure-volume curve and that physiological interventions, particularly exercise and autotransfusion, did not approach the critical pressure-volume point at which pressure begins to rise sharply for a given increase in PBV. In pathological states, in which chronic abnormal elevations of the pulmonary vascular pressures have been present, the PBV elevation at rest or with exercise has been less impressive than the increase in P,. Atria1 tachypacing in the presence of mitral stenosis mimics the response to exercise, but without a change in ventilation or cardiac output. Transfusion and phlebotomy result in significant alteration in P, but with relatively little change in PBV. These findings suggest restriction of the pulmonary vascular bed which is reflected by a large increase in pressure for a relatively small increment in PBV. The most marked abnormality in the pressure-volume relationships was observed at rest in a group of 23 patients with severe heart failure (Fig. 9). Of these, eight had severe mitral stenosis; two, mitral regurgitation; and nine, cardiomyopathy. In these groups, the mean P, was 30 mm Hg, and the mean PBV less than 250 ml/sqm. In three patients with ischemic heart disease, whose previous clinical course had not been as chronic, the P, averaged 34.5 mm Hg, and the PBV averaged 308 ml/sqm. In none of these patients was it medically prudent to stress their circulations further. The remaining patient with the highest P,, of 55.5 mm Hg (PAm 71, LAm 40 mm Hg) was studied during an episode of acute pulmonary edema. At the time, the P, was 55.5 mm Hg, but the PBV was only 306 ml/sqm. Previous studies from this laboratory corroborated the extreme pressure changes which occurred in patients with valvular heart disease in pulmonary edema. The average PAm during the control period was 57 mm Hg (six patients), during pulmonary edema 76 mm Hg (three patients), and in recovery 37 mm Hg (five patients). Pulmonary wedge pressure measured in two patients during pulmonary edema averaged 39 mm Hg.fiG Although it is tenuous to construct a pressure-volume curve on the basis of data at rest and one patient studied in acute pulmonary edema, it is tempting to speculate that the curve is very steep and may be nearly semivertical with respect to the PBV axis. If the findings of others and ourselves have validity, certain observations

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made in patients with congestive heart failure must be explai;d. Among them are: What is the mechanism by which the PBV is normal or actually decreased? What is the role of the PBV in congestive heart failure and its relationship to pulmonary pressure ? What mechanisms are responsible for abnormalities in pulmonary function? How can the clinical and pathological manifestations of pulmonary congestion be explained? Progressive pulmonary vascular obstruction is well recognized in association with chronic pulmonary venous hypertension. This process is most pronounced in severe mitral valve disease, but is also well recognized in chronic left ventricular decompensation resulting from aortic valve disease, coronary artery disease, or cardiomyopathy. The pathological changes most frequently encountered include medial hypertrophy and intimal proliferation in pulmonary arteries and veins, dilatation of pulmonary lymphatics with augmentation of lymphatic flow, interstitial fibrosis and interstitial and alveolar edema, thrombosis in situ and/or pulmonary embolism, and functional vasoconstriction secondary to hypoxemia.‘+“! It would appear reasonable to suggest that these pathophysiological changes form a spectrum, from patients with little or no physiological impairment on one hand, to those with advanced clinical disease on the other. For example, in mitral stenosis, when pulmonary venous hypertension is modest and of relatively short duration, moderate elevations in left atria1 pressure would tend to enlarge the pulmonav vascular bed, either by opening of parallel channels or by actual “distension” of existing ones. Structural forces opposing this process would be minor, and the overall PBV would tend to be increased. Since Dollery and West have demonstrated a decrease in the lower lobe perfusion in the upright position, the increase in PBV probably would be achieved in the middle and upper lobes of the lung.” On the other hand, when pulmonary venous hypertension is severe and protracted, the overall volume of the pulmonary vascular bed may be compromised despite the distending force of left atria1 hypertension. As a result of these mechanisms, the PBV becomes relatively fixed and even minor increase in volume result in elevations in pressures which are of major clinical import (Fig. 9). Thus, an elevated PBV is not the sine qua non either in pulmonary congestion or in edema with chronic pulmonary venous hypertension. Pressure elevations dominate the hemodynamic picture. In these circumstances, pulmonary vascular compliance is markedly reduced. When pulmonary venous and capillary pFcSSLUYS become elevated above colloid osmotic pressure, significant transudation of fluid from the intravascular compartment to the interstitium and subsequently to the alveoli occurs in a nonlinear time sequence. An increase in PBV per se does not seem important in producing pulmonary edema in other clinical conditions. For instance, in most patients with atria1 septal defects, large increases in the V,:+;’ and presumably in the PBV are commonly present with normal pulmonary capillary pressures; however, signs or symptoms of pulmonary congestion or edema are infrequently encountered. Despite the foregoing analyses, it should not be construed that the PBV may not be significantly increased in acute pulmonary congestion and pulmonary edema. Although there are no hemodynamic observations in man, it seems

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clear that, on the basis of the pressure-volume curves of Sarnoff and Berglund,G” clinical situations could arise in which the PBV is markedly elevated. These would include patients with normal cardiovascular function as well as patients with compensated heart disease who have elevated PBV and elevated pulmonary vascular pressures. They may develop acute left ventricular failure after injudicious intravenous administration of fluids or blood. Experimental support in the dog for this concept has been reported by Levine and associates.43. In the presence of heart failure, the reduction in pulmonary compliance reflects alterations in the elastic properties of the lung.‘?-;* This change cannot be explained on the basis of an increased PBV; nor are there good correlations between elevations of pulmonary vascular pressures and decreased compliance.T”-;6 It is likely that compliance changes are more directly related to interstitial changes within the lung, including fibrosis and the accumulated interstitial fluid, both of which would tend to diminish lung elasticity.

THE ROLEOF EXTRAVAKXJLAR VOLUMEIN

THE LUNGS

If PBV elevation is not the dominant mechanism in the pathogenesis of congestive heart failure, which factors are important in understanding impaired pulmonary function and the radiographic evidence of pulmonary “congestion?” Both abnormalities are explainable by postulating that the congestion is primarily an extravascular rather than an intravascular phenomenon, and that it results from fluid accumulation in the interstitial tissues and in the air passages. The former site probably includes the larger interstitial spaces and pulmonary lymphatics. The precise location of fluid transfer into the interstitium is incompletely defined, although from the Starling hypothesis it undoubtedly includes the capillary alveolar interface.Q In addition, Staub and associates have suggested that a significant amount of fluid may be transferred into the interstitium at both pre-and postcapillary siteseT Two lines of evidence (one experimental and one clinical) point to the importance of the interstitial space in pulmonary congestion. Experiments

in Animals

In 1965, Levine and associates differentiated pulmonary congestion with edema from pulmonary congestion alone, based upon measurements of PBV and PEV in dogs. 43 In the presence of pulmonary congestion alone, the PBV was increased, but the PEV remained normal. When pulmonary edema supervened, the PEV increase1 significantly while the PBV showed no further change from the values determined during pulmonary congestion. Subsequent studies from the same laboratory depicted the morphological correlates of these experiments. 9 In hemodynamic pulmonary edema, there was interstitial edema with swelling of connective tissues around some, but not all, lobar and segmental pulmonary arteries and veins. The major alterations seen by electron microscopy involve1 the interstitial portions of the septum. Collagen-containing areas were expanded and fibrils widely separated. However, in portions of the septum devoid of collagen, where the blood-air spaces are normally thinnest, no enlargement was noted. Similar results

74

SCHREllVER

ET

AL.

have been reported by Staub et al.,;; who, as a consequence of more prolonged observations, reported alveolar-endothelial interface thickening and accumulation of fluid in alveoli. The formation of edema in these experiments could be regarded as merely an accentuation of the normal processes of fluid exchange, Cottrell et al. have suggestel that the interstitial sites could serve as reservoirs to collect excess fluid which may enter the interstitial space, This mechanism would bind fluid and funcion as a sponge to maintain dryness in the alveoli.g The dominance of intravascular forces, as proposed in the Starling hypothesis of the genesis of pulmonary congestion, has been questioned by Levine and co-workers.*s Using serial determinations of PEV at a constant difference between intravascular hydrostatic pressure and osmotic pressure of plasma proteins, they found the rate of accumulation of lung water to be nonlinear with respect to time. They suggested three possible mechanisms which could be responsible for this nonlinear change: ( 1) unmeasured pericapillary forces, (2) changes in filtration coefficient, or (3) lymphatic drainage from the lung. It appeared by exclusion that pericapillary forces, mainly interstitial percapillary hydrostatic pressure, may have an appreciable effect on the exchange of fluid across the pulmonary capillary membrane. Evidence was also presented to suggest that the lung behaved in a manner similar to subcutaneous tissues’8-8” resulting in the following changes: transcapillary filtration was associated with a change in pericapillary hydrostatic pressure from negative to positive; pericapillary interstitial fluid could alter the pressure-volume characteristics of the tissue which would allow continued fluid accumulation without increasing tissue pressure; and resistance to fluid movement through the tissue spaces decreased as interstitial fluid pressure exceeded atmospheric pressure. West has postulated that perivascular edema and increased tissue pressure may be important in regulating regional pulmonary vascular resistance in the dependent zones of the lung in the presence of either normal or elevated left atria1 pressure. 81 However, the recent studies of Ritchic ct al. could not confirm this postulation.“” Investigations

in Humans

The technique of measuring PEV has been carried on by a number of workers including ourselves. 83-8Q The value for PEV in 26 normal subjects averaged 80 to 90 ml/sqm. 83-s6 In two series, the reported values in milliliters were divided by an assumed body surface area of 1.8 sqm.83-R~ The findings in more than 55 patients studied in our laboratory are summarized in Fig. 11 and Table 1. In general, there was good correlation between PEV and PD, particularly when P D was considerably elevated as in patients with predominant mitral stenosis. Among patients with ischemic or primary myocardial disease and those with aortic valve disease, there was considerable variation in PEV when both P, and left atria1 pressures were nearly normal. If the values of PEV were analyzed according to the functional classification of the patients, it becomes apparent that those with a mild degree of disability (Class I and II) had almost normal values for PEV and had little or no left atria1 hypertension. In Class III patients, however, both LAm

PATHOPHYSIOLOGY

OF

PULMONARY

75

CONGESTION

A 40

A

0

cI cl 0

5 r&y3 20

Fig. Il.-The relationship between pulmonary vascular distending pressure (PJ and pulmonary extravascular volume (PEV) is depicted for patients with valvular and mvocardial disease.

b

0

10 2

a OA

3i

:o’

250 PEV (nd/Mz)

and PEV were elevated. The PEV values were conspicuously higher in patients with mitral valve disease than in those with aortic valve disease and suggested that persistently elevated left atria1 and presumably pulmonary capillary pressures are associated with marked increases in lung water (Table 1). These findings are in substantial agreement with those reported by McCredies” and by Luepker. 86 Of the six patients in functional Class IV, a significant increase of PEV was associated with marked elevation of LAm and P,. Similar results have been reported by Lilenfield and Ramsey and their respective associates.831si Of particular interest was the relationship between the radiographic findings, the PEV, and the left atria1 pressure in a subgroup of 30 patients.*” The radiological findings were interpreted independently by an experienced radiologist. Of the 12 patients with no radiological evidence of pulmonary congestion or edema, the PEV averaged 89 ml/‘sqm (range, 66-122 ml/sqm), and the LAm pressure was normal. The nine patients with radiographic evidence of pulmonary venous congestion had an average PEV of 113 ml,/sqm Table -

l.-Pulmonary

Extravascular

Volume

(ml/sqm)

in Patients Functional

I and II

Disease

With

Heart Disease

Classification*

III

IV

122

163

_-.Irchemic primary disease

and myocardial

87f (8)t

nlitral

valve

disease ci

Aortic

valve

disease

113 (6)

(14)

(3)

163 (15)

-

E

184 (3)

*Functional fAverage $Nnmber

classification according PEV in ml/sqm. of patients in each group

to the New enclosed

York

Heart

in parentheses.

Association.

76

SCHREINER

ET AL.

(range, 86-156 ml/sqm). Their left atria1 mean pressures varied from I6 to 26 mm Hg. In nine patients with evidence of interstiti;rl fluid by X ray, the PEV averaged 158 ml/sqm (range, 117-198 ml/sqm), and in all but one the LAm exceeded 22 mm Hg. It is, therefore, apparent that in the pathophysiology of pulmonary congestion, the PEV and its ramifications must be considered in addition to measurements of PBV and the relationship between flows and pressures. %JMMARY

AND

CONCLUSIONS

Pulmonary congestion has been defined in terms of clinical findings, X ray evaluation, and pathological examination. Pertinent aspects of the anatomy and physiology of the pulmonary circulation, including capillary-alveolar interface, lymphatics, capillary bed, and the distribution of pulmonary blood flow have been briefly reviewed. The pathophysiology of pulmonary congestion in chronic valvular or primary myocardial heart disease has been elucidated in terms of the relationship of pulmonary vascular pressure to pulmonary blood volume during control observations in patients with varying degrees of functional disability and during physiological interventions including supine exercise, atria1 tachypacing, autotransfusion, and phlebotomy. In addition, the relationship of pulmonary vascular pressure to pulmonary extravascular volume has been investigated in similar groups of patients at rest. It is concluded that the pressure-volume relationships within the pulmonary vascular bed are greatly altered in patients with chronic pulmonary venous hypertension. As functional incapacitation progresses through Class III, elevations in pulmonary blood volume are associated with disproportionate increases in pulmonary artery and left atria1 mean pressures. These changes are magnified by supine exercise, autotransfusion, and in patients with mitral stenosis, by atria1 tachypacing. In Class IV patients, pulmonary vascular pressures become even further elevated, while the pulmonary blood volume is normal or less than normal, Thus, reduced pulmonary vascular compliance can result in an aggravation of pulmonary congestion from further pressure elevations without appreciable increments in intravascular volume. In contrast to the behavior of the pulmonary blood volume, the pulmonary extravascular volume continues to increase in Class IV patients and is roughly proportional to the magnitude of left atria1 hypertension. Therefore, accumulation of fluid in the interstitial tissues of the lung and subsequently in the alveoli is largely responsible for the clinical and radiographic manifestations of pulmonary congestion. REFERENCES

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CONGESTION

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79

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