Experimental Pulmonary Venous Occlusion T a t Hin Ong, F.R.A.C.S., and Mark M. Ravitch, M.D.

ABSTRACT Complete interruption of pulmonary venous return from the left lung in rabbits is compatible in some instances with prolonged survival with little systemic effect. The main cause of death less than 48 hours after interruption of pulmonary venous return is pulmonary-pulmonary aspiration and respiratory insufficiency due to spillover of frothy, bloody fluid, after which infection may play a part. Marked anemia after unilateral pulmonary venous ligation attests to the loss of blood into the lung. Death from unilateral pulmonary venous ligation did not occur if the corresponding main bronchus was ligated to prevent pulmonary-pulmonary aspiration. Despite ligation of the pulmonary veins the corresponding pulmonary artery remained patent.

E

arly interest in the effects of pulmonary venous ligation focused on the influence of pulmonary congestion upon tuberculosis [6, 11, 131. Limited clinical trials were carried out by Kirschner [71 and OShaughnessy [9],but the results were equivocal. Although most of the investigations were confined to studying the results of ligation of selected pulmonary lobar veins, Hyndman and colleagues [6], in the course of their studies on the influence of congestion upon tuberculosis, completely ligated the pulmonary veins to the left lung in several dogs and remarked that the procedure was “not in the least incompatible with life.” It had formerly been thought that complete ligation of the pulmonary veins to one lung was invariably fatal. Since then there have been a few other reports. Swan and Mulligan [ l l ] reported that complete ligation of the pulmonary veins from one lung was fatal in 2 dogs. Hanlon and associates [5] studied complete pulmonary venous occlusion in 25 dogs. All 8 dogs with leftsided pulmonary venous ligation survived, while 7 of 17 dogs died following pulmonary venous occlusion on the right side. Guertzenstein and colleagues [4] performed complete pulmonary venous ligation on the right side in 3 dogs with 2 deaths and on the left side in 2 dogs with 1 death. Galarza and co-workers [31 studied complete pulmonary venous ligation on the left side in 5 dogs, 3 of which died. More recently, in this laboratory Somasundaram and associates [ 101 studied the effects of ligation of the pulmonary vasculature in the rabbit fetus and reported that ligation of the pulmonary veins to the left lung resulted in death within a few hours. They suggested hemorrhage into the infarcted lung or humoral factors secondary to engorgement as possible causes of death. They

From the Departments of Surgery, Montefiore Hospital and University of Pittsburgh Health Center, Pittsburgh, Pa. Accepted for publication Sept. 17. 1974. Address reprint requests td Dr. Ravitch, Montefiore Hospital, 3459 Fifth Ave., Pittsburgh, Pa. 15213.

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ONG AND RAVITCH reported a similar fatal outcome in pilot experiments on adult rabbits. It was obvious on review of the literature that some adult animals survived unilateral pulmonary venous occlusion while others died. The purpose of this study was to determine the cause of death in the adult rabbit following pulmonary venous occlusion.

Materials and Methods The experiments were performed on adult New Zealand white rabbits weighing between 2,050and 4,900 gm. After premedication with atropine, the rabbit was anesthetized with ether and intubated with a 3.5 mm For-Clear transparent endotracheal tube, and anesthesia was maintained with an airlether mixture [ 121. The rabbit was placed in the right lateral position and procaine penicillin, 300,000 IU, was given intramuscularly just prior to operation. A left thoracotomy was performed through the fifth intercostal space using aseptic technique. In the control set of rabbits the left hilar structures were merely dissected out, the open thoracotomy otherwise the same as in the other experimental groups. In experimental Group 1 the left superior and inferior pulmonary veins were ligated in continuity with 3-0silk. In the immediate postoperative period this group of rabbits was placed with the operated (left) side up during recovery from anesthesia, which lasted from $4 to 2 hours. In Group 2 complete left pulmonary venous ligation was again performed, but these animals were placed with the operated (left) side down during the recovery phase. In experimental Group 3 the left main bronchus was ligated with 3-0 Tevdek, and the left pulmonary veins were ligated as before. In the Group 4 rabbits the left pulmonary artery was dissected away from the rest of the hilar structures, and a single 3-0Tevdek ligature was used to occlude simultaneously the left main bronchus and the left pulmonary veins and bronchial vessels. The last two groups of rabbits were placed with the operated side up during the recovery phase. Throughout the various operative procedures, particular care was taken not to cause a contralateral pneumothorax or any laceration to the lung on the operated side. Three rabbits that had gross pneumothorax on the right side and 1 that sustained laceration of the left lung, all of which were recognized during the operative procedure, were excluded from the series. These 4 animals died within 48 hours of the operation, but complete postmortem examination was not performed. At completion of the selected intrathoracic procedure, underwater intercostal drainage was provided during closure of the chest wall. Prior to placing the final skin stitch, the chest was compressed to expel as much air as possible before the intercostal tube was removed. The animals operated upon were closely observed for 6 hours to see that they recovered satisfactorily from anesthesia. One rabbit intended for experimental Group 3 died during this period from postoperative inhalation resulting in aspiration into the right lung and was excluded from the series. Procaine penicillin (300,000IU) was administered intramuscularly daily for 4 postoperative days. 416

T H E ANNALS OF THORACIC SURGERY

Experimental Pulmonary Venous Occlusion The rabbits that died spontaneously were examined postmortem with particular attention paid to the chest. The ligatures around the left superior and inferior pulmonary veins were identified, and the completeness of ligation of the pulmonary veins was ascertained with a fine lacrimal duct probe. The lungs were removed at the hilum and were weighed before preservation in 10%formalin for later histological studies. The rabbits of all experimental groups that survived 7 days or more were killed between 7 and 21 days postoperatively (Table 1). Immediately after each animal was killed, a left atrial angiogram was performed through a sternumsplitting thoracotomy to show that the left pulmonary veins had been completely ligated. The heart and lungs were then removed en bloc, and after ligation of the superior and inferior venae cavae and the aorta, a left atrial angiogram followed by a pulmonary arteriogram was performed to ascertain the state of the pulmonary vessels (see Figs. 3 , 4 ) . The lungs were removed at the hilum, weighed, and then preserved for histological studies. In order to exclude as many variables as possible and to determine the effects of experimental venous occlusion, we excluded from the series deaths due to anesthesia (4) and technical errors (2) and rabbits that sustained gross pneumothorax of the right pleural cavity recognized at operation, those that sustained laceration of the lung during thoracotomy, and animals found to have preexisting disease of the lung, particularly of the right one. Of the 3 animals in the last category, 2 died promptly; 1 of these had chronic empyema of the right chest while the other had multiple intrapulmonary abscesses involving the right upper and middle lobes. The third rabbit had a solitary nodule in the right upper lobe and survived 2 weeks after ligation of the left main bronchus and left pulmonary veins but was excluded from the series because of its preexisting lung disease.

Results CONTROL GROUP

All 10 rabbits in the control group survived operation and were killed between 1 and 21 days postoperatively. Manipulation of the left lung produced no significant change in its weight. The mean weights of the left and right lungs were 5.12 gm and 7.38 gm, respectively. GROUP 1, 15 RABBITS

In this group, which underwent left pulmonary venous ligation with the left side up in the recovery phase, 6 of 15 rabbits died between 6 and 72 hours postoperatively; at postmorten examination all had aspiration of the right lung with consolidation of varying degrees. The left lung was purplish in color and showed intense hemorrhagic consolidation; the bronchi were filled with bloody, frothy fluid. Lung weights in the rabbits that died are shown in Table 2; compared with the lung weights of the control group, there were significant increases in weight in both the right and left lungs. Of the 9 survivors, 1 proved to have empyama on the left side; in another, resolving pulmonary-pulmonary aspiration of the right lung involved only part of the cardiac lobe.

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i2

4

~

_

_

2 9

0

6

0 8

1 0 1 14

0

15

Group 4 t

*Data for Groups 1 and 2 reflect the results of left pulmonary venous ligation alone. Total deaths in these two groups, 11; total survivors, 19. ?Data for Group 3 reflect the results of ligation of the left main bronchus and pulmonary veins. Group 4 animals had ligation of the pulmonary veins, bronchus, and bronchial vessels. Total deaths in these two groups, 4; total survivors, 26. p (from the Fischer chi-square table) = 0.10. PA = pulmonary artery; PV = pulmonary veins; B = bronchus; BV = bronchial vessels.

_

1

1

1 2 6

0 10

7 2

2 1 3 12

4 1 0 5 10

6 0 0 6 9

15

15

15

10

Group 3 t

No. of rabbits Cause of death Pulm.-pulm. aspiration Infection Other causes Total deaths Total survivors Time killed 1 wk 2 wk 3 wk

Group 2*

Control

Data

Group 1*

TABLE 1. RESULTS OF EXPERIMENTAL PULMONARY VENOUS OCCLUSION

Experimental Pulmonary Venous Occlusion GROUP 2, 15 RABBITS

In this group, which had left pulmonary venous occlusion with the left side down in the recovery phase, there were 4 deaths from spillover of bloody bronchial fluid from the hemorrhagic left lung into the right lung and 1 death from bilateral bronchopneumonia occurring after the hemorrhagic consolidation of the left lung had resolved. Ten of the 19 survivors from Groups 1 and 2 underwent left thoracotomy 1 week after ligation for visual inspection of the left lung. In 7 the left lung showed brick red congestion without consolidation, while in 2 rabbits there was gross evidence of resolving consolidation. One rabbit had a left empyema which was drained. This rabbit, despite the infection, survived until killed 3 weeks postoperatively. All of the lungs inspected, except the one with empyema, appeared fully inflated. GROUP 3, 15 RABBITS

In this group, which underwent in’dividualligation of the left main bronchus and left pulmonary veins, 12 animals survived uneventfully. There were no deaths from spillover and pulmonary aspiration pneumonia in the right lung, although 1 death resulted from bronchopneumonia of the right lung, 1 from empyema in the left (operated) thorax, and 1 from peritonitis secondary to necrosis and rupture of the left diaphragm and fundus of the stomach. GROUP 4, 15 RABBITS

In this group, which had mass ligation of the left pulmonary hilar pedicle exclusive of the pulmonary artery, 1 rabbit died of bronchopneumonia of the right lung. There were no deaths from crossover spillage of hemorrhagic bronchial fluid. Comment Complete ligation of the left pulmonary veins in the 30 rabbits in experimental Groups 1 and 2 resulted in 10 deaths from spillover of bloody bronchial fluid into the air passages of the right lung and 1 incidental death from bronchopneumonia. Seven out of 10 deaths resulting from pulmonary-pulmonary aspiration occurred within 48 hours of the ligation. In the 30 Group 3 and 4 rabbits in which the pulmonary veins and bronchus of the left lung were ligated, there were no deaths from spillover of bronchial fluid from the left lung. Confirmation that pulmonary-pulmonary aspiration was the major cause of death from complete unilateral pulmonary venous ligation was derived from the unintentional ligation, in 2 rabbits, of the left pulmonary veins but mZy the left lower lobe bronchus. Both these animals died of pulmonary-pulmonary aspiration on the fourth postoperative day. At postmortem examination the left upper lobe bronchus was found to have been left patent. While studying experimental venous occlusion in dogs, Hanlon and associates 151considered three possible causes of death: acute blood loss, ventilatory insufficiency, and infection. They also mentioned the mechanism of pulmonarypulmonary aspiration but concluded that “from the data at hand, no positive

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419

2 4 11 23 24 46 14 35 49 55 60 21 52 64 78

1

4

3

2

Rabbit No.

Experimental Group Rabbit 2,150 2,700 2,910 4,460 3,650 3,020 3,270 2,720 2,520 4,050 3,740 4,000 3,600 2,620 4,140

Time of Death Postop. 6-24 hr 3rd day 6-24 hr 2nd day 2nd day 6-24 hl6th clay 3rd day 2nd day 6-24 hr 14th day 8th day 3rd clay 5th day 1 1th day

15.0 25.3 17.3 22.3 23.3 25.6 35.3 24.6 21.4 28.7 14.1 12.8 15.6 7.8 20.3

8.2 18.5 16.1 21.7 19.7 25.8 26.6 25.9 23.0 26.3 10.8 25.4 68.4 49.1 43.0

Weight (gin) Right Lung Left Lung

Pu1m.-pulm. aspiration Pu1m.-pulm. aspiration Pu1m.-pulm. aspiration Pu1m.-pulm. aspiration Pu1m.-pulm. aspiration Pu1m.-pultn. aspiration Pu1m.-pultn. aspiration Pu1m.-pulm. aspiration Pu1m.-pulm. aspiration Pu1m.-pulm. aspiration Bilateral bronchopneumonia Empyema of left lung Bronchopneumonia on right side Peritonitis Bronchopneumonia on right side

Cause of Death

TABLE 2. CAUSES OF DEATH IN EXPERIMENTAL PULMONARY VENOUS OCCLUSION

Experimental Pulmonary Venous Occlusion conclusion may be drawn regarding the precise mechanism of death in our animals.” Galarza and colleagues [3], in their studies, pointed out that hemoptysis was an important prognostic sign. All their animals that showed substantial hemoptysis died. In our experiments we have shown that respiratory insufficiency secondary to pulmonary-pulmonary aspiration is the major cause of death occurring less than 48 hours postoperatively, but infection may play a role after the second postoperative day despite penicillin therapy. Ligating the left main bronchus prevents pulmonary-pulmonary aspiration, resulting in a significant increase in survival rate. The posture of the rabbits during the period of recovery from anesthesia -difference between Group 1 and Group 2 - does not appear to be important in causing or avoiding pulmonary-pulmonary aspiration. We believe that the degree of pulmonary hemorrhagic congestion (which may be governed by the rapidity of development of bronchial and pleural venous collaterals) that develops after pulmonary venous occlusion is the predominant factor determining the occurrence of pulmonary-pulmonary aspiration. After unilateral ligation of the pulmonary veins the‘lung almost immediately assumes a brick red color. The rabbit invariably exhibits a pallor noticeable in 24 hours and persisting up to 2 weeks. Table 3 shows the effects of ligation of the left pulmonary vein on hemoglobin and hematocrit in 5 rabbits compared with the effect in 5 others of left pulmonary artery ligation. Thoracotomy and pulmonary artery ligation produced a small drop in hemoglobin and hematocrit. There was always a substantial drop after pulmonary vein ligation: hemoglobin dropping progressively in 3 days from a preoperative average of 12.1 gm to a postoperative average of 8.0 gm and hematocrit dropping from a preoperative average of 36% to a postoperative average of 23%.The signs of impending death were productive cough with blood-stained, mucoid sputum which caused staining of the nostrils; sluggishness; anorexia; and increasing dyspnea and cyanosis. One rabbit under observation on the second postoperative day appeared well except for some pallor; within 15 minutes, however, it coughed, sputtered bloody sputum, and died. Immediate postmortem examination revealed gross pulmonary-pulmonary aspiration. A more gradual sequence of events reflecting increasing, progressive respiratory insufficiency was more commonly observed. Despite antibiotic therapy, infection, pneumonia of the lung, and empyema occurred. These usually manifested themselves more than 48 hours postoperatively. Figures 1 and 2 show the typical appearance of the lungs on postmortem examination in rabbits that died from pulmonary-pulmonary aspiration. The left lung was intensely congested and blue-black in color. The bronchial tree was filled with frothy, blood-stained aspirate, and the dependent segments of the right lung, invariably the middle lobe and the medial lobule of the right inferior lobe [I], and adjacent portions of both the superior and inferior lobes were congested with hemorrhagic bronchial aspirate. The mean weights of the lungs of the 10 rabbits that died from pulmonary-pulmonary aspiration were 2 1.18 gm for the left lung and 23.88 gm for the right lung, compared with 5.12 gm and 7.38 gm respectively, for the control left and right lungs. The average increase of 16.06gm in the weight VOL. 19, NO. 4, APRIL, 1975

42 1

106

s

_

12.0 35 12.2 36 12.9 38 12.2 37 11.5 33

Preop.

_

10.4 28 9.4 27 10.2 26 9.8 25 9.2 27

Day 1 Postop.

~

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8.6 25 8.6 24 9.4 24 8.2 23 8.6 25

Day 2 Postop.

Left Pulmonary Vein

~

7.8 23 7.6 23 8.6 22 7.8 22 8.2 24

Day 3 Postop.

114

113

112

111

110

Rabbit No. 13.6 39.5 12.5 38 11.7 35 11.9 37.5 13.1 39

Preop.

13.4 37.5 11.9 35 11.3 33 11.1 35 12.0 36

Day 1 Postop.

13.4 36 11.8 34 11.0 32.5 10.9 35 11.8 36

Day 2 Postop.

Left Pulmonary Artery

'First measurement is hemoglobin (in mg per 100 mi); second measurement is hematocrit (in 7%).

109

108

107

105

$

$2

Rabbit No.

Gn

c

X 0

4

B

13.3 36 11.8 32.5 11.0 32.5 10.9 35 11.7 35.5

Day 3 Postop.

Experimental Pulmonary Venous Occlusion

FIG. 1. Heart and lungs of Rabbit 24, which died 29 hours after complete ligation of left pulmonary veins. The lejl lung shows gross hemorrhagic consolidation while the right lung exhibits the typical appearance of pulmonarypulmonary aspiration.

of the left lung, in which the pulmonary veins were ligated, reflects the average maximal blood loss (16.06 ml) caused by the pumping of blood through a patent left pulmonary artery into the parenchyma of the left lung. This amount of blood loss in our rabbits, which weighed an average of 3.15 kg, is unlikely by itself to cause death. Downman and colleagues [2]have shown that unanesthetized rabbits and rabbits “lightly” anesthetized may lose up to one-third of their blood volume without distress or deterioration of condition. Using their assumption that adult rabbits have a blood volume of 70 ml per kilogram of body weight, our average rabbit would have had to lose 73.5 ml of blood to make up this one-third. The survivors of complete unilateral pulmonary venous ligation showed very little systemic effects except for some pallor. After 1 week the majority showed no evidence of gross hemorrhagic consolidation of the ligated lung. The lung in vivo usually showed brick red congestion, while a few had evidence of resolving consolidation. Microscopical studies showed increased cellularity and thickened FIG. 2. Lateral view of right lung of Rabbit 24 shows that consolidation of the dependent segments involves the whole of the middle lobe and adjacent portions of both the superior and inferior lobes as a result of pulmonary-pulmonary aspiration. Arrow shows the ligated left lung with intense hemorrhagic consolidation.

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ONG AND RAVITCH

FIG. 3. Left atrial ang-iogram of a heart-lung specimenfrom a rabbit killed 3 week after complete l g t pulmonary venous occlusion shows that the right pulmonary veins are patent and that the l$t pulmonaq veins have been completely ligated.

alveolar walls. The alveoli appeared to contain air rather than being filled with exudate. After 2 weeks there was little difference in parenchyma architecture between the nonligated right and the ligated left lung. In rabbits that survived ligation of the left main bronchus and left pulmonary veins there was gross hemorrhagic consolidation of the left lung at 1 and 2 weeks postoperatively and various degrees of necrosis and fibrosis of the parenchymal tissue. The lung was swollen and large. After 3 weeks the lung contracted and shrank. Besides the lung changes occurring with unilateral pulmonary venous ligation, pulmonary arteriograms of heart-lung specimens done immediately after the rabbits were killed showed that the left main pulmonary artery in all instances remained patent (Fig. 4). Even with ligation of the left main bronchus and left pulmonary veins, thrombosis and spontaneous occlusion of the left main pulmonary artery did not occur, though the artery did become smaller than normal. FIG. 4 . Pulmonary arteriogram using meglumine iothalnmate solution on a heart-lung specimenf r m a rabbit killed 3 weeks after complete left pulmonary venous occlusion shows that the left pulmonary artev remains patent.

424

THE ANNALS OF THORACIC SURGERY

Experimental Pulmonary Venous Occlusion

Although Miller and associates [8] found in their studies on dogs that pulmonary arterial flow ceases within 4 seconds of venous ligation, it appears to us that a trickle must continue initially to cause the hemorrhagic congestion of the lung; also, some drainage of blood occurs through the bronchial and hilar pleural vessels until the hemodynamics equilibrate. This collateral route is sufficient for the congested lung to recover in time.

References In E. H. Craigie (Ed), Practical Anatomy of the Rabbit: An Elementary Laborato?y Textbook in Mammalian Anatomy (7th ed, rev). Philadelphia: Blakiston, 1945. P 100. Downman, C. B. B., Mackenzie, C. C., and McSwiney, B. A. The effects of acute hemorrhage on the peripheral blood pressure in unanaesthetized and anaesthetized rabbits. J Physiol 103:350, 1944. Galarza, V. G., Bravo, T. C., and Contreras, M. S. Ligadura de venas pulmonares. Neum Cir Torax 23:401, 1962. Guertzenstein, E., Netto, M. B., Siervi, M. D., Noqueira, C., and Ramos, C. F. A ligadura experimental des veias pulmonares. Rev Bras Cir 34:475, 1956. Hanlon, C. R., Sabiston, D. C., and Burke, D. R. Experimental pulmonary venous occlusion.J Thorac Surg 24:190, 1952. Hyndman, 0. R., Landt, H., and Mathes, D. The influence of congestion upon tuberculosis in the lung of the dog. Ann Surg 111:564, 1940. Kirschner, F. Die Ligatur der vena pulmonalis bei Lungentuberkulose: Ein neuer Versuch ihrer chirurgischen Behandlung. 2 Tuberk 60: 198, 1931. Miller, G. E., Aberg, T. H. J., and Gerbode, F. Effect of pulmonary vein ligation on pulmonary artery flow in dogs. J Thorac Cardiovasc Surg 55:668, 1968. OShaughnessy, L. Surgery of the lung root. Lancet 1:476, 1935. Somasundaram, K., Ravitch, M. M., and Sherman, F. Effects of ligation of the pulmonary vasculature in the rabbit fetus. J Pediatr Surg 7:644, 1972. Swan, H., and Mulligan, R. M. An experimental study of the effect of ligation of pulmonary veins in the dog. J Thorac Surg 17:44, 1948. Thomasson, B. H., and Ravitch, M. M. Fetal surgery in the rabbit. Surgery 66: 1092,

1. Bensley, B. A. 2. 3. 4. 5. 6. 7. 8.

9. 10. 11. 12.

1969. ~. 13. Walsh, G. ~~

Ligation of the pulmonary vein: An experimental operative procedure in the treatment of pulmonary tuberculosis. JAMA 49: 1282, 1907.

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Experimental pulmonary venous occlusion.

Complete interruption of pulmonary venous return from the left lung in rabbits is compatible in some instances with prolonged survival with little sys...
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