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Differential Division of Hilar Tissue: Effects upon Lung Function in the Dog
DISEASES oj the CHEST Volume 50
NOVEMBER, 1966
Number 5
Differential Division of Hilar Tissue: Effects upon Lung Function in the Dog* SADAN ERASLAN, M.D. AND JAMES
D.
HARDY, M.D.
I ackson, Mississippi
T
tubes to positive pressure automatic respirators. The left hemithorax was entered through the fourth intercostal space. Bronchospirometry, pulmonary artery pressure measurements and histologic studies were performed before and after the various procedures. The animals were grouped as follows: Group I (ten dogs). The left main stem bronchus, pulmonary artery and pulmonary veins (at the atrium) were freed up from the surrounding tissue but were themselves left intact, and the chest was closed (Fig. 1). Group II (ten dogs). The bronchial and hilar adventitial arteries were ligated and divided. In two of these dogs pulmonary artery pressure measurements were also taken at one, 24 and 48 hours by means of a plastic catheter inserted at the initial operation. Group III (five dogs). The lymphatics were severed by breaking the connections of the peribronchial lymph nodes. The blood and nerve supplies were left intact. Group IV (18 dogs). The vagus nerve was severed and the stumps ligated high in the chest as well as near the diaphragm The branches of this isolated section were then severed and the segment was stripped away. In three dogs the pulmonary artery pressure was recorded preoperatively and at one, 24 and 48 hours postoperatively. Bronchospirometry was performed one, two, five and ten days postoperatively in the above four groups of animals.
H E FUNCTION OF THE REIMPLANTED
lung has been studied by numerous investigators.t'":" Rarely is the postoperative function of this organ normal, though substantial respiratory activity is usually achieved. Specifically, a reimplanted lung almost always exhibits a reduced oxygen uptake and in most instances fails to sustain respiratory requirements when contralateral pneumonectomy is performed a short time after the reimplantation. Although successful staged bilateral lung reimplantation was reported ,29 the precise cause of the reduced function immediately after transplantation has remained obscure. It has been suggested that the dysfunction is produced in part by the obviously unavoidable division of the hilar structures," but no definite explanation for this reduced function following division of these structures was available. The present study was designed to evaluate the effects of the differential division of bronchial arteries, lymphatics, the vagus nerve and a combination of these without actual division of the pulmonary artery, pulmonary veins and main stem bronchus. MATERIALS AND METHODS
Fifty-four healthy adult mongrel dogs weighing from 14 to 23 kilograms were divided into eight groups. All were anesthetized and connected by cuffed endotracheal *From the Department of Surgery, University of Mississippi Medical Cente. Supported by Army Contract No. DA-49-007MD-627 and National Institutes of Health Grant No. HE 06163.
Copyright, 1966, by the American College of Chest Physicians
449
Group V (three dogs). These dogs were used as controls. The chest was opened, closed and the respirator disconnected. This procedure was repeated at three, six and 24 hours along with pulmonary artery pressure measurements and bilateral lung biopsies. Bronchospirometry was performed at 24 hours and compared to preoperative control values. Group VI (three dogs). These animals were also used as controls. The chest remained open for seven hours with the functioning respirator connected to the endotracheal tube. Pulmonary artery pressure was recorded and bilateral biopsies were taken at one, three and six hours. The chest was then closed and reopened at 24 hours for repeat biopsies and pulmonary artery pressure measurements. Bronchospirometry was performed preoperatively and at 24 hours postoperatively. Group VII (two dogs). These animals were subjected to vagus nerve division, as described above, and the respirator remained connected for six hours. The chest -
VAGUS
N
I I I
I
I I
I I
I
\ \
Diseases of the Chest
ERAS LAN AND HARDY
45°
\
lol erol
vi ew
of
left
hilu m
1 : Differential division of the anatomic elements of the pulmonary hilum is readily achieved. FIGURE
was left open and pulmonary artery pressure measurements and bilateral lung biopsies were taken at one, three, five and six hours after the procedure. Group VIII (three dogs). These animals underwent vagus nerve division in the same manner as before j the chest was closed and the respirator disconnected. Three hours following closure, the chest was reopened and biopsies were taken from both lungs while pulmonary artery pressure was measured. The chest was reclosed and the respirator disconnected. This procedure was repeated for the same purposes at six and 24 hours. Bronchospirometry was performed before reopening the chest at 24 hours. RESULTS
Group I. Divison of All Hilar Tissues Except Bronchus and Pulmonary Artery and Veins. The oxygen uptake by the lung on the operated side decreased from the control level of 45 per cent to 34 per cent of the total for both lungs, an average decrease of 25 per cent . The average percentage decrease in ventilation (12 per cent) was proportionally less than the average decrease in oxygen uptake at 24 hours following operation. At 48 hours, the average decrease in oxygen uptake by the left lung of all dogs was 27 per cent below its control level, and this change was highly significant (p
Volume ~O. No.5 November. 1966
45 1
DIFFERENTIAL DIVISION OF HILAR TISSUE
TABLE 1-02 CONSUMPTION AND VENTILATION RATES FOLLOWING TOTAL HILAR TISSUE DIVISION OF LEFT LUNG (BRONCHIAL ARTERIES+LvMPHATICS+VAGUS NERVE) IN 10 ANIMALS
24 Hours Postop.
Control
%
%
02
02
Average ±S.D.
48 Hours Postop.
%
%
O2
02
%
02
Uptake
Vent.
Uptake
Vent.
Uptake
Vent.
44±3
34±6.5
39±5
33±6
37±5.5
41±6.5
41 ±3.5
46±3
42±6
25%
12%
27%
16%
9%
7%
j4%
j5%
Decrease %
P<0.005 P<0.025 P<0.005 P
Significance of t value
firmed the presence of pulmonary edema, but otherwise the tissue exhibited no significant abnormalities. Group II. Division of Bronchial Arteries. None of the animals showed a change in oxygen uptake. There was a slight decrease in ventilation, but this returned to control values within ten days (Table 2). No gross or histologic changes in the lung were noted at sacrifice 48 hours postoperatively. Pulmonary artery pressure measurements in two animals showed no change at one, 24, and 48 hours postoperatively. Group III. Division of Lymphatics. No animal showed a change either in oxygen consumption or in ventilation (Table 3). The gross and histologic appearance of the lungs was normal at necropsy 48 hours following the procedure. Group IV. Division of Vagus Nerve. Thirteen of 18 dogs exhibited a significant decrease in oxygen uptake by the denervated left lung at 24 hours, and three more TABLE
10 Days Postop.
Uptake Vent. 45±3
..
Uptake Vent.
insignificant ~
animals at 48 hours (average decrease, 27 per cent). One animal exhibited no change in oxygen uptake. One died within 24 hours, during which pulmonary artery measurements were performed, but bronchospirometry could not be done. At both periods, the decrease in oxygen uptake was statistically highly significant (p
2.:-.-02
CONSUMPTION AND VENTIL.~TION FOLLOWING THE DIVISION OF BRONCHIAL AND HILAR TISSUE ARTERIES OF THE LEFT LUNG IN 10 ANIMALS
Control
O2
Upt.
%
Average ±S.D.
5 Days Postop.
46±1
24 Hours Postop.
Vent.
48 Hours Postop.
%
O2 Upt.
Vent.
47±1
45±3
42±3
%
%
5 Days Postop.
O2 Upt.
Vent.
%
Upt.
45±0
43±5
45±3
%
02
%
10 Days Postop.
Vent.
O2
%
Upt.
40±4
44±1
Vent.
%
%
46±2
not significan t PULMONARY ARTERY PRESSURE IN Two ANIMALS
Dog No.
0-15 0-16
Control mrn.Hg
I Hour Postop. rnm.Hg
24 Hours Postop. mm.Hg
48 Hours Postop. mm.Hg
18-7(11 Mean) 19-7 (11 Mean)
22-3(9.5) 19-5 (9.5)
20-8(12) 19-8( 12.5)
22-7(12) 22-7(12)
Diseases of the Chest
ERASLAN AND HARDY
45 2
TABLE 3-02 CONSUMPTION AND VENTILATION FOLLOWING DIVISION OF THE LYMPHATICS OF THE LEFT LUNG IN 5 ANIMALS 48 I-Iours Control 24 Hours 5 Days Postop. Postop. Postop.
O2
Upt.
Vent. %
0·. Upt.
Vent.
47±1
46±1
45±3
43±3
%
Average ±S.D.
•
%
O2
Upt. %
%
not significant
..
ual increase was observed. One dog showing a significant increase in one hour postoperatively (from 7.5 to 16 mm.Hg mean pressure) died within 24 hours. At necropsy, there was extensive edema in both lung fields and histologic examination revealed massive congestion, hemorrhage and edema. These changes in pulmonary artery pressure are presented in Table 5. None of the control animals in Groups V and V I showed a significant change in either oxygen uptake or ventilation. In only one dog did the pulmonary artery pressure rise from 13.5 mm.Hg control mean pressure to 18 mm.Hg at 24 hours. Bronchospirometry in the same animal exhibited absence of respiration on the operated side, and at necropsy, the lung was found to be collapsed. Histologic studies of the remaining lungs showed no change. In Group VII, both animals showed no increase in pulmonary artery pressure after nerve division as long as the respirator was left connected for six hours postoperatively. Histologic studies of specimens taken at one, three, five and six hours postoperatively showed no change during these periods. Both animals died within 24 hours and at necropsy the left lung, which had been deTABLE
Average ±S.D. Decrease % Significance of t value
47±3
Vent.
10 Days Postop.
%
02 Upt.
Vent.
%
02 Upt.
Vent.
45±3
48±1
46±1
47±1
44±3
%
%
%
nervated, was found to be heavy, wet and edematous. In the right lung only the upper lobes were edematous. The histologic examination showed massive, diffuse hemorrhage and edema in the entire left lung. These changes may have been due in part to the prolonged open thoracotomy and assisted ventilation. All animals in Group VIII reflected gradually increasing pulmonary artery pressures postoperatively, from a control of 11 mm.Hg mean pressure to 19 mm.Hg after three hours, 20.6 mm.Hg after six hours, and 26.5 mm.Hg after 24 hours. The remaining animals showed a 47 per cent decrease in oxygen uptake and 27 per cent decrease in ventilation, when measured 24 hours after surgery (Table 6). Histologic studies of lung tissue obtained at biopsy and at necropsy revealed that during the first six hours there was mild interstitial edema of the alveolar walls. The histologic findings at 24 hours consisted of mild congestion and interstitial edema in the left lung and minimal congestion in the right. DISCUSSION
The results reported herein indicate that the division of all hilar tissue, including nerves, bronchial arteries, hilar adventitial
CONSUMPTION AND VENTILATION FOLLOWING DIVISION OF VAGUS NERVE Control 24 Hours 48 Hours 5 Days 10 Days Postop. Postop. Postop. Postop.
4-~
~
Vent. %
Upt. %
46±2
44±3
~
Upt. %
Vent. %
34±7 27%
~
~
~
Upt. %
Vent. %
Upt, %
Vent. %
Upt. %
Vent. %
38±5.5
33±6
34±7
40±6.5
38±3
45±5
41±6
14%
28.5%
7%
4%
7%
23%
9%
P
Volume 50, No.5 November, 1966
453
DIFFERENTIAL DIVISION OF HILAR TISSUE
TABLE 5-PULMONARY ARTERY PRESSURE AFTER NERVE DIVISION IN 3 ANIMALS Dog No.
Control mrn.Hg
1 Hour Postop. mm.Hg
24 Hours Postop. mm.Hg
48 Hours Postop. mm.Hg
D-28 D-29 D-44
Mean 7.5-20(11) 12.5-25(16) 2-18(7.5)
5-22.5(11) 7.5-20(11) 6-38(16)
7.5-25(13.5) 12.5-27.5(17.5) Died
15-32.5(21) 15-27.5(19)
arteries and lymphatics, usually causes a significant decrease in oxygen uptake, which is also seen after denervation only. Two dogs showed no change, one following nerve division and one following total hilar tissue division. This could possibly have been due to incomplete nerve division or to afferent nerve pathways in the bronchial wall." Edema often developed on the operated side, which undoubtedly reduced pulmonary function following hilar stripping. Denervation alone also impaired lung function, but division of the bronchial arterial supply and the perihilar lymphatics was without effect. Bronchial Arteries. In a series of studies, Bogardus' reported that after bronchial and hilar tissue arteries were divided the survival rate following contralateral pneumonectomy was strikingly reduced. On the other hand, Borrie et al' reported that oxygen uptake was unchanged over a period of two months following bronchial artery ligation, and this finding was in agreement with our results; in fact, we noted no change in oxygen uptake in any animal
after ligation of the bronchial and hilar adventitial arteries. The pulmonary artery pressure, measured 48 hours after this procedure, was normal. It has long been known that a definite capillary communication exists between the bronchial and pulmonary arterial systems at the capillary venous level in the lung.".." As long as a certain pressure is maintained in either the pulmonary or bronchial circulation, the mixture of the blood is extremely limited. If, however, the pressure falls to zero in either system the possibility of supply from the other system becomes real, In any case, our studies have further shown that the nutritive functions normally carried out by the bronchial arterial circulation can be largely replaced by the pulmonary arterial circulation following lung transplantation. Lymphatics. The function of the lymphatic system is to return excess tissue fluid to the blood stream, but pulmonary lymph flow is normally of limited volume.' Experiments have shown that the pulmonary lymph flow does not increase until left atrial pressure has reached from 30 to 50
TABLE 6-3 ANIMALS' RESPIRATION DISCONNECTED AFTER VAGAL NERVE DIVISION Pulmonary Artery Pressure Dog No. Control mm.Hg 3 Hours Postop. 6 Hours Postop. 24 Hours Postop. D-45 D-45 D-47 Mean: (Range)
10-21 (Mean 13) 8-14( 10) 8-13 (10) 11
15-18(16) 20-30(23) 15-26(19) 19
13-22(16) 22-34(26) 14-32 (20) 20.6
Died 25-33 (28) 20-35(25) 26.5
O, UPTAKE AND VENTILATION IN THE SAME ANIMALS
Control %
02
24 Hours Postop.
Dog No.
Upt.
Vent.
D-45 D-46 D-47
42 45 45
45 46 44
OJ
Upt. 29.3 19 47% decrease
Vent. 36 30 27% decrease
454
ERASLAN AND HARDY
mm.Hg, at which time pulmonary edema becomes evident." Selective lymphatic division in our experiments produced no effect on lung function as measured by bronchospirometry. Although the accumulation of tissue fluid may be augmented by lymphatic division, other factors are perhaps more important. Lymphatics were also demonstrated to regenerate within 7-12 days following reimplantation, which might assist in the dissipation of lung congestion. IS Nerve Supply. The importance of the nerve supply to the lung was further substantiated by our studies. Dogs who underwent vagal nerve division showed decreased oxygen uptake and ventilation on the operated side, similar to those who had complete hilar tissue division; they also exhibited increased pulmonary artery pressure within the first few hours postoperatively, before edema had become evident. Borison and Kovacs' and Rech and Borison" produced lung edema by performing bilateral vagotomy, and found that if artificial ventilation was maintained continuously after vagotomy, the formation of edema could be delayed but not prevented. Our own experiments suggest that the effects of vagal nerve division can be largely or perhaps completely prevented by continuous automatic positive pressure ventilation. Two dogs demonstrated no changes in either pulmonary artery pressure or in the gross or histologic appearance of the lung, so long as the respirator was employed for at least seven hours following nerve division. The effects of the nerve supply on respiratory reflexes have been investigated by many workers.r":":" Portin et al" demonstrated a loss of the Hering-Breur reflex in the reimplanted lung in a dog 35 months after reimplantation. More recently this was confirmed by our group" and by others." We have also found that both these animals which showed a decreased oxygen uptake after total hilar tissue division and those in the vagal nerve division group presented an identical respiratory pattern; that is, deep forced respiration with longer
Diseases of the Chest
periods of apnea following blockage of the normal lung's airway at the beginning of inspiration. After a few such respirations, the intervals shortened, but did not soon begin the normal pattern. On the other hand, the right lung exhibited no change in its respiratory pattern when the left airway was blocked. Edema formation is intimately associated with the effect of the vagus nerve on respiratory reflexes. In explanation of this effect, it is suggested that the loss of the Hering-Breuer reflex caused an impairment in ventilation of the denervated side. This may change the alveolar membrane resistance and result in an increase in the pulmonary artery pressure, in edema and in a decreased oxygen uptake. The caliber of the smaller bronchi may also be altered by denervation, producing increased resistance to air flow. Although oxygen uptake returned to normal levels within ten days following the denervation procedure, persistent abnormal changes such as an elevated pulmonary artery pressure and decreased oxygen uptake can be observed in some animals subjected to reimplantation.f'":" However, the reimplanted lung has been found to have a normal histologic appearance and normal pulmonary artery pressure a few months after reimplantation. Therefore, these changes could possibly be attributed to the presence of partial or scattered small atelectatic areas in the reimplanted lung. In our laboratory it was observed that oxygen uptake decreased considerably within the first 24 hours and returned to a constant level within 10-14 days after reimplantation." Pulmonary artery pressure increased within the first 24 hours to levels even higher than those found in denervated animals which also returned to normal levels.It In four of the five animals which were observed, pulmonary artery pressure reached mean values of 23, 32, 40 and 50 mm.Hg respectively, when the pulmonary artery was occluded on the normal side by means of a tape which was placed around the artery at the time of reimplantation
Volume 50. No.5 November. 1966
DIFFERENTIAL DIVISION OF HILAR TISSUE
and the free ends brought through an opening in the chest. l\lican and Hardyl concluded that the reflexes originating in the lung are important, and that the neural connections of at least a portion of one lung must be present to permit essentially normal respiratory reflexes and muscular activity. Subsequently, it was found that six to eight months following lung reimplantation contralateral pneumonectomy could be well tolerated." Recently, however, staged successful bilateral lung reimplantation has been reported by several investigators,IO_II'" even at one week intervals. 11 Duvoisin et al" also demonstrated the loss of stretch reflexes in chronic survivor animals, i.e., those which survived contralateral pneumonectomy six weeks after the original operation. They concluded that survival of a reimplanted lung, after contralateral pneumonectomy, is dependent upon adequate pulmonary function without structural defects, rather than on the presence of peripheral pulmonary stretch receptor activity. This fact woud appear to support the theory of a peripheral chemo-receptor mechanism: Even so, a degree of pulmonary edema almost invariably occurs in the postoperative period, which subsides within ten days in the animals which are subjected to hilar stripping and within 10 to 14 days in those which have a transplanted lung." It is apparent from such studies that the survival rate of the animals which are subjected to contralateral pneumonectomy depends on functional capacity of the transplanted lung, which may be partially impaired by the absence of nerve supply. However, as it was shown in two animals, this impairment can be largely prevented by means of support with a positive pressure respirator. SUMMARY AND CONCLUSIONS
The roles of hilar tissues in supporting lung function have been studied by selective
455
division of the vagus nerve, bronchial arteries and lymphatics. Loss of vagal innervation was found to impair both the ventilation and the oxygen uptake of the lung. Division of the bronchial arteries and the lymphatics had no significant effect upon lung function. While it has been shown that an intact pulmonary vagal nerve supply is not absolutely essential for survival of the animal, there can be little question that denervation does impair the functional capacity of the lung. ACKNOWLEDGMENTS: The authors wish to express their appreciation to Mn. Anne C. Turner for the statistical analyses and Dr. Charles B. Itzig for technical assistance. RESUMEN
La participacion de los componentes hiliares en el funcionalismo pulmonar ha sido investigada mediante la secci6n selectiva del nervio vago, las arterias bronquiales y los Iinfaticos. La perdida de la inervaci6n vagal disminuye tanto la ventilaci6n como la utilizaci6n del oxigeno por el pulm6n. La secci6n de las arterias bronquiales y de los linfaticos no tiene efecto alguno de significaci6n sobre la funci6n pulmonar. Si bien se ha demostrado que la integridad de la inervaci6n por el vago no es indispensable para la supervivencia del animal, es incuestionable que la denervaci6n compromete la capacidad funcional del pulm6n. ZUSAM~(ENFASSUNG
Die Rollen des Hilusgewebes in bezug auf die Lungenfunktion sind durch Selektivunterbrechung des Vagusnervens, der Bronchusarterien und der Lyrnphgefasse studiert worden. Beim Verlust der Vagusinnervation stellte sich eine Versclechterung sowohl der Ventilation als auch der Sauerstoffaufnahme der Lunge heraus. Die Unterbrechung der Bronchusarterien und der Lymphgefasse hatte keine bedeutende Wirkung auf die Lungenfunktion. Wahrend man aufgezeigt hat, dass eins intakte pulmonale VagusnervenVersorgung nieht absolute nowendig fur das Oberleben eines Tieres ist, besteht keine Frage, dass die Denervation die funktionelle Kapazitat der Lunge beeintrachtigt, Complete reference list will appear in reprints.
For reprints, please write: Dr. Hardy, 2500 North State Street, Jackson, Miss.
NOVEMBER, 1966
Number 5
Differential Division of Hilar Tissue: Effects upon Lung Function in the Dog* SADAN ERASLAN, M.D. AND JAMES
D.
HARDY, M.D.
I ackson, Mississippi
T
tubes to positive pressure automatic respirators. The left hemithorax was entered through the fourth intercostal space. Bronchospirometry, pulmonary artery pressure measurements and histologic studies were performed before and after the various procedures. The animals were grouped as follows: Group I (ten dogs). The left main stem bronchus, pulmonary artery and pulmonary veins (at the atrium) were freed up from the surrounding tissue but were themselves left intact, and the chest was closed (Fig. 1). Group II (ten dogs). The bronchial and hilar adventitial arteries were ligated and divided. In two of these dogs pulmonary artery pressure measurements were also taken at one, 24 and 48 hours by means of a plastic catheter inserted at the initial operation. Group III (five dogs). The lymphatics were severed by breaking the connections of the peribronchial lymph nodes. The blood and nerve supplies were left intact. Group IV (18 dogs). The vagus nerve was severed and the stumps ligated high in the chest as well as near the diaphragm The branches of this isolated section were then severed and the segment was stripped away. In three dogs the pulmonary artery pressure was recorded preoperatively and at one, 24 and 48 hours postoperatively. Bronchospirometry was performed one, two, five and ten days postoperatively in the above four groups of animals.
H E FUNCTION OF THE REIMPLANTED
lung has been studied by numerous investigators.t'":" Rarely is the postoperative function of this organ normal, though substantial respiratory activity is usually achieved. Specifically, a reimplanted lung almost always exhibits a reduced oxygen uptake and in most instances fails to sustain respiratory requirements when contralateral pneumonectomy is performed a short time after the reimplantation. Although successful staged bilateral lung reimplantation was reported ,29 the precise cause of the reduced function immediately after transplantation has remained obscure. It has been suggested that the dysfunction is produced in part by the obviously unavoidable division of the hilar structures," but no definite explanation for this reduced function following division of these structures was available. The present study was designed to evaluate the effects of the differential division of bronchial arteries, lymphatics, the vagus nerve and a combination of these without actual division of the pulmonary artery, pulmonary veins and main stem bronchus. MATERIALS AND METHODS
Fifty-four healthy adult mongrel dogs weighing from 14 to 23 kilograms were divided into eight groups. All were anesthetized and connected by cuffed endotracheal *From the Department of Surgery, University of Mississippi Medical Cente. Supported by Army Contract No. DA-49-007MD-627 and National Institutes of Health Grant No. HE 06163.
Copyright, 1966, by the American College of Chest Physicians
449
Group V (three dogs). These dogs were used as controls. The chest was opened, closed and the respirator disconnected. This procedure was repeated at three, six and 24 hours along with pulmonary artery pressure measurements and bilateral lung biopsies. Bronchospirometry was performed at 24 hours and compared to preoperative control values. Group VI (three dogs). These animals were also used as controls. The chest remained open for seven hours with the functioning respirator connected to the endotracheal tube. Pulmonary artery pressure was recorded and bilateral biopsies were taken at one, three and six hours. The chest was then closed and reopened at 24 hours for repeat biopsies and pulmonary artery pressure measurements. Bronchospirometry was performed preoperatively and at 24 hours postoperatively. Group VII (two dogs). These animals were subjected to vagus nerve division, as described above, and the respirator remained connected for six hours. The chest -
VAGUS
N
I I I
I
I I
I I
I
\ \
Diseases of the Chest
ERAS LAN AND HARDY
45°
\
lol erol
vi ew
of
left
hilu m
1 : Differential division of the anatomic elements of the pulmonary hilum is readily achieved. FIGURE
was left open and pulmonary artery pressure measurements and bilateral lung biopsies were taken at one, three, five and six hours after the procedure. Group VIII (three dogs). These animals underwent vagus nerve division in the same manner as before j the chest was closed and the respirator disconnected. Three hours following closure, the chest was reopened and biopsies were taken from both lungs while pulmonary artery pressure was measured. The chest was reclosed and the respirator disconnected. This procedure was repeated for the same purposes at six and 24 hours. Bronchospirometry was performed before reopening the chest at 24 hours. RESULTS
Group I. Divison of All Hilar Tissues Except Bronchus and Pulmonary Artery and Veins. The oxygen uptake by the lung on the operated side decreased from the control level of 45 per cent to 34 per cent of the total for both lungs, an average decrease of 25 per cent . The average percentage decrease in ventilation (12 per cent) was proportionally less than the average decrease in oxygen uptake at 24 hours following operation. At 48 hours, the average decrease in oxygen uptake by the left lung of all dogs was 27 per cent below its control level, and this change was highly significant (p
Volume ~O. No.5 November. 1966
45 1
DIFFERENTIAL DIVISION OF HILAR TISSUE
TABLE 1-02 CONSUMPTION AND VENTILATION RATES FOLLOWING TOTAL HILAR TISSUE DIVISION OF LEFT LUNG (BRONCHIAL ARTERIES+LvMPHATICS+VAGUS NERVE) IN 10 ANIMALS
24 Hours Postop.
Control
%
%
02
02
Average ±S.D.
48 Hours Postop.
%
%
O2
02
%
02
Uptake
Vent.
Uptake
Vent.
Uptake
Vent.
44±3
34±6.5
39±5
33±6
37±5.5
41±6.5
41 ±3.5
46±3
42±6
25%
12%
27%
16%
9%
7%
j4%
j5%
Decrease %
P<0.005 P<0.025 P<0.005 P
Significance of t value
firmed the presence of pulmonary edema, but otherwise the tissue exhibited no significant abnormalities. Group II. Division of Bronchial Arteries. None of the animals showed a change in oxygen uptake. There was a slight decrease in ventilation, but this returned to control values within ten days (Table 2). No gross or histologic changes in the lung were noted at sacrifice 48 hours postoperatively. Pulmonary artery pressure measurements in two animals showed no change at one, 24, and 48 hours postoperatively. Group III. Division of Lymphatics. No animal showed a change either in oxygen consumption or in ventilation (Table 3). The gross and histologic appearance of the lungs was normal at necropsy 48 hours following the procedure. Group IV. Division of Vagus Nerve. Thirteen of 18 dogs exhibited a significant decrease in oxygen uptake by the denervated left lung at 24 hours, and three more TABLE
10 Days Postop.
Uptake Vent. 45±3
..
Uptake Vent.
insignificant ~
animals at 48 hours (average decrease, 27 per cent). One animal exhibited no change in oxygen uptake. One died within 24 hours, during which pulmonary artery measurements were performed, but bronchospirometry could not be done. At both periods, the decrease in oxygen uptake was statistically highly significant (p
2.:-.-02
CONSUMPTION AND VENTIL.~TION FOLLOWING THE DIVISION OF BRONCHIAL AND HILAR TISSUE ARTERIES OF THE LEFT LUNG IN 10 ANIMALS
Control
O2
Upt.
%
Average ±S.D.
5 Days Postop.
46±1
24 Hours Postop.
Vent.
48 Hours Postop.
%
O2 Upt.
Vent.
47±1
45±3
42±3
%
%
5 Days Postop.
O2 Upt.
Vent.
%
Upt.
45±0
43±5
45±3
%
02
%
10 Days Postop.
Vent.
O2
%
Upt.
40±4
44±1
Vent.
%
%
46±2
not significan t PULMONARY ARTERY PRESSURE IN Two ANIMALS
Dog No.
0-15 0-16
Control mrn.Hg
I Hour Postop. rnm.Hg
24 Hours Postop. mm.Hg
48 Hours Postop. mm.Hg
18-7(11 Mean) 19-7 (11 Mean)
22-3(9.5) 19-5 (9.5)
20-8(12) 19-8( 12.5)
22-7(12) 22-7(12)
Diseases of the Chest
ERASLAN AND HARDY
45 2
TABLE 3-02 CONSUMPTION AND VENTILATION FOLLOWING DIVISION OF THE LYMPHATICS OF THE LEFT LUNG IN 5 ANIMALS 48 I-Iours Control 24 Hours 5 Days Postop. Postop. Postop.
O2
Upt.
Vent. %
0·. Upt.
Vent.
47±1
46±1
45±3
43±3
%
Average ±S.D.
•
%
O2
Upt. %
%
not significant
..
ual increase was observed. One dog showing a significant increase in one hour postoperatively (from 7.5 to 16 mm.Hg mean pressure) died within 24 hours. At necropsy, there was extensive edema in both lung fields and histologic examination revealed massive congestion, hemorrhage and edema. These changes in pulmonary artery pressure are presented in Table 5. None of the control animals in Groups V and V I showed a significant change in either oxygen uptake or ventilation. In only one dog did the pulmonary artery pressure rise from 13.5 mm.Hg control mean pressure to 18 mm.Hg at 24 hours. Bronchospirometry in the same animal exhibited absence of respiration on the operated side, and at necropsy, the lung was found to be collapsed. Histologic studies of the remaining lungs showed no change. In Group VII, both animals showed no increase in pulmonary artery pressure after nerve division as long as the respirator was left connected for six hours postoperatively. Histologic studies of specimens taken at one, three, five and six hours postoperatively showed no change during these periods. Both animals died within 24 hours and at necropsy the left lung, which had been deTABLE
Average ±S.D. Decrease % Significance of t value
47±3
Vent.
10 Days Postop.
%
02 Upt.
Vent.
%
02 Upt.
Vent.
45±3
48±1
46±1
47±1
44±3
%
%
%
nervated, was found to be heavy, wet and edematous. In the right lung only the upper lobes were edematous. The histologic examination showed massive, diffuse hemorrhage and edema in the entire left lung. These changes may have been due in part to the prolonged open thoracotomy and assisted ventilation. All animals in Group VIII reflected gradually increasing pulmonary artery pressures postoperatively, from a control of 11 mm.Hg mean pressure to 19 mm.Hg after three hours, 20.6 mm.Hg after six hours, and 26.5 mm.Hg after 24 hours. The remaining animals showed a 47 per cent decrease in oxygen uptake and 27 per cent decrease in ventilation, when measured 24 hours after surgery (Table 6). Histologic studies of lung tissue obtained at biopsy and at necropsy revealed that during the first six hours there was mild interstitial edema of the alveolar walls. The histologic findings at 24 hours consisted of mild congestion and interstitial edema in the left lung and minimal congestion in the right. DISCUSSION
The results reported herein indicate that the division of all hilar tissue, including nerves, bronchial arteries, hilar adventitial
CONSUMPTION AND VENTILATION FOLLOWING DIVISION OF VAGUS NERVE Control 24 Hours 48 Hours 5 Days 10 Days Postop. Postop. Postop. Postop.
4-~
~
Vent. %
Upt. %
46±2
44±3
~
Upt. %
Vent. %
34±7 27%
~
~
~
Upt. %
Vent. %
Upt, %
Vent. %
Upt. %
Vent. %
38±5.5
33±6
34±7
40±6.5
38±3
45±5
41±6
14%
28.5%
7%
4%
7%
23%
9%
P
Volume 50, No.5 November, 1966
453
DIFFERENTIAL DIVISION OF HILAR TISSUE
TABLE 5-PULMONARY ARTERY PRESSURE AFTER NERVE DIVISION IN 3 ANIMALS Dog No.
Control mrn.Hg
1 Hour Postop. mm.Hg
24 Hours Postop. mm.Hg
48 Hours Postop. mm.Hg
D-28 D-29 D-44
Mean 7.5-20(11) 12.5-25(16) 2-18(7.5)
5-22.5(11) 7.5-20(11) 6-38(16)
7.5-25(13.5) 12.5-27.5(17.5) Died
15-32.5(21) 15-27.5(19)
arteries and lymphatics, usually causes a significant decrease in oxygen uptake, which is also seen after denervation only. Two dogs showed no change, one following nerve division and one following total hilar tissue division. This could possibly have been due to incomplete nerve division or to afferent nerve pathways in the bronchial wall." Edema often developed on the operated side, which undoubtedly reduced pulmonary function following hilar stripping. Denervation alone also impaired lung function, but division of the bronchial arterial supply and the perihilar lymphatics was without effect. Bronchial Arteries. In a series of studies, Bogardus' reported that after bronchial and hilar tissue arteries were divided the survival rate following contralateral pneumonectomy was strikingly reduced. On the other hand, Borrie et al' reported that oxygen uptake was unchanged over a period of two months following bronchial artery ligation, and this finding was in agreement with our results; in fact, we noted no change in oxygen uptake in any animal
after ligation of the bronchial and hilar adventitial arteries. The pulmonary artery pressure, measured 48 hours after this procedure, was normal. It has long been known that a definite capillary communication exists between the bronchial and pulmonary arterial systems at the capillary venous level in the lung.".." As long as a certain pressure is maintained in either the pulmonary or bronchial circulation, the mixture of the blood is extremely limited. If, however, the pressure falls to zero in either system the possibility of supply from the other system becomes real, In any case, our studies have further shown that the nutritive functions normally carried out by the bronchial arterial circulation can be largely replaced by the pulmonary arterial circulation following lung transplantation. Lymphatics. The function of the lymphatic system is to return excess tissue fluid to the blood stream, but pulmonary lymph flow is normally of limited volume.' Experiments have shown that the pulmonary lymph flow does not increase until left atrial pressure has reached from 30 to 50
TABLE 6-3 ANIMALS' RESPIRATION DISCONNECTED AFTER VAGAL NERVE DIVISION Pulmonary Artery Pressure Dog No. Control mm.Hg 3 Hours Postop. 6 Hours Postop. 24 Hours Postop. D-45 D-45 D-47 Mean: (Range)
10-21 (Mean 13) 8-14( 10) 8-13 (10) 11
15-18(16) 20-30(23) 15-26(19) 19
13-22(16) 22-34(26) 14-32 (20) 20.6
Died 25-33 (28) 20-35(25) 26.5
O, UPTAKE AND VENTILATION IN THE SAME ANIMALS
Control %
02
24 Hours Postop.
Dog No.
Upt.
Vent.
D-45 D-46 D-47
42 45 45
45 46 44
OJ
Upt. 29.3 19 47% decrease
Vent. 36 30 27% decrease
454
ERASLAN AND HARDY
mm.Hg, at which time pulmonary edema becomes evident." Selective lymphatic division in our experiments produced no effect on lung function as measured by bronchospirometry. Although the accumulation of tissue fluid may be augmented by lymphatic division, other factors are perhaps more important. Lymphatics were also demonstrated to regenerate within 7-12 days following reimplantation, which might assist in the dissipation of lung congestion. IS Nerve Supply. The importance of the nerve supply to the lung was further substantiated by our studies. Dogs who underwent vagal nerve division showed decreased oxygen uptake and ventilation on the operated side, similar to those who had complete hilar tissue division; they also exhibited increased pulmonary artery pressure within the first few hours postoperatively, before edema had become evident. Borison and Kovacs' and Rech and Borison" produced lung edema by performing bilateral vagotomy, and found that if artificial ventilation was maintained continuously after vagotomy, the formation of edema could be delayed but not prevented. Our own experiments suggest that the effects of vagal nerve division can be largely or perhaps completely prevented by continuous automatic positive pressure ventilation. Two dogs demonstrated no changes in either pulmonary artery pressure or in the gross or histologic appearance of the lung, so long as the respirator was employed for at least seven hours following nerve division. The effects of the nerve supply on respiratory reflexes have been investigated by many workers.r":":" Portin et al" demonstrated a loss of the Hering-Breur reflex in the reimplanted lung in a dog 35 months after reimplantation. More recently this was confirmed by our group" and by others." We have also found that both these animals which showed a decreased oxygen uptake after total hilar tissue division and those in the vagal nerve division group presented an identical respiratory pattern; that is, deep forced respiration with longer
Diseases of the Chest
periods of apnea following blockage of the normal lung's airway at the beginning of inspiration. After a few such respirations, the intervals shortened, but did not soon begin the normal pattern. On the other hand, the right lung exhibited no change in its respiratory pattern when the left airway was blocked. Edema formation is intimately associated with the effect of the vagus nerve on respiratory reflexes. In explanation of this effect, it is suggested that the loss of the Hering-Breuer reflex caused an impairment in ventilation of the denervated side. This may change the alveolar membrane resistance and result in an increase in the pulmonary artery pressure, in edema and in a decreased oxygen uptake. The caliber of the smaller bronchi may also be altered by denervation, producing increased resistance to air flow. Although oxygen uptake returned to normal levels within ten days following the denervation procedure, persistent abnormal changes such as an elevated pulmonary artery pressure and decreased oxygen uptake can be observed in some animals subjected to reimplantation.f'":" However, the reimplanted lung has been found to have a normal histologic appearance and normal pulmonary artery pressure a few months after reimplantation. Therefore, these changes could possibly be attributed to the presence of partial or scattered small atelectatic areas in the reimplanted lung. In our laboratory it was observed that oxygen uptake decreased considerably within the first 24 hours and returned to a constant level within 10-14 days after reimplantation." Pulmonary artery pressure increased within the first 24 hours to levels even higher than those found in denervated animals which also returned to normal levels.It In four of the five animals which were observed, pulmonary artery pressure reached mean values of 23, 32, 40 and 50 mm.Hg respectively, when the pulmonary artery was occluded on the normal side by means of a tape which was placed around the artery at the time of reimplantation
Volume 50. No.5 November. 1966
DIFFERENTIAL DIVISION OF HILAR TISSUE
and the free ends brought through an opening in the chest. l\lican and Hardyl concluded that the reflexes originating in the lung are important, and that the neural connections of at least a portion of one lung must be present to permit essentially normal respiratory reflexes and muscular activity. Subsequently, it was found that six to eight months following lung reimplantation contralateral pneumonectomy could be well tolerated." Recently, however, staged successful bilateral lung reimplantation has been reported by several investigators,IO_II'" even at one week intervals. 11 Duvoisin et al" also demonstrated the loss of stretch reflexes in chronic survivor animals, i.e., those which survived contralateral pneumonectomy six weeks after the original operation. They concluded that survival of a reimplanted lung, after contralateral pneumonectomy, is dependent upon adequate pulmonary function without structural defects, rather than on the presence of peripheral pulmonary stretch receptor activity. This fact woud appear to support the theory of a peripheral chemo-receptor mechanism: Even so, a degree of pulmonary edema almost invariably occurs in the postoperative period, which subsides within ten days in the animals which are subjected to hilar stripping and within 10 to 14 days in those which have a transplanted lung." It is apparent from such studies that the survival rate of the animals which are subjected to contralateral pneumonectomy depends on functional capacity of the transplanted lung, which may be partially impaired by the absence of nerve supply. However, as it was shown in two animals, this impairment can be largely prevented by means of support with a positive pressure respirator. SUMMARY AND CONCLUSIONS
The roles of hilar tissues in supporting lung function have been studied by selective
455
division of the vagus nerve, bronchial arteries and lymphatics. Loss of vagal innervation was found to impair both the ventilation and the oxygen uptake of the lung. Division of the bronchial arteries and the lymphatics had no significant effect upon lung function. While it has been shown that an intact pulmonary vagal nerve supply is not absolutely essential for survival of the animal, there can be little question that denervation does impair the functional capacity of the lung. ACKNOWLEDGMENTS: The authors wish to express their appreciation to Mn. Anne C. Turner for the statistical analyses and Dr. Charles B. Itzig for technical assistance. RESUMEN
La participacion de los componentes hiliares en el funcionalismo pulmonar ha sido investigada mediante la secci6n selectiva del nervio vago, las arterias bronquiales y los Iinfaticos. La perdida de la inervaci6n vagal disminuye tanto la ventilaci6n como la utilizaci6n del oxigeno por el pulm6n. La secci6n de las arterias bronquiales y de los linfaticos no tiene efecto alguno de significaci6n sobre la funci6n pulmonar. Si bien se ha demostrado que la integridad de la inervaci6n por el vago no es indispensable para la supervivencia del animal, es incuestionable que la denervaci6n compromete la capacidad funcional del pulm6n. ZUSAM~(ENFASSUNG
Die Rollen des Hilusgewebes in bezug auf die Lungenfunktion sind durch Selektivunterbrechung des Vagusnervens, der Bronchusarterien und der Lyrnphgefasse studiert worden. Beim Verlust der Vagusinnervation stellte sich eine Versclechterung sowohl der Ventilation als auch der Sauerstoffaufnahme der Lunge heraus. Die Unterbrechung der Bronchusarterien und der Lymphgefasse hatte keine bedeutende Wirkung auf die Lungenfunktion. Wahrend man aufgezeigt hat, dass eins intakte pulmonale VagusnervenVersorgung nieht absolute nowendig fur das Oberleben eines Tieres ist, besteht keine Frage, dass die Denervation die funktionelle Kapazitat der Lunge beeintrachtigt, Complete reference list will appear in reprints.
For reprints, please write: Dr. Hardy, 2500 North State Street, Jackson, Miss.