of Pulmonary Hypertension

Transcription

1 Experimental Studies on the Reversibility of Pulmonary Hypertension Bert A. Glass, M.D., Jack C. Harold M. Albert, M.D. Geer, M.D., and t is well known that elevation of pulmonary arterial pressure and microscopic pulmonary vascular changes occur from left-to-right shunts. In many instances both the pressure elevation and the vascular changes regress following closure of the shunt, while in others the pressure remains elevated presumably due to irreversible pulmonary vascular change. An experimental study was instituted to attempt to correlate the severity of the microscopic vascular lesions with the degree of pulmonary hypertension and to determine at which stage the vascular lesions become irreversible. METHOD Unilobar pulmonary hypertension was produced in beagle puppies weighing from 2.8 to 8.2 kg. using a modification of the method of Muller et al. [7]. Three preparations were used (Fig. 1). The first (Fig. 1A) consisted of a 3 mm. diameter side-to-side aortico-pulmonary artery anastomosis. A constricting band placed on the left pulmonary artery proximal to the anastomosis served the dual purpose of shunting aortic blood into the left lung and protecting the right lung from the effects of the shunt. The constricting band was tightened sufficiently to narrow the left pulmonary artery to approximately one-third of its original diameter, leaving the lumen large enough for subsequent passage of a No. 6 cardiac catheter. The left upper and middle lobes were then removed, leaving the lower lobe to bear the entire load of the left-toright shunt. Specimens were taken by biopsy from the excised lobes for microscopic study. Method two (Fig. 1B) was identical with method one except that From the Departments of Surgery and Pathology, Louisiana State University School of Medicine, New Orleans, La. Supported by Grants HE and HE from the National Heart Institute of the National Institutes of Health, U.S. Public Health Service. Presented at the Eleventh Annual Meeting of the Southern Thoracic Surgical Association, Atlanta, Ga., Nov , VOL. 1, NO. 2, MAR.,

2 GLASS, GEER, AND ALBERT A FIG. 1. Methods used in producing pulmonary hypertension in experiment01 animals studied. (A) Three mm. diameter side-to-side aortico-pulmonary anastomosis with proximal constricting band on left pulmonary artery. (B) Identical to (A) but with ligation of upper and middle lobe arteries and lung left intact. (C) Three mm. diameter side-to-side anastomosis between descending aorta and artery to left lower lobe, with constricting band on left pulmonary artery between middle lobe artery and anastomosis. (0) Restoration of Normotensive state after achievement of desired microscopic vascular changes or lower lobe pressure. levels with closure of shunt, removal of pulmonary artery band, and removal of stricture at band site by resection and end-to-end anastomosis of pulmonary artery. the upper and middle lobe arteries were ligated and the lung was left intact to prevent overexpansion of the left lower lobe. A lung biopsy was performed to obtain specimens for microscopic study. Method three (Fig. 1C) consisted of a 3 mm. diameter side-to-side anastomosis performed between the descending aorta and the artery to the left lower lobe. The constricting band was placed on the left pul- 160 THE ANNALS OF THORACIC SURGERY

3 Reversibility of Pulmonary Hypertension monary artery between the middle lobe artery and the anastomosis. This shunted aortic blood into the left lower lobe, while protecting the upper and middle lobes. A lung biopsy was performed to provide specimens for microscopic study. Regardless of the initial method used to produce unilobar hypertension, the subsequent steps and results were identical. Method two was utilized because it was thought that overdistention of the lower lobe might influence vascular pathology. Method three replaced method FIG. 2. Photomicrograph of grade IZ vascular lesions. (Dog ) tx540.) (A) Muscular thickening in small pulmonary artery. (B) Thickened pulmonary arteriole. (C) Same animal 3 months after removal of shunt. Note normal vascularity. VOL. 1, NO. 2, MAR.,

4 GLASS, GEER, AND ALBERT two because ligation of the lobar arteries caused dense, vascular adhesions to develop between visceral and parietal pleura. The use of method three made subsequent procedures technically easier but, to repeat, results were essentially the same with all three initial methods. At approximately monthly intervals following the initial procedure, pressures were measured either by catheterization or at thoracotomy, in the main and left pulmonary arteries proximal to the band, in the left lower lobe artery distal to the band, and in either the aorta or a systemic vessel. Biopsies of the involved lobe and of a control lobe were performed when appropriate elevations of pressure occurred in the left lower lobe artery. In most instances this occurred at 5 to 8 weeks after the initial procedure. Microscopic vascular lesions in the biopsy specimens were graded from I to VI using a modifiation of the classification of Health and Edwards [4]. Grade I lesions were defined as slight thickening of the small muscular pulmonary arteries. In our experience there was so much variation between peripheral biopsies and necropsy sections that these lesions could not be accurately assessed. This grade, therefore, was not used in evaluating lesions. Grade I1 lesions were characterized by definite thickening in small muscular pulmonary arteries (Fig. 2) and muscular pulmonary arterioles. There was usually a moderate increase in adventitial collagen about small muscular arteries with grade I1 lesions. Grade I11 lesions were characterized by intimal thickening in muscular pulmonary arteries (Fig. 3). Grade IV lesions exhib- FIG. 3. Grade 111 lesions: intimal thickening in miiscular pulmonary arteries. (Dog ) (X540.) 162 THE ANNALS OF THORACIC SURGERY

5 Reuersibility of Pzilmonary Hypertension ited plexiform intimal thickening (Fig. 4). Grade V, generalized dilatation lesions, as described by Heath and Edwards [4], were not observed in our animals. Grade VI lesions (Fig. 5) were characterized by fibrinoid FIG. 4. Grade ZV lesions: plexiform intimal thickening in muscular pulmonary arteries. (Dog 60-8.) (~540.) FIG. 5. Photomicrograph of grade VZ lesion characterized by fibrinoid necrosis of muscular artery. (Dog ) (X540.j VOL. 1, NO. 2, MAR.,

6 GLASS, GEER, AND ALBERT necrosis of muscular arteries. The grade of lesion in each case was determined by the predominant vascular pathology present and not necessarily by the most severe or advanced lesion seen. When the desired lower lobe pressure or the desired microscopic vascular changes were produced, a normotensive state was restored in the lower lobe by another surgical procedure. The aortic-pulmonary shunt was closed, the pulmonary artery band removed, and the stricture at the site of the band eliminated by resection and end-to-end anastomosis of the pulmonary artery (Fig. 1D). Pressures were measured in the pulmonary artery and the aorta before and after closure of the shunt. Subsequent catheterizations and lung biopsies were performed at 3- to 6-month intervals after shunt closure in order to follow regression of hypertension and vascular changes. All surgical procedures were performed under intravenous pentobarbital sodium anesthesia. Respiration was controlled by endotracheal positive pressure from a Harvard respirator. A fifth interspace posterolateral thoracotomy was utilized for all thoracotomies. Cardiac catheterizations were done via the external jugular vein, utilizing a 5-inch image intensifier. Arterial pressures were measured using Statham transducers and an Electronics for Medicine multichannel recorder. Lung specimens were sectioned and stained with hematoxylin and eosin and Weigert-van Gieson stains. Prior to any experiment, peripheral blood smears were examined for microfilaria. Any dog found to have either microfilaria or adult heartworms at any stage of the experiment was excluded from the study. RESULTS Sixty-six animals were studied. Of 31 dogs surviving 4 weeks or longer after the initial procedure, 26 developed significant distal left pulmonary artery pressure elevations. Seventeen animals developed microscopic vascular lesions ranging from grade I1 to grade VI. In the absence of pulmonary hypertension no animal developed vascular lesions, but there was little correlation between the degree of pulmonary artery pressure elevation and the grade of microscopic vascular lesion (Table 1). Five dogs with no elevation of pressure showed no arterial lesions. However, nine animals with elevated pressures showed no vascular lesions although the pulmonary artery pressure approached systemic pressure in 3. Conversely, of 6 dogs with grade IV lesions (Table Z), only 3 had pulmonary artery pressures approaching systemic pressure. Five of 11 dogs with grade I1 to I11 lesions developed pulmonary artery pressures approaching systemic pressures (Table 3). 164 THE ANNALS OF THORACIC SURGERY

7 Reversibility of Pulmonary Hypertension TABLE 1. ANIMALS SHOWING ELEVATED PULMONARY ARTERY PRESSURE WITHOUT VASCULAR LESIONS P.A. Pressure Dog No. (shunted lobe) Systemic Pressure / 10 20/12 30/10 25/15 45/20 110/80 80/20 90/40 85/55 72/20 75/50 50/30 60/40 55/30 90/ /80 120/70 90/40 1 l0/70 140/ /80 90/40 140/ /70 145/ /95 150/ /70 Dog No TABLE 2. ANIMALS SHOWING GRADE IV VASCULAR LESIONS P.A. Pressure (shunted lobe) 100/90 130/ /120 95/85 75/50 Not measured Systemic Pressure 110/85 130/ / /95 125/75 Not measured TABLE 3. ANIMALS SHOWING GRADE 11 TO I11 VASCULAR LESIONS P.A. Pressure Dog No. Grade Lesion (shunted lobe) Systemic Pressure I1 to I11 115/ / I1 55/38 55/ I1 to I11 125/70 125/ I1 (one or two VI) 150/70 Not measured I1 100/30 Not measured I1 to I11 80/60 135/ I1 60/25 80/ I1 (a few IV) 65/55 110/ I1 85/75 125/ I1 60/30 110/ I1 80/30 110/40 In all animals studied the pulmonary artery pressure dropped to normal as soon as the shunt was closed. This finding was anticipated since the remainder of the pulmonary vascular bed would be expected to be normal, and indeed proved to be so on biopsy of control lobes. Of the 17 dogs with vascular lesions from grade I1 to VI, 9 survived the multiple surgical assaults and were studied for regression of their VOL. I, NO. 2, MAR.,

8 GLASS, GEER, AND ALBERT TABLE 4. REGRESSION OF LESIONS AFTER CLOSURE OF LEFT-TO-RIGHT SHUNT Dog No Grade Lesion IV IV IV IV I1 to 111 I1 to I1 I11 Mo. Followed After Closure of Shunt Degree of Regression ~ Grade IV, no regression Grade IV, no regression Grade IV, no regression Grade IV, no regression Regressed to grade 0 Regressed to grade 0 Regressed to grade 0 Heartworms; regression? Awaiting biopsy microscopic vascular lesions (Table 4). None of the 4 dogs with grade IV vascular changes showed any regression of their lesions up to 14 months after shunt removal and restoration of normal pulmonary artery pressure. Three animals with grade I1 to I11 lesions, however, showed regression of their vascular lesions within 3 to 6 months. One grade I1 animal developed heartworms sometime between the third and sixth month after closure of the shunt, and it was impossible to evaluate microscopically the regression of vascular lesions. The last dog in this group is still awaiting biopsy. Figures 2A and 2B demonstrate grade I1 lesions in a lung biopsy specimen from dog No (Table 4) at the time his shunt was closed. Three months later there was complete regression of these lesions, as shown in Figure 2C. DISCUSSION The results of this study are essentially in agreement with experimental studies by Blank et al. [l], Dammann et al. [2, 31 and Lynn and Bahnson [6] concerning the production of pulmonary hypertension. Our results also concur with the clinical observations of Heath et al. [5] concerning reversibility of pulmonary vascular lesions. Arterial lesions characterized by medial hypertrophy and muscular pulmonary arterioles (grade 11) reverted to normal after ablation of the inciting factor, the left-to-right shunt. The point of irreversibility appeared to be marked intimal thickening in muscular pulmonary arteries and plexiform lesions (grade IV). It is interesting that there was little correlation between pulmonary artery pressures and the severity of vascular lesions other than the fact that no animals developed vascular changes in the absence of hypertension. Pulmonary hypertension approaching systemic levels was present in animals with no vascular lesions, with reversible lesions, and with irreversible lesions in about equal proportions. Certainly the length of time between establishment of a left-toright shunt and the development of microscopic vascular changes 166 THE ANNALS OF THORACIC SURGERY

9 Reuersibility of Piilnaonary Hypertension should be pertinent. It would appear reasonable to assume that, with a standard anastomosis, the grade of vascular lesion would depend primarily on the length of time the shunt existed. This point proved difficult to evaluate in our hands. In spite of attempts to create shunts of uniform size, some variation in the diameter of the anastomosis invariably occurs with this procedure. Grade IV lesions have been observed as early as 5 weeks following the establishment of a shunt (dog ). Conversely, one animal (dog 59-24) developed pulmonary artery pressures approaching systemic in the shunted lobe 10 weeks following establishment of a shunt, but had failed to develop microscopic vascular lesions when sacrificed 9% months later. We originally expected the production of vascular lesions to proceed in some sort of orderly fashion with respect to time. As the above examples illustrate, this aspect of the experiment was frustrating. We can only conclude that factors other than time apparently play a part in the development of microscopic vascular lesions associated with left-to-right shunts. COhTCL USIONS From the foregoing findings it would appear that the level of pulmonary artery pressure, by itself, is an unreliable index, clinically, of which left-to-right shunts should be closed and which should not. Lung biopsy may be a useful adjunct in determining operability. We realize the dangers of transferring results of animal experinients to patients, but in view of clinical studies by Heath et al. [5] and the animal results reported here, the above stateinelit would appear valid. A plan of management of ventricular septa1 defects with pulmonary hypertension is therefore suggested. Pulmonary artery pressure is known to be the result of flow and pulmonary arteriolar resistance. The following situations may prevail in individual patients. With very large left-to-right shunts and normal to moderately elevated arteriolar resistance, pulmonary hypertension of marked degree has been noted in some cases. These patients are benefited immediately after closure of the intracardiac defect and pulmonary artery pressures decrease. In infancy, such patients are benefited by banding the main pulmonary artery. A retrospective clinical study by Heath et al. [5] demonstrated predoniinantly low-grade vascular lesions in such patients. On the other end of the scale are patients with markedly elevated pulmonary arteriolar resistance and reversal of their shunts in addition to their pulmonary hypertension. These patients are usually not considered candidates for surgery. In a limited number of such patients submitted to lung biopsy the pulmonary vascular changes have been grade IV. VOL. 1, NO. 2, MAR.,

10 GLASS, GEER, AND ALBEKT In between these two extremes we have encountered the occasional patient with pulmonary hypertension, a definitely elevated pulmonary arteriolar resistance, and either a balanced shunt or a small left-to-right shunt. These patients do very poorly following shunt closure, the pulmonary artery pressure remains elevated, and right ventricular failure often ensues. A few patients in this category have been noted to have grade I1 or grade I11 lesions which we think should be reversible if relieved of the deleterious effects of increased pressure and/or flow. Banding of the main pulmonary artery in such patients is not as successful as in the patient with increased flow and low resistance because the further resistance of the band on the main pulmonary artery converts the shunt into a right-to-left shunt and produces a quite cyanotic child. Because we believe grade I1 and I11 lesions are reversible it is theorized that banding of the left or right pulmonary artery alone will decrease the flow and pressure load on the banded lung. The vascular changes in this lung can be followed by lung biopsy until regression occurs. At that time, removal of the unilateral band and closure of the intracardiac defect would be feasible. This would provide one lung containing normal vasculature, presumably with normal arteriolar resistance, following closure of the defect. The danger of postoperative right heart failure would thereby be lessened. Admittedly, suitable candidates for such a procedure are not the general rule among patients having ventricular septal defects. Patients considered for such a program should have ventricular septal defects, pulmonary hypertension, elevated vascular resistance, and either small left-to-right or balanced shunts. In addition, lung biopsy should demonstrate vascular lesions no worse than grade I1 or grade 111. We have adopted this program on a limited clinical experimental basis. We are not yet prepared to report on results, but believe the idea has merit. Because a limited number of patients fit the necessary criteria, the program is presented in the hope that others may see fit to utilize the principle in properly selected cases. SUMMARY Unilobar pulmonary hypertension was produced in beagle puppies. The development of hypertension and vascular lesions was followed by catheterization and lung biopsy. When desired vascular changes were produced, the inciting cause (a left-to-right shunt) was removed and regression of vascular changes observed by subsequent lung biopsies. Grade IV lesions were found to be irreversible when followed for periods up to 14 months. Lesions as severe as grades I1 and I11 reverted to normal within 3 to 6 months. The clinical application of this information is discussed. 168 THE ANNALS OF THORACIC SURGERY

11 Reuersibility of Pulmonary Hypertension REFEREhlCES 1. Blank, K. H., Muller, W. H., Jr., antl Dammann, J. F., Jr. Experimental pulmonary arterial hypertension. Amer. J. S z q. 101: 143, Dammann, J. F., Jr., Barker, J. P., antl Muller, MI. H.,,Jr. Pulmonary vascular changes induced by experimentally produced pulmonary arterial hypertension. Surg. Gynec. Obstet. 105: 16, Dammann, J. F., Jr., Smith, R. T., antl Muller, W. H., Jr. The experimental production of pulmonary vascular disease. Slug. Forum 6: 155, Heath, D., and Edwards, J. E. The pathology of hypertensive pulmonary vascular disease: A description of six grades of structural changes in the pulmonary arteries with special reference to congenital septa1 tlelects. Circulation 18:533, Heath, D., Helmholz, H. F., Jr., Burchell, H. B., DuShane, J. W., Kirklin, J. W., and Edwards, J. E. Relation between structural changes in the small pulmonary arteries and the immediate reversibility of pulmonary hypertension following closure of ventricular antl atrial septa1 defects. Circulation 18:1167, Lynn, R. B., antl Bahnson, H. T. Experimental pulmonary hypertension with increased pulmonary blood flow. Surg. Forum (i:290, Muller, W. H., Jr., Dammann, J. F., Jr., and Head, W. H., Jr. Changes in the pulmonary vessels prorlucctl by experimental pulmonary hypertension. Surgery 34:363, VOI.. 1, NO. 2, MAR.,