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Revascularization of the bronchial arteries in lung transplantation: An overview
Revascularization of the Bronchial Arteries in Lung Transplantation: An Overview Martin A. Norgaard, MD, Peter S. Olsen, MD, PhD, Ulrik G. Svendsen, MD, PhD, and G6sta Pettersson, MD, PhD Departments of Cardiovascular Surgery and Cardiology, Copenhagen University Hospital, Copenhagen, Denmark
Development of the surgical technique has minimized the incidence of airway problems associated with single as well as sequential bilateral lung transplantation. Although early results are good, long-term results remain unsatisfactory. The main problems after lung transplantation are pulmonary infections and the bronchiolitis obliterans syndrome. The bronchiolitis obliterans syndrome is usually considered to be chronic rejection, but a multifactorial genesis including airway ischemia has been suggested. We reviewed the literature relevant to direct bronchial artery revascularization during lung transplantation. Although information is limited, there
are good reasons to believe that reestablishment of the dual blood supply to the transplanted lung is beneficial not only for healing of the airway anastomoses, but also for the airway and the lung responses to pathologic conditions. In small series, methods of bronchial artery revascularization have proved successful and have been associated with good early results. We believe it is justified to test the impact of direct bronchial artery revascularization on outcome after lung transplantation in large clinical series.
he lungs have a dual blood supply: from the pulmonary arteries, providing desaturated blood under low pressure, and from the bronchial arteries, providing oxygenated blood under arterial pressure. Lung transplantation has stimulated an interest in the role and importance of the bronchial artery blood supply. Many lung transplant surgeons are uncertain about the role of the bronchial arteries, ie, whether they can or even should be neglected [11. In the beginning of lung transplantation, it was clear that bronchial complications were a major cause of death in the early postoperative period [2]. When Veith and associates [3] and Cooper [41 analyzed the early clinical cases of lung transplantation, they found that of the first 38 patients who had undergone lung or lobe transplantation, only 1 survived more than 3 weeks. The single dominating cause of death was dehiscence of the bronchial anastomosis. Already in 1950, Metras [5] had proposed that the bronchial artery circulation could be important in lung transplantation. To pursue this theory, Metras performed experimental single-lung transplantations with direct bronchial revascularization in dogs. Several anatomic [6] and experimental studies [7-9] have been done to develop an effective and reliable method for revascularization of the bronchial arteries. Haglin and colleagues [10] performed direct bronchial artery revascularization in a left lung transplant in 1973. In practice, however, bronchial artery revascularization
was considered too difficult and unreliable to be used clinically, and other methods of protecting the bronchial anastomosis were developed and applied. With respect to airway healing, these methods have proved very successful. It was not until 1992 that Couraud and co-workers [11] reported the first clinical series of 8 patients with en bloc double-lung transplantation with successful bronchial artery revascularization. Since then, reports of successful en bloc double-lung transplantation with bronchial revascularization have been published from Harefield [12] and Copenhagen [13, 14]. The Mayo Clinic has recently reported single and bilateral lung transplantation with bronchial artery revascularization [15, 16]. Based on our own experience, we believe that direct bronchial artery revascularization during lung transplantation is possible with a high success rate. Although bronchial healing can be achieved without revascularization, there could be other reasons to believe that a normal arterial blood supply is beneficial to the transplanted lungs. It is important to evaluate available information about the bronchial artery circulation that indicates a possible beneficial effect of direct bronchial artery revascularization in lung transplantation that goes beyond healing of the airways. It has been suggested that ischemia (versus effective bronchial revascularization) could be important in the development of bronchiolitis obliterans syndrome [13, 17]. We reviewed the published information relevant to direct bronchial artery revascularization.
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Address reprint requests to Dr Norgaard, Thoraxkirurgisk afd RT, 2152, Blegdamsvej 9, 2100 Copenhagen O, Denmark.
© 1996 bv The Societv of Thoracic Surgeons Published bv Elsevier Science lnc
(Ann Thorac Sure, 1996;62:1215-21)
0003~4975/96/$15.00 PII S0003-4975(96)00539-5
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Anatomy The existence of small arteries to the lungs in animals has been k n o w n since G a l e n [18]. The a n a t o m y of the h u m a n bronchial arteries as they branch from the aorta has been s t u d i e d carefully by several investigators. Cauldwell and associates [19] p e r f o r m e d 150 cadaver dissections, and Liebow [20] p e r f o r m e d corrosion casts of the bronchial arteries in 50 cadavers. N u m e r o u s variations of the origin of the bronchial arteries were found. These authors [19, 20] a g r e e d that the most c o m m o n pattern is two left arteries a n d one right artery, which was found in 20% a n d 41%, respectively. One or two arteries for each side was f o u n d in a total of 40% and 42% of the cases, respectively. All other possible combinations of one to four arteries for each side, up to a total of six bronchial arteries, were f o u n d in 40% a n d 17%, respectively. Bronchial arteries originating in the d e s c e n d i n g aorta to s u p p l y both sides were always found. The bronchial arteries follow the bronchial tree d e e p l y into the l u n g p a r e n c h y m a , f o r m i n g a p e r i b r o n c h i a l plexus, a n d small arterioles penetrate the muscularis to form a s u b m u c o s a l plexus. The bronchial arteries also contribute arterial blood s u p p l y to the visceral pleura, the walls of the p u l m o n a r y arteries and veins as vasa vasorum, the mediastinal tissue, esophagus, mediastinal a n d hilar l y m p h nodes, pericardium, a n d vagal a n d s y m p a thetic nerves; even b r a n c h e s to the m y o c a r d i u m can be f o u n d in h u m a n s [21]. Studies of the microvascular a n a t o m y have found the venous drainage to be partially to the azygos a n d hemiazygos veins [20] a n d partially t h r o u g h a n a s t o m o s e s b e t w e e n the bronchial arteries a n d p u l m o n a r y alveolar microvessels, called " b r o n c h o p u l m o n a r y arteries" [22]. Tobin [23] d e s c r i b e d these anastomotic vessels as coiled, possibly b e c a u s e of spiral musculature in their walls, and s u g g e s t e d that this structure " m i g h t help to regulate the p r e s s u r e g r a d i e n t from bronchial to p u l m o n a r y vessels." Tobin also d e s c r i b e d c o m m u n i c a t i o n s b e t w e e n the bronchial arteries and the p u l m o n a r y veins. In 1990, S c h r e i n e m a k e r s a n d colleagues [6] p u b l i s h e d an anatomic s t u d y of the bronchial arteries in 30 autopsy cases. Based on these studies, a technique for procurem e n t of the lungs along with the r e t r o e s o p h a g e a l right intercostobronchial artery was developed. In 17 of 19 dissections, it was possible to p r e p a r e a bronchial artery pedicle with a patch of aorta holding the intercostobronchial artery a n d its origins, which would have been possible to r e i m p l a n t in the a s c e n d i n g aorta of a recipient after a double lung transplantation. C o u r a u d a n d associates [11] were the first to publish a series of patients having en bloc double lung t r a n s p l a n tation with bronchial artery revascularization. The clinical series was p r e c e d e d b y an anatomic study of the tracheobronchial blood s u p p l y in 20 h u m a n cadavers and by angiographic studies in 50 patients having thoracic operations. A right intercostobronchial artery was found in 95% of the cases. In 50°'0 of the cases, orifices of additional bronchial arteries were f o u n d 0.5 to 1.5 cm from the intercostobronchial artery orifice. A c o m m o n
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bronchial artery trunk giving b r a n c h e s to both the right and left sides was f o u n d in about half of the cases.
Physiology and Pathophysiology C o m p a r a t i v e anatomic studies of the bronchial arteries of different species have b e e n p e r f o r m e d [24, 25] a n d have c o n c l u d e d that the a n a t o m y of the sheep, cow, pig, a n d horse a p p e a r s to be similar to h u m a n a n a t o m y [24]. These animals have b e e n u s e d to establish m u c h of the basic k n o w l e d g e about the physiology a n d p a t h o p h y s i ology related to the bronchial arteries. The flow of the bronchial arteries has b e e n m e a s u r e d in h u m a n s d u r i n g c a r d i o p u l m o n a r y b y p a s s conditions. Baile a n d colleagues [26] found the flow of the bronchial arteries to be 3.23% z 4% of cardiac output. Deal a n d co-workers [27] found it to be 3.8% +- 2.7% of cardiac o u t p u t d u r i n g the s a m e conditions. In dogs, the bronchial artery flow has b e e n found to be t e m p e r a t u r e d e p e n d e n t , with a m a x i m u m flow at 36°C [28]. Also in dogs, Deffebach a n d associates [29] d e m o n s t r a t e d that the bronchial artery flow is capable of a sevenfold increase as a response to lung injury by intravascular administration of c~-naphthylthiourea or by airway instillation of glucose with glucose oxidase. The function of the bronchial arteries d u r i n g p u l m o nary artery occlusion a n d reperfusion has b e e n s t u d i e d in rabbits by Kowalski a n d associates [30]. An inverse correlation was f o u n d b e t w e e n bronchial artery flow d u r i n g ischemia a n d the lung w e t - t o - d r y ratio after reperfusion. The authors s p e c u l a t e d w h e t h e r a critical level of bronchial artery flow is necessary d u r i n g p u l m o nary artery occlusion and reperfusion to p r e v e n t lung injury. Their findings have been s u p p o r t e d by Pearse and W a g n e r [31[, w h o s u g g e s t e d that the bronchial artery flow decreases e d e m a formation after ischemia a n d reperfusion. C h a r a n a n d colleagues [32] s t u d i e d the role a n d response of the bronchial arteries d u r i n g severe lung infection in sheep suffering from multiple lung abscesses. It was f o u n d that the walls of the abscess cavities were s u r r o u n d e d b y a dense vascular plexus that was b e i n g s u p p l i e d exclusively by the bronchial arteries. C u d k o wicz [33] s t u d i e d the vasculature of tuberculous lungs in five p o s t m o r t e m examinations a n d found that the t u b e r culous cavities h a d a rich blood supply. In lungs with bronchiectasis, Cudkowicz found evidence of proliferation a n d e n l a r g e m e n t of the bronchial arteries along with large b r o n c h o p u l m o n a r y anastomoses. D e v e l o p m e n t of bronchiolitis obliterans s y n d r o m e as a c o n s e q u e n c e of airway ischemia has b e e n s u g g e s t e d b y Yousem a n d co-workers [17]. Closset a n d associates [34] investigated this possible correlation in 15 dogs u n d e r going severing of the left bronchial arteries by hilar stripping and b r o n c h o t o m y followed by i m m e d i a t e reanastomosis. With a follow-up time of up to 3.5 months, no sign of obliterative bronchiolitis was found. Closset and associates c o n c l u d e d that ischemia is not an i m p o r tant factor in obliterative bronchiolitis.
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Experimental Animal Studies of Bronchial Artery Revascularization in Lung Transplantation A wide variety of experimental animals and operative methods have been used to develop the operative technique for bronchial artery revascularization. Already in 1950, Metras [5] performed single-lung transplantation with direct revascularization of the bronchial arteries in dogs. In 1964, Nettleblad and colleagues [35] reported successful revascularization of a bronchial artery in canine left lower lobe transplantation. A donor aortic pouch including the bronchial arteries was anastomosed to the recipient's descending aorta in a side-toside fashion. In 1970, Mills and co-workers [36] published a controlled study of the effects of reestablishment of the bronchial artery blood supply on outcome after left lung homotransplantation in 21 mongrel dogs. A preliminary anatomic study had been performed to determine the bronchial artery supply of the left lung. In group 1 (10 dogs), the left bronchial artery with a patch of aortic wall was anastomosed to the recipient's descending aorta. In group 2 (11 dogs), the bronchial artery supply was not reestablished and the left bronchial artery was ligated. In group 1, two instances of bronchial complications were found. One dog died of bronchial disruption on the seventh postoperative day, and the bronchial artery was found to be occluded. The other died from pneumonia 23 days postoperatively, and an ulcerated area was found in the donor bronchus. The bronchial artery was patent at autopsy. In group 2, nine bronchial complications occurred, including ulceration in 5 dogs, bronchial disruption in 3, and development of bronchial stenosis in 1. In 1990, Nazari and associates [7] published a study of left lung transplantation in 33 pigs. Bronchial artery revascularization was performed in 24 pigs, in which an aortic patch containing the bronchial artery orifice was anastomosed to the recipient's descending aorta. The perioperative mortality rate was high, with only 8 of 28 pigs alive on the 11th postoperative day. Little can be concluded from this study regarding the effect of bronchial artery revascularization except that the anatomy of the pig allows easy identification and preservation of the left bronchial arteries. In 1991, Laks and colleagues [9] published a method for bronchial artery revascularization tested in 5 baboons. Three had double-lung transplantation; I had a single left lung and one had a single right lung transplanted. A pouch of descending aorta from the proximal to the left subclavian artery to the level of the pulmonary hilum (holding the bronchial artery branches) was prepared and anastomosed to the recipient's left subclavian artery or ascending aorta. Angiograms of the 3 surviving baboons (1 double, 1 single right, i single left lung) performed after 14 days and postmortem examinations after 22, 30, and 30 days demonstrated patent anastomoses, no pouch thrombi, and normal healing of the tracheal and bronchial anastomoses. The effect of direct bronchial artery revascularization on the airway mucosal blood flow was investigated by
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Aoki and colleagues [37] in 1991. In a model of modified unilateral lung transplantation in pigs, the mucosal blood flow was measured at the donor main carina and at the upper lobe carina using laser Doppler velocimetry and radioisotope studies with radiolabeled erythrocytes. The mucosal blood flow was significantly higher in animals with than in those without bronchial artery revascularization. Fujino and co-workers [81 published a similar study in 1992. In 23 mongrel dogs, radical hilar stripping and transection of the right main bronchus and the right bronchial artery were performed. The right main bronchus was immediately reanastomosed. Group A had the bronchial artery ligated. In group B, the bronchial artery was anastomosed to the right internal thoracic artery using microsurgical technique. The effect of revascularization was estimated by laser Doppler velocimetry. The peripheral bronchial mucosal blood flow immediately after operation had diminished to 59% of the original in group A and to 78% in group B. A statistically significant difference in mucosal blood flow between the groups continued on days 1, 3, 5, and 7. From day 10 on, there was no difference. Two dogs in group B were found to have occlusion of the anastomosis when sacrified after 14 days. No airway complications were observed in either group. Clinical
Experience
In 1964, Meshalkin and co-workers [38] reported eight single pulmonary autotransplantations (five left, three right). The transplantations were performed as an experimental treatment of asthma. Two of these patients died of bronchial disruption and bleeding from bronchopulmonary artery fistulas. In 1970, Mills and colleagues [36] polled the 18 investigators responsible for the first 25 human lung allotransplantations registered in the International Transplant Registry in Chicago. Seventeen investigators returned the questionnaire and reported 13 instances of bronchial complications, including ulceration, necrosis, and disruption. In 1973, Haglin and associates [10] reported a case of direct left bronchial artery revascularization of a left lung using a method almost the same as described earlier by Mills and colleagues [36]. In addition, the right lung was transplanted without bronchial revascularization after an ischemic time of 11 hours. The patient died of septicemia and pulmonary insufficiency on the 11th postoperative day. At autopsy, the left (revascularized) bronchial wall remained viable, whereas the right (nonrevascularized) bronchial wall showed extensive necrosis. As mentioned earlier, Couraud and associates [11] were the first to publish a series of patients having en bloc double-lung transplantation with bronchial artery revascularization. Organ procurement was done according to the method described by Schreinemakers and colleagues [6]. Couraud and associates included a tracheal anastomosis. The bronchial artery revascularization was done with a saphenous vein graft from the
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recipient's ascending aorta to an aortic patch including the origin of the right intercostobronchial artery and, in addition in a few cases, one or more left bronchial arteries. The distal anastomosis of the s a p h e n o u s vein graft was done on a side table before introducing the donor lungs into the recipient. The proximal s a p h e n o u s vein to recipient aorta anastomosis was done at the end of the operation. It was stressed that dissection a r o u n d the carina and individual mobilization of the bronchial arteries should be a v o i d e d so as not to interfere with the bronchial blood supply. The additional ischemic time n e e d e d for p e r f o r m i n g the bronchial artery revascularization was estimated as 1 hour. The bronchial b l o o d s u p p l y was evaluated by r e p e a t e d endoscopic studies and in 7 patients by arter i o g r a p h y 2 weeks postoperatively. The a r t e r i o g r a p h y results showed an o p e n vein graft with visualization of bronchial arteries in 5 patients, w h e r e a s 2 s h o w e d t h r o m botic occlusion of the vein graft. N o r m a l tracheal healing was o b s e r v e d in all patients. O n e patient d i e d of gastrointestinal h e m o r r h a g e on day 30, a n d 1 died of a fulminant Pseudomonas aeruginosa p n e u m o n i a on day 35. Later in 1992, C o u r a u d and associates [39] enlarged their clinical experience b y 3 patients, 2 having en bloc double a n d I having right single lung transplantation. No patients h a d anastomosis healing p r o b l e m s or stenosis. In 2 of the additional patients, a r t e r i o g r a p h y results s h o w e d a functional s a p h e n o u s vein graft a n d visualization of the bronchial arteries. One patient d i e d of h e p a torenal failure on day 16. In 1993, Daly a n d c o l l e a g u e s [12] p u b l i s h e d the Harefield series of 8 patients who had nine en bloc d o u b l e - l u n g transplantations with bronchial artery revascularizafion. The m e t h o d of organ p r o c u r e m e n t was modified from those d e s c r i b e d previously [6, 9]. The bronchial arteries were identified and confirmed by probing. The largest vessel going in the direction of the carina was chosen for revascularization with the left internal m a m m a r y artery. The m a m m a r y to bronchial artery anastomosis was done at the end of the operation. The orifice of the bronchial artery was b r o u g h t into view by pulling on the proximal end of the donor aorta. Orifices in the donor d e s c e n d i n g aorta p r o d u c i n g backb l e e d i n g w e r e oversewn. The total a d d i t i o n a l time n e e d e d to p e r f o r m the bronchial artery revascularization was estimated to be 30 to 60 minutes, a n d the d o n o r organ ischemic time was p r o l o n g e d b y 20 to 22 minutes. The bronchial artery blood s u p p l y was evaluated b y r e p e a t e d bronchoscopic examinations, a n d a r t e r i o g r a p h y was p e r f o r m e d 12 days to 2 m o n t h s postoperatively. In 1 patient with angiographic evidence of bronchial artery occlusion, a large ulcer d e v e l o p e d in the tracheal anastomosis. In all other patients, the internal m a m m a r y artery graft was patent, with good bronchial artery perfusion a n d n o r m a l healing, including 1 patient who had r e t r a n s p l a n t a t i o n after 1 m o n t h because of p u l m o n a r y emboli. The internal m a m m a r y artery graft was chosen instead of a s a p h e n o u s vein graft b e c a u s e of expected better l o n g - t e r m patency. In 1994, Daly and colleagues [15] p u b l i s h e d the results
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of direct bronchial artery revascularization in 10 singlelung transplantations from the Mayo Clinic. The a d d i tional ischemic time for the revascularization p r o c e d u r e was e s t i m a t e d as 15 to 20 minutes. One patient d i e d perioperatively of d o n o r organ dysfunction. In the surviving 9 patients, a n g i o g r a p h y results d e m o n s t r a t e d excellent perfusion of the bronchial arteries in 7 a n d no perfusion in 2. Bronchial healing was excellent in all. These investigators d e m o n s t r a t e d that it is possible to p e r f o r m bronchial artery revascularization of two single lungs from the s a m e donor b y dividing the d o n o r aorta a n d the m e d i a s t i n a l tissue b e t w e e n two bronchial arteries. M c G r e g o r a n d co-workers [16], also in 1994, docum e n t e d 4 patients who had bronchial artery revascularization a m o n g the first 15 lung t r a n s p l a n t recipients at the Mayo Clinic having different p r o c e d u r e s for b r o n chial anastomosis protection. W e p r e s u m e that these 4 patients r e p r e s e n t part of the group of 10 patients p u b lished earlier [15]. In 1994, we p u b l i s h e d the results of our first 14 en bloc double lung t r a n s p l a n t a t i o n s with bronchial artery revascularization [13] using the left internal thoracic artery. The m e t h o d used was a modification of that d e s c r i b e d by Daly and colleagues [12[. O u r own experience with bronchial artery revascularization now includes 63 patients: 49 double lung, 5 single lung, and 9 heart lung transplantations. Preparation of the donor organs for revascularization a d d s a b o u t 15 to 20 m i n u t e s of ischemic time. On one occasion, we perf o r m e d bronchial artery revascularization of two single lungs from the s a m e d o n o r by dividing the block so that the bronchial arteries were p r e s e n t for both sides. O u r ambition is to achieve complete bronchial artery revascularization, ie, a n a s t o m o s e s to all identified bronchial arteries. W h e n m o r e than one artery is revascularized, one c o m m o n or sequential m a m m a r y a n a s t o m o s e s are performed. Each anastomosis takes about 10 m i n u t e s or less. After the block has b e e n introduced, the bronchial artery revascularization is p e r f o r m e d first. In en bloc d o u b l e lung transplantation, the left lung is h u n g backw a r d s over the heart, which gives excellent exposure of the bronchial artery o p e n i n g s in the d o n o r d e s c e n d i n g aorta. I m m e d i a t e bronchial reperfusion is b e g u n a n d m a i n t a i n e d during the rest of the procedure. W e have e n c o u n t e r e d anastomotic b l e e d i n g on three occasions. In one instance, the extra hemostatic sutures resulted in occlusion of the anastomosis. The p r o b l e m was diagnosed i m m e d i a t e l y b y arteriography. The patient u n d e r w e n t reoperation, and the bronchial artery revascularization was successfully reestablished. The arterial b l o o d s u p p l y of the bronchial tree is e v a l u a t e d by r e p e a t e d endoscopic and arteriographic studies. In the first double lung series, 10 of 12 patients s h o w e d successful revascularization at angiography, a n d excellent tracheal healing was observed. In 2 patients, the internal thoracic artery was open but there was no c o m m u n i c a t i o n to the bronchial arteries. Both patients experienced s u b m u c o s a l necrosis in the central bronchi and s u b s e q u e n t stenosis of the left m a i n bronchus; even-
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Table 1. Results of Bronchial Artery Revascularization in Lung Transplantation Study Location Bordeaux [11, 39] Harefield, London [12] Mayo Clinic [15] Copenhagen, Denmark [13] Copenhagen, after the first series
Number of Operations
Arteriography Performed a
Arteriography Not Performed
10 DLTX 1 SLTX 8 DLTX 10 SLTX 14 DLTX 35 DLTXb 5 SLTX 9 HLTX
8 [6 (0)•2 (0)] 1 [1 (0)/0 (0)] 8 [7 (0)/1 (0)] 9 [7 (0)/2 (0)] 12 [10 (0)/2 (2)] 31 [30b(0)/1 (1)] 4 [4 (0)/0 (0)l 6 [6 (0)/0 (0)]
0 (0) 0 (0) 1 (0) 2 (0) 5 (1) 1 (0) 3 (0)
.7 N u m b e r [successful/failed]. Parentheses indicate severe bronchial healing problems. after i m m e d i a t e reoperation.
b In 1 patient with primary' failed grafting, successful grafting
DLTX
SLTX - single-lung transplantation.
en bloc d o u b l e - l u n g transplantation;
H[_TX
h e a r t - l u n g transplantation;
tually a left-side p n e u m o n e c t o m y had to be performed. Early survival was 100°A,. O u r results show that of the 63 patients in w h o m bronchial artery revascularization was attempted, 53 had a n g i o g r a p h y p e r f o r m e d 1 day to 5 m o n t h s p o s t o p e r a tively, showing successful revascularization in 50 (in 1 after reoperation for anastomotic occlusion) and failed revascularization in 3 (including the 2 patients in the early series). Nine of 10 patients not examined by arter i o g r a p h y for various reasons h a d normal bronchial healing, w h e r e a s 1 had poor bronchial healing, suggesting failed revascularization. Sixteen patients have been reexa m i n e d after 2 years, showing 100% long-term patency of the bronchial artery revascularization. Using the KaplanMeier m e t h o d (and the International Society for Heart and Lung Transplantation working formulation [40]), the proportion of patients having double lung transplantation with bronchial artery revascularization who were free from bronchiolitis obliterans s y n d r o m e after 1, 2, a n d 3 years was, respectively, 85%, 82%, a n d 67%. O n e of 6 patients having single lung transplantation with bronchial artery revascularization h a d bronchiolitis obliterans s y n d r o m e after 12 months. None of our 9 patients having heart lung transplantation with bronchial artery revascularization have so far d e v e l o p e d bronchiolitis obliterans syndrome. Table 1 s u m m a r i z e s the p u b l i s h e d results of lung transplantation with bronchial artery revascularization. Comment Because of lack of interest a n d methodologic p r o b l e m s due to the a w k w a r d location of the bronchial arteries, only a few facts about these arteries have b e e n established from humans. From the work p e r f o r m e d on exp e r i m e n t a l animals by several authors, as described earlier, we have l e a r n e d that the bronchial arteries seem to play an i m p o r t a n t role in the response of the lungs and airways to m a n y physiologic and pathologic conditions. It is difficult not to be i m p r e s s e d by the high flow a n d the reactivity of the bronchial arteries. The possible impact of direct bronchial artery revascularization in lung transplantation is interesting. In a g r e e m e n t with the experi-
mental studies [30, 31], we have been i m p r e s s e d by the absence of e d e m a early after operation in the majority of the lungs t r a n s p l a n t e d with bronchial artery revascularization. W e expect the revascularized lungs to be m o r e resistant to infection, as indicated b y the study of lung abscesses in sheep [32]. That revascularization might have an i m p a c t on obliterative bronchiolitis s y n d r o m e r e m a i n s speculative. The evidence against such a relation, however, [34] is not impressive. The e x p e r i m e n t s in this study [34] were of autotransplantation, a n d the authors did not d o c u m e n t that airway ischemia was actually p r e s e n t after the operation. It m a y f u r t h e r m o r e be a r g u e d that the 3.5 m o n t h s of follow-up m a y be too short to find any signs of obliterative bronchiolitis. O u r interpretation of available studies is that it s e e m s unlikely that the bronchial arteries can be neglected d u r i n g t r a n s p l a n t a t i o n without adverse consequences, ie, the recipient will have lungs with a severed physiologic response to pathologic conditions as a result of the absence of the bronchial artery blood supply. In the early era of lung transplantation, healing of the airway anastomosis was a major concern. The m e t h o d used for anastomotic protection a n d airway revascularization in the first successful h u m a n lung t r a n s p l a n t a tions, single as well as en bloc double, was to w r a p the airway anastomosis with o m e n t u m [41]. W r a p p i n g the anastomosis with o m e n t u m has b e e n shown to enhance early ingrowth of vessels a r o u n d the airway anastomosis [42]. For single-lung transplantation, this m e t h o d prod u c e d g o o d early results, w h e r e a s double lung transplantation p e r f o r m e d en bloc with a tracheal anastomosis was still associated with a high incidence of tracheal anastomosis a n d bronchial p r o b l e m s [43]. Based on these o b s e r v a t i o n s - - s u g g e s t i n g that the i n t r a p u l m o n a r y part of the bronchial tree is less d e p e n d e n t on the arterial blood s u p p l y than are the main bronchi and t r a c h e a - - t h e technique of p e r f o r m i n g d o u b l e - l u n g t r a n s p l a n t a t i o n as sequential bilateral lung t r a n s p l a n t a t i o n was i n t r o d u c e d [44[. This m e t h o d has been associated with a low rate of bronchial complications a n d good early results [45]. With i m p r o v e d technique, the incidence of airway p r o b l e m s today is very, low, even without w r a p p i n g the bronchial
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anastomoses. This m e t h o d is, however, associated with a p r o l o n g e d ischemic time, especially for the second lung. A l t h o u g h the logical m e t h o d to prevent bronchial and lung i s c h e m i a - - d i r e c t bronchial artery revascularizat i o n - - w a s i n t r o d u c e d experimentally by Metras already in 1950 [5] a n d clinically b y C o u r a u d a n d associates [11, 39] in 1992, the Harefield group in 1993 [12], the Mayo Clinic in 1994 I15[, a n d the C o p e n h a g e n group in 1994 [13, 141, most lung t r a n s p l a n t surgeons have not yet decided to use the method. The main a r g u m e n t s for not performing bronchial artery, revascularization have b e e n as follows: (1) good early results without bronchial artery revascularization, (2) lack of evidence of the effectiveness of the method, (3) p r o l o n g e d operation time a n d prolonged ischemic time, and (4) increased risk of bleeding. Until this publication, 33 en bloc d o u b l e - l u n g a n d 11 single-lung transplantations with bronchial artery, revascularization have been published. Concerning early results and effectiveness of the method, 28 of 33 r e p o r t e d patients with bronchial artery revascularization d u r i n g en bloc double lung t r a n s p l a n t a t i o n s were s t u d i e d by angiography. Twenty-three showed good revascularization of the bronchial arteries, a n d none of these patients h a d airwav healing problems. In 5, the bronchial artery revascularization h a d failed; 3 of these h a d airway healing p r o b l e m s including necrosis, and 2 h a d s u b s e q u e n t d e v e l o p m e n t of severe bronchial stenosis. As m e n t i o n e d earlier, we can a d d 31 en bloc d o u b l e lung transplantation patients, in w h o m a n g i o g r a p h y verified successful revascularization in 30 a n d failure in 1. This failure was in a r e t r a n s p l a n t a t i o n patient who d i e d of p n e u m o n i a 30 days postoperatively. Ten of the 11 r e p o r t e d patients with single lung transplantations were checked by arteriography. Two revascularization p r o c e d u r e s h a d failed. All patients h e a l e d their bronchial a n a s t o m o s e s without complications. W e can a d d five single-lung procedures, with successful revascularization verified by a n g i o g r a p h y in four. In the last patient, a n g i o g r a p h y was not performed. All patients h e a l e d without airway complications. We also have a d d e d nine bronchial artery revascularizations in heart lung transplantations. Successful revascularization was verified b y a r t e r i o g r a p h y in six. Arter i o g r a p h y was not p e r f o r m e d in the r e m a i n i n g three. Tracheal anastomosis healing was n o r m a l in all. Prolongation of the ischemic time r e q u i r e d for performing the bronchial artery revascularization has b e e n 20 to 60 minutes, d e p e n d i n g on the m e t h o d used. With our method, the ischemic time is shortened rather than p r o l o n g e d because early bronchial artery reperfusion is allowed. W h e n calculating the ischemic time involved in performing bronchial artery revascularization, it is necessary to c o m p a r e the time used for this p r o c e d u r e with the increased surgical t r a u m a and the potential risk of abd o m i n a l complications involved with w r a p p i n g the anastomosis with o m e n t u m . Bilateral sequential lung transplantation using a clamshell incision takes longer than en bloc d o u b l e - l u n g t r a n s p l a n t a t i o n including bronchial artery revascularization. Postoperative b l e e d i n g as a consequence of bronchial
Ann Thorac Surg 1996;62:1215-21
artery revascularization has been rare, and in all instances has b e e n controllable.
Conclusion A l t h o u g h the initial series of patients u n d e r g o i n g lung transplantation with bronchial artery revascularization have b e e n s m a l l the results have b e e n good, a n d the correlation b e t w e e n healing of the airway anastomosis and the function of the bronchial artery revascularization has b e e n convincing. This m e t h o d is the obvious choice for achieving good healing of the airway anastomosis in en bloc d o u b l e - l u n g transplantation. W e conclude that reliable bronchial artery revascularization is possible. W h e n using the m a m m a r y artery as conduit, long-term patency can be expected. However, airway healing is not the only issue. Longterm results after lung t r a n s p l a n t a t i o n are still not convincing, and the early results after a t t e m p t e d direct bronchial artery revascularization are definitely g o o d enough to justify, its use in large series to allow studies of long-term results.
References 1. Patterson GA. Airway revascularization: is it necessary? [Editorial]. Ann Thorac Surg 1993;56:807-8. 2. Yeh TJ, Ellison LT, Ellison RG. Functional evaluation of the autotransplanted lung in the dog. Am Rev Respir Dis 1962; 86:791. 3. Veith FJ, Kamholz SL, Mollenkopf FP, Montefusco CM. Lung transplantation 1983. Transplantation 1983;35:271-8. 4. Cooper JD. Lung transplantation. Ann Thorac Surg 1989;47: 28-44. 5. Metras H. Note pr61iminaire sur la gr6ffe totale du poumon chez le chien. C R Acad Sci [III] 1950;231:1176-7. 6. Schreinemakers HH, Weder W, Miyoshi S, et al. Direct revascularization of bronchial arteries for lung transplantation: an anatomical study. Ann Thorac Surg 1990;49:44-54. 7. Nazari S, Prati U, Berti A, Hoffmann JW, Moncalvo F, Zonta A. Successful bronchial revascularization in experimental single lung transplantation. Eur J Cardiothorac Surg 1990;4: 561-6. 8. Fujino S, lnoue S, Yamashita N, Mori A. An experimental study on direct revascularization of bronchial circulation by microvascular anastomosis. J Thorac Cardiovasc Surg 1992; 104:1067-74. 9. Laks H, Louie HW, Haas GS, et al. New technique of vascularization of the trachea and bronchus for lung transplantation. J Heart Lung Transplant 1991;10:280-7. 10. Haglin JJ, Ruiz E, Baker RC, et al. Histologic studies of human lung allotransplantation. In: Wildevuur C, ed. Morphology in lung transplantation. Basel: S. Karger, 1973:13-22. 11. Couraud L, Baudet E, Martigne C, et al. Bronchial revascularization in double-lung transplantation: a series of 8 patients. Bordeaux Lung and Heart-Lung Transplant Group. Ann Thorac Surg 1992;53:88-94. 12. Daly RC, Tadjkarimi S, Khaghani A, Banner NR, Yacoub MH. Successful double-lung transplantation with direct bronchial artery revascularization. Ann Thorac Surg 1993;56: 885-92. 13. Pettersson G, Arendrup H, Mortensen SA, et al. Early experience of double-lung transplantation with bronchial artery revascularization using mammary artery. Eur J Cardiotlaorac Surg 1994;8:520-4. 14. Arendrup H, Pettersson G, Thiis J, et al. Double-lung transplantation with bronchial artery revascularization using a mammary, artery. Transplant Proc 1994;26:1809-10.
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15. Daly RC, McGregor CG. Routine immediate direct bronchial artery revascularization for single-lung transplantation. Ann Thorac Surg 1994;57:1446-52. 16. McGregor CG, Daly RC, Peters SG, et al. Evolving strategies in lung transplantation for emphysema. Ann Thorac Surg 1994;57:1513-20. 17. Yousem SA, Dauber JH, Grihrith BP. Bronchial cartilage alterations in lung transplantation. Chest 1990;98:1121-4. 18. Ellis FH, Grindlay JH, Edwards JE. The bronchial arteries: experimental occlusion. Surgery 1951;30:810-6. 19. Cauldwell EW, Siekert RG, Liniwger RE, Anson BJ. The bronchial arteries. An anatomic study of 150 human cadavers. Surg Gynecol Obstet 1948;86:395-412. 20. Liebow AA. Patterns of origin and distribution of the major bronchial arteries in man. Am J Anat 1965;117:19-32. 21. Moberg A. Anastomoses between extracardiac vessels and coronary arteries. 3. Microangiographic appearance, Acta Radiol l~iagn Stockh 1968;7:33-47. 22. Wagenvoort CA, Wagenvoort N. Arterial anastomoses, bronchopulmonary arteries, and pulmobronchial arteries in perinatal lungs. Lab Invest 1967;16:13-24. 23. Tobin CE. The bronchial arteries and their connections with other vessels in the human lung. Surg Gynecol Obstet 1952; 95:741-50. 24. Magno M. Comparative anatomy of the tracheobronchial circulation. Eur Respir J Suppl 1990;12:557s-62s. 25. McLaughlin RF. Bronchial artery distribution in various mammals and in humans. Am Rev Respir Dis 1983;128: $57-8. 26. Baile EM, Ling H, Heyworth JR, Hogg JC, Pare PD. Bronchopulmonary, anastomotic and noncoronary collateral blood flow in humans during cardiopulmonary bypass. Chest 1985; 87:749-54. 27. Deal CW, Louis E, Kerth WJ, Osborn JJ, Gerbode FG. Bronchopulmonary precapillary blood flow during cardiopulmonary bypass. Am Heart J 1968;75:43-8. 28. Agostoni PG, Deffebach ME, Kirk W, Brengelmann GL. Temperature dependence of intraparenchymal bronchial blood flow. Respir Physiol 1987;68:259-67. 29. Deffebacb ME, Lakshminarayan S, Kirk W, Butler J. Bronchial circulation and cyclooxygenase products in acute lung injury. J Appl Physiol 1987;63:1083-8. 30. Kowalski TF, Guidotti S, Deffebach M, Kubilis P, Bishop M. Bronchial circulation in pulmonary artery occlusion and reperfusion. J Appl Physiol 1990;68:125-9. 31. Pearse DB, Wagner EM. Role of the bronchial circulation in ischemia-reperfusion lung injury. J Appl Physiol 1994;76: 259-65.
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32. Charan NB, Turk GM, Dhand R. The role of bronchial circulation in lung abscess. Am Rev Respir Dis 1985;131: 121-4. 33. Cudkowicz L. The human bronchial circulation in health and disease. Baltimore: Williams and Wilkins, 1968. 34. Closset J, Vanderhoeft PJ, Delcour C. Bronchiolar morphology after systemic arterial interruption. Angiology 1990;41: 946-56. 35. Nettleblad SC, Soroff HS, Sachs BF, et al. Experimental studies of the response to homotransplantation of pulmonary tissues. Ann N Y Acad Sci 1964;120:689-709. 36. Mills NL, Boyd AD, Gheranpong C. The significance of bronchial circulation in lung transplantation. J Thorac Cardiovasc Surg 1970;60:866-74. 37. Aoki M, Schafers HJ, Inui K, et al. Bronchial circulation after experimental lung transplantation: the effect of direct revascularization of a bronchial artery. Eur J Cardiothorac Surg 1991;5:561-5. 38. Meshalkin EN, Sergievsky VS, Feofilov GL, Savinsky GA, Baeva AV. First attempts at treatment of bronchial asthma by the method of pulmonary autotransplantation. Eksp Khir Anest 1964;9:26. 39. Couraud L, Baudet E, Nashef SA, et al. Lung transplantation with bronchial revascularisation. Surgical anatomy, operative technique and early results. Eur J Cardiothorac Surg 1992;6:490-5. 40. Cooper JD, Billingham M, Egan T, et al. A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. International Society for Heart and Lung Transplantation. J Heart Lung Transplant 1993;12:713-6. 41. The Toronto Lung Transplant Group, Experience with single-lung transplantation for pulmonary fibrosis. JAMA 1988; 259:2258- 62. 42. Turrentine MW, Kesler KA, Wright CD, et al. Effect of omental, intercostal, and internal mammary artery pedicle wraps on bronchial healing. Ann Thorac Surg 1990;49:574-8. 43. Patterson GA, Todd TR, Cooper JD, Pearson FG, Winton TL, Maurer J. Airway complications following double lung transplantation. Toronto Lung Transplant Group. J Thorac Cardiovasc Surg 1990;99:14-21. 44. Pasque MK, Cooper JD, Kaiser LR, Haydock DA, TriantafilIou A, Trulock EP. Improved technique for bilateral lung transplantation: rationale and initial clinical experience. Ann Thorac Surg 1990;49:785-91. 45. Griffith BP, Magee MJ, Gonzalez IF, et al. Anastomotic pitfalls in lung transplantation. J Thorac Cardiovasc Surg 1994;107:743-53,
Development of the surgical technique has minimized the incidence of airway problems associated with single as well as sequential bilateral lung transplantation. Although early results are good, long-term results remain unsatisfactory. The main problems after lung transplantation are pulmonary infections and the bronchiolitis obliterans syndrome. The bronchiolitis obliterans syndrome is usually considered to be chronic rejection, but a multifactorial genesis including airway ischemia has been suggested. We reviewed the literature relevant to direct bronchial artery revascularization during lung transplantation. Although information is limited, there
are good reasons to believe that reestablishment of the dual blood supply to the transplanted lung is beneficial not only for healing of the airway anastomoses, but also for the airway and the lung responses to pathologic conditions. In small series, methods of bronchial artery revascularization have proved successful and have been associated with good early results. We believe it is justified to test the impact of direct bronchial artery revascularization on outcome after lung transplantation in large clinical series.
he lungs have a dual blood supply: from the pulmonary arteries, providing desaturated blood under low pressure, and from the bronchial arteries, providing oxygenated blood under arterial pressure. Lung transplantation has stimulated an interest in the role and importance of the bronchial artery blood supply. Many lung transplant surgeons are uncertain about the role of the bronchial arteries, ie, whether they can or even should be neglected [11. In the beginning of lung transplantation, it was clear that bronchial complications were a major cause of death in the early postoperative period [2]. When Veith and associates [3] and Cooper [41 analyzed the early clinical cases of lung transplantation, they found that of the first 38 patients who had undergone lung or lobe transplantation, only 1 survived more than 3 weeks. The single dominating cause of death was dehiscence of the bronchial anastomosis. Already in 1950, Metras [5] had proposed that the bronchial artery circulation could be important in lung transplantation. To pursue this theory, Metras performed experimental single-lung transplantations with direct bronchial revascularization in dogs. Several anatomic [6] and experimental studies [7-9] have been done to develop an effective and reliable method for revascularization of the bronchial arteries. Haglin and colleagues [10] performed direct bronchial artery revascularization in a left lung transplant in 1973. In practice, however, bronchial artery revascularization
was considered too difficult and unreliable to be used clinically, and other methods of protecting the bronchial anastomosis were developed and applied. With respect to airway healing, these methods have proved very successful. It was not until 1992 that Couraud and co-workers [11] reported the first clinical series of 8 patients with en bloc double-lung transplantation with successful bronchial artery revascularization. Since then, reports of successful en bloc double-lung transplantation with bronchial revascularization have been published from Harefield [12] and Copenhagen [13, 14]. The Mayo Clinic has recently reported single and bilateral lung transplantation with bronchial artery revascularization [15, 16]. Based on our own experience, we believe that direct bronchial artery revascularization during lung transplantation is possible with a high success rate. Although bronchial healing can be achieved without revascularization, there could be other reasons to believe that a normal arterial blood supply is beneficial to the transplanted lungs. It is important to evaluate available information about the bronchial artery circulation that indicates a possible beneficial effect of direct bronchial artery revascularization in lung transplantation that goes beyond healing of the airways. It has been suggested that ischemia (versus effective bronchial revascularization) could be important in the development of bronchiolitis obliterans syndrome [13, 17]. We reviewed the published information relevant to direct bronchial artery revascularization.
T
Address reprint requests to Dr Norgaard, Thoraxkirurgisk afd RT, 2152, Blegdamsvej 9, 2100 Copenhagen O, Denmark.
© 1996 bv The Societv of Thoracic Surgeons Published bv Elsevier Science lnc
(Ann Thorac Sure, 1996;62:1215-21)
0003~4975/96/$15.00 PII S0003-4975(96)00539-5
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Anatomy The existence of small arteries to the lungs in animals has been k n o w n since G a l e n [18]. The a n a t o m y of the h u m a n bronchial arteries as they branch from the aorta has been s t u d i e d carefully by several investigators. Cauldwell and associates [19] p e r f o r m e d 150 cadaver dissections, and Liebow [20] p e r f o r m e d corrosion casts of the bronchial arteries in 50 cadavers. N u m e r o u s variations of the origin of the bronchial arteries were found. These authors [19, 20] a g r e e d that the most c o m m o n pattern is two left arteries a n d one right artery, which was found in 20% a n d 41%, respectively. One or two arteries for each side was f o u n d in a total of 40% and 42% of the cases, respectively. All other possible combinations of one to four arteries for each side, up to a total of six bronchial arteries, were f o u n d in 40% a n d 17%, respectively. Bronchial arteries originating in the d e s c e n d i n g aorta to s u p p l y both sides were always found. The bronchial arteries follow the bronchial tree d e e p l y into the l u n g p a r e n c h y m a , f o r m i n g a p e r i b r o n c h i a l plexus, a n d small arterioles penetrate the muscularis to form a s u b m u c o s a l plexus. The bronchial arteries also contribute arterial blood s u p p l y to the visceral pleura, the walls of the p u l m o n a r y arteries and veins as vasa vasorum, the mediastinal tissue, esophagus, mediastinal a n d hilar l y m p h nodes, pericardium, a n d vagal a n d s y m p a thetic nerves; even b r a n c h e s to the m y o c a r d i u m can be f o u n d in h u m a n s [21]. Studies of the microvascular a n a t o m y have found the venous drainage to be partially to the azygos a n d hemiazygos veins [20] a n d partially t h r o u g h a n a s t o m o s e s b e t w e e n the bronchial arteries a n d p u l m o n a r y alveolar microvessels, called " b r o n c h o p u l m o n a r y arteries" [22]. Tobin [23] d e s c r i b e d these anastomotic vessels as coiled, possibly b e c a u s e of spiral musculature in their walls, and s u g g e s t e d that this structure " m i g h t help to regulate the p r e s s u r e g r a d i e n t from bronchial to p u l m o n a r y vessels." Tobin also d e s c r i b e d c o m m u n i c a t i o n s b e t w e e n the bronchial arteries and the p u l m o n a r y veins. In 1990, S c h r e i n e m a k e r s a n d colleagues [6] p u b l i s h e d an anatomic s t u d y of the bronchial arteries in 30 autopsy cases. Based on these studies, a technique for procurem e n t of the lungs along with the r e t r o e s o p h a g e a l right intercostobronchial artery was developed. In 17 of 19 dissections, it was possible to p r e p a r e a bronchial artery pedicle with a patch of aorta holding the intercostobronchial artery a n d its origins, which would have been possible to r e i m p l a n t in the a s c e n d i n g aorta of a recipient after a double lung transplantation. C o u r a u d a n d associates [11] were the first to publish a series of patients having en bloc double lung t r a n s p l a n tation with bronchial artery revascularization. The clinical series was p r e c e d e d b y an anatomic study of the tracheobronchial blood s u p p l y in 20 h u m a n cadavers and by angiographic studies in 50 patients having thoracic operations. A right intercostobronchial artery was found in 95% of the cases. In 50°'0 of the cases, orifices of additional bronchial arteries were f o u n d 0.5 to 1.5 cm from the intercostobronchial artery orifice. A c o m m o n
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bronchial artery trunk giving b r a n c h e s to both the right and left sides was f o u n d in about half of the cases.
Physiology and Pathophysiology C o m p a r a t i v e anatomic studies of the bronchial arteries of different species have b e e n p e r f o r m e d [24, 25] a n d have c o n c l u d e d that the a n a t o m y of the sheep, cow, pig, a n d horse a p p e a r s to be similar to h u m a n a n a t o m y [24]. These animals have b e e n u s e d to establish m u c h of the basic k n o w l e d g e about the physiology a n d p a t h o p h y s i ology related to the bronchial arteries. The flow of the bronchial arteries has b e e n m e a s u r e d in h u m a n s d u r i n g c a r d i o p u l m o n a r y b y p a s s conditions. Baile a n d colleagues [26] found the flow of the bronchial arteries to be 3.23% z 4% of cardiac output. Deal a n d co-workers [27] found it to be 3.8% +- 2.7% of cardiac o u t p u t d u r i n g the s a m e conditions. In dogs, the bronchial artery flow has b e e n found to be t e m p e r a t u r e d e p e n d e n t , with a m a x i m u m flow at 36°C [28]. Also in dogs, Deffebach a n d associates [29] d e m o n s t r a t e d that the bronchial artery flow is capable of a sevenfold increase as a response to lung injury by intravascular administration of c~-naphthylthiourea or by airway instillation of glucose with glucose oxidase. The function of the bronchial arteries d u r i n g p u l m o nary artery occlusion a n d reperfusion has b e e n s t u d i e d in rabbits by Kowalski a n d associates [30]. An inverse correlation was f o u n d b e t w e e n bronchial artery flow d u r i n g ischemia a n d the lung w e t - t o - d r y ratio after reperfusion. The authors s p e c u l a t e d w h e t h e r a critical level of bronchial artery flow is necessary d u r i n g p u l m o nary artery occlusion and reperfusion to p r e v e n t lung injury. Their findings have been s u p p o r t e d by Pearse and W a g n e r [31[, w h o s u g g e s t e d that the bronchial artery flow decreases e d e m a formation after ischemia a n d reperfusion. C h a r a n a n d colleagues [32] s t u d i e d the role a n d response of the bronchial arteries d u r i n g severe lung infection in sheep suffering from multiple lung abscesses. It was f o u n d that the walls of the abscess cavities were s u r r o u n d e d b y a dense vascular plexus that was b e i n g s u p p l i e d exclusively by the bronchial arteries. C u d k o wicz [33] s t u d i e d the vasculature of tuberculous lungs in five p o s t m o r t e m examinations a n d found that the t u b e r culous cavities h a d a rich blood supply. In lungs with bronchiectasis, Cudkowicz found evidence of proliferation a n d e n l a r g e m e n t of the bronchial arteries along with large b r o n c h o p u l m o n a r y anastomoses. D e v e l o p m e n t of bronchiolitis obliterans s y n d r o m e as a c o n s e q u e n c e of airway ischemia has b e e n s u g g e s t e d b y Yousem a n d co-workers [17]. Closset a n d associates [34] investigated this possible correlation in 15 dogs u n d e r going severing of the left bronchial arteries by hilar stripping and b r o n c h o t o m y followed by i m m e d i a t e reanastomosis. With a follow-up time of up to 3.5 months, no sign of obliterative bronchiolitis was found. Closset and associates c o n c l u d e d that ischemia is not an i m p o r tant factor in obliterative bronchiolitis.
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Experimental Animal Studies of Bronchial Artery Revascularization in Lung Transplantation A wide variety of experimental animals and operative methods have been used to develop the operative technique for bronchial artery revascularization. Already in 1950, Metras [5] performed single-lung transplantation with direct revascularization of the bronchial arteries in dogs. In 1964, Nettleblad and colleagues [35] reported successful revascularization of a bronchial artery in canine left lower lobe transplantation. A donor aortic pouch including the bronchial arteries was anastomosed to the recipient's descending aorta in a side-toside fashion. In 1970, Mills and co-workers [36] published a controlled study of the effects of reestablishment of the bronchial artery blood supply on outcome after left lung homotransplantation in 21 mongrel dogs. A preliminary anatomic study had been performed to determine the bronchial artery supply of the left lung. In group 1 (10 dogs), the left bronchial artery with a patch of aortic wall was anastomosed to the recipient's descending aorta. In group 2 (11 dogs), the bronchial artery supply was not reestablished and the left bronchial artery was ligated. In group 1, two instances of bronchial complications were found. One dog died of bronchial disruption on the seventh postoperative day, and the bronchial artery was found to be occluded. The other died from pneumonia 23 days postoperatively, and an ulcerated area was found in the donor bronchus. The bronchial artery was patent at autopsy. In group 2, nine bronchial complications occurred, including ulceration in 5 dogs, bronchial disruption in 3, and development of bronchial stenosis in 1. In 1990, Nazari and associates [7] published a study of left lung transplantation in 33 pigs. Bronchial artery revascularization was performed in 24 pigs, in which an aortic patch containing the bronchial artery orifice was anastomosed to the recipient's descending aorta. The perioperative mortality rate was high, with only 8 of 28 pigs alive on the 11th postoperative day. Little can be concluded from this study regarding the effect of bronchial artery revascularization except that the anatomy of the pig allows easy identification and preservation of the left bronchial arteries. In 1991, Laks and colleagues [9] published a method for bronchial artery revascularization tested in 5 baboons. Three had double-lung transplantation; I had a single left lung and one had a single right lung transplanted. A pouch of descending aorta from the proximal to the left subclavian artery to the level of the pulmonary hilum (holding the bronchial artery branches) was prepared and anastomosed to the recipient's left subclavian artery or ascending aorta. Angiograms of the 3 surviving baboons (1 double, 1 single right, i single left lung) performed after 14 days and postmortem examinations after 22, 30, and 30 days demonstrated patent anastomoses, no pouch thrombi, and normal healing of the tracheal and bronchial anastomoses. The effect of direct bronchial artery revascularization on the airway mucosal blood flow was investigated by
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Aoki and colleagues [37] in 1991. In a model of modified unilateral lung transplantation in pigs, the mucosal blood flow was measured at the donor main carina and at the upper lobe carina using laser Doppler velocimetry and radioisotope studies with radiolabeled erythrocytes. The mucosal blood flow was significantly higher in animals with than in those without bronchial artery revascularization. Fujino and co-workers [81 published a similar study in 1992. In 23 mongrel dogs, radical hilar stripping and transection of the right main bronchus and the right bronchial artery were performed. The right main bronchus was immediately reanastomosed. Group A had the bronchial artery ligated. In group B, the bronchial artery was anastomosed to the right internal thoracic artery using microsurgical technique. The effect of revascularization was estimated by laser Doppler velocimetry. The peripheral bronchial mucosal blood flow immediately after operation had diminished to 59% of the original in group A and to 78% in group B. A statistically significant difference in mucosal blood flow between the groups continued on days 1, 3, 5, and 7. From day 10 on, there was no difference. Two dogs in group B were found to have occlusion of the anastomosis when sacrified after 14 days. No airway complications were observed in either group. Clinical
Experience
In 1964, Meshalkin and co-workers [38] reported eight single pulmonary autotransplantations (five left, three right). The transplantations were performed as an experimental treatment of asthma. Two of these patients died of bronchial disruption and bleeding from bronchopulmonary artery fistulas. In 1970, Mills and colleagues [36] polled the 18 investigators responsible for the first 25 human lung allotransplantations registered in the International Transplant Registry in Chicago. Seventeen investigators returned the questionnaire and reported 13 instances of bronchial complications, including ulceration, necrosis, and disruption. In 1973, Haglin and associates [10] reported a case of direct left bronchial artery revascularization of a left lung using a method almost the same as described earlier by Mills and colleagues [36]. In addition, the right lung was transplanted without bronchial revascularization after an ischemic time of 11 hours. The patient died of septicemia and pulmonary insufficiency on the 11th postoperative day. At autopsy, the left (revascularized) bronchial wall remained viable, whereas the right (nonrevascularized) bronchial wall showed extensive necrosis. As mentioned earlier, Couraud and associates [11] were the first to publish a series of patients having en bloc double-lung transplantation with bronchial artery revascularization. Organ procurement was done according to the method described by Schreinemakers and colleagues [6]. Couraud and associates included a tracheal anastomosis. The bronchial artery revascularization was done with a saphenous vein graft from the
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recipient's ascending aorta to an aortic patch including the origin of the right intercostobronchial artery and, in addition in a few cases, one or more left bronchial arteries. The distal anastomosis of the s a p h e n o u s vein graft was done on a side table before introducing the donor lungs into the recipient. The proximal s a p h e n o u s vein to recipient aorta anastomosis was done at the end of the operation. It was stressed that dissection a r o u n d the carina and individual mobilization of the bronchial arteries should be a v o i d e d so as not to interfere with the bronchial blood supply. The additional ischemic time n e e d e d for p e r f o r m i n g the bronchial artery revascularization was estimated as 1 hour. The bronchial b l o o d s u p p l y was evaluated by r e p e a t e d endoscopic studies and in 7 patients by arter i o g r a p h y 2 weeks postoperatively. The a r t e r i o g r a p h y results showed an o p e n vein graft with visualization of bronchial arteries in 5 patients, w h e r e a s 2 s h o w e d t h r o m botic occlusion of the vein graft. N o r m a l tracheal healing was o b s e r v e d in all patients. O n e patient d i e d of gastrointestinal h e m o r r h a g e on day 30, a n d 1 died of a fulminant Pseudomonas aeruginosa p n e u m o n i a on day 35. Later in 1992, C o u r a u d and associates [39] enlarged their clinical experience b y 3 patients, 2 having en bloc double a n d I having right single lung transplantation. No patients h a d anastomosis healing p r o b l e m s or stenosis. In 2 of the additional patients, a r t e r i o g r a p h y results s h o w e d a functional s a p h e n o u s vein graft a n d visualization of the bronchial arteries. One patient d i e d of h e p a torenal failure on day 16. In 1993, Daly a n d c o l l e a g u e s [12] p u b l i s h e d the Harefield series of 8 patients who had nine en bloc d o u b l e - l u n g transplantations with bronchial artery revascularizafion. The m e t h o d of organ p r o c u r e m e n t was modified from those d e s c r i b e d previously [6, 9]. The bronchial arteries were identified and confirmed by probing. The largest vessel going in the direction of the carina was chosen for revascularization with the left internal m a m m a r y artery. The m a m m a r y to bronchial artery anastomosis was done at the end of the operation. The orifice of the bronchial artery was b r o u g h t into view by pulling on the proximal end of the donor aorta. Orifices in the donor d e s c e n d i n g aorta p r o d u c i n g backb l e e d i n g w e r e oversewn. The total a d d i t i o n a l time n e e d e d to p e r f o r m the bronchial artery revascularization was estimated to be 30 to 60 minutes, a n d the d o n o r organ ischemic time was p r o l o n g e d b y 20 to 22 minutes. The bronchial artery blood s u p p l y was evaluated b y r e p e a t e d bronchoscopic examinations, a n d a r t e r i o g r a p h y was p e r f o r m e d 12 days to 2 m o n t h s postoperatively. In 1 patient with angiographic evidence of bronchial artery occlusion, a large ulcer d e v e l o p e d in the tracheal anastomosis. In all other patients, the internal m a m m a r y artery graft was patent, with good bronchial artery perfusion a n d n o r m a l healing, including 1 patient who had r e t r a n s p l a n t a t i o n after 1 m o n t h because of p u l m o n a r y emboli. The internal m a m m a r y artery graft was chosen instead of a s a p h e n o u s vein graft b e c a u s e of expected better l o n g - t e r m patency. In 1994, Daly and colleagues [15] p u b l i s h e d the results
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of direct bronchial artery revascularization in 10 singlelung transplantations from the Mayo Clinic. The a d d i tional ischemic time for the revascularization p r o c e d u r e was e s t i m a t e d as 15 to 20 minutes. One patient d i e d perioperatively of d o n o r organ dysfunction. In the surviving 9 patients, a n g i o g r a p h y results d e m o n s t r a t e d excellent perfusion of the bronchial arteries in 7 a n d no perfusion in 2. Bronchial healing was excellent in all. These investigators d e m o n s t r a t e d that it is possible to p e r f o r m bronchial artery revascularization of two single lungs from the s a m e donor b y dividing the d o n o r aorta a n d the m e d i a s t i n a l tissue b e t w e e n two bronchial arteries. M c G r e g o r a n d co-workers [16], also in 1994, docum e n t e d 4 patients who had bronchial artery revascularization a m o n g the first 15 lung t r a n s p l a n t recipients at the Mayo Clinic having different p r o c e d u r e s for b r o n chial anastomosis protection. W e p r e s u m e that these 4 patients r e p r e s e n t part of the group of 10 patients p u b lished earlier [15]. In 1994, we p u b l i s h e d the results of our first 14 en bloc double lung t r a n s p l a n t a t i o n s with bronchial artery revascularization [13] using the left internal thoracic artery. The m e t h o d used was a modification of that d e s c r i b e d by Daly and colleagues [12[. O u r own experience with bronchial artery revascularization now includes 63 patients: 49 double lung, 5 single lung, and 9 heart lung transplantations. Preparation of the donor organs for revascularization a d d s a b o u t 15 to 20 m i n u t e s of ischemic time. On one occasion, we perf o r m e d bronchial artery revascularization of two single lungs from the s a m e d o n o r by dividing the block so that the bronchial arteries were p r e s e n t for both sides. O u r ambition is to achieve complete bronchial artery revascularization, ie, a n a s t o m o s e s to all identified bronchial arteries. W h e n m o r e than one artery is revascularized, one c o m m o n or sequential m a m m a r y a n a s t o m o s e s are performed. Each anastomosis takes about 10 m i n u t e s or less. After the block has b e e n introduced, the bronchial artery revascularization is p e r f o r m e d first. In en bloc d o u b l e lung transplantation, the left lung is h u n g backw a r d s over the heart, which gives excellent exposure of the bronchial artery o p e n i n g s in the d o n o r d e s c e n d i n g aorta. I m m e d i a t e bronchial reperfusion is b e g u n a n d m a i n t a i n e d during the rest of the procedure. W e have e n c o u n t e r e d anastomotic b l e e d i n g on three occasions. In one instance, the extra hemostatic sutures resulted in occlusion of the anastomosis. The p r o b l e m was diagnosed i m m e d i a t e l y b y arteriography. The patient u n d e r w e n t reoperation, and the bronchial artery revascularization was successfully reestablished. The arterial b l o o d s u p p l y of the bronchial tree is e v a l u a t e d by r e p e a t e d endoscopic and arteriographic studies. In the first double lung series, 10 of 12 patients s h o w e d successful revascularization at angiography, a n d excellent tracheal healing was observed. In 2 patients, the internal thoracic artery was open but there was no c o m m u n i c a t i o n to the bronchial arteries. Both patients experienced s u b m u c o s a l necrosis in the central bronchi and s u b s e q u e n t stenosis of the left m a i n bronchus; even-
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Table 1. Results of Bronchial Artery Revascularization in Lung Transplantation Study Location Bordeaux [11, 39] Harefield, London [12] Mayo Clinic [15] Copenhagen, Denmark [13] Copenhagen, after the first series
Number of Operations
Arteriography Performed a
Arteriography Not Performed
10 DLTX 1 SLTX 8 DLTX 10 SLTX 14 DLTX 35 DLTXb 5 SLTX 9 HLTX
8 [6 (0)•2 (0)] 1 [1 (0)/0 (0)] 8 [7 (0)/1 (0)] 9 [7 (0)/2 (0)] 12 [10 (0)/2 (2)] 31 [30b(0)/1 (1)] 4 [4 (0)/0 (0)l 6 [6 (0)/0 (0)]
0 (0) 0 (0) 1 (0) 2 (0) 5 (1) 1 (0) 3 (0)
.7 N u m b e r [successful/failed]. Parentheses indicate severe bronchial healing problems. after i m m e d i a t e reoperation.
b In 1 patient with primary' failed grafting, successful grafting
DLTX
SLTX - single-lung transplantation.
en bloc d o u b l e - l u n g transplantation;
H[_TX
h e a r t - l u n g transplantation;
tually a left-side p n e u m o n e c t o m y had to be performed. Early survival was 100°A,. O u r results show that of the 63 patients in w h o m bronchial artery revascularization was attempted, 53 had a n g i o g r a p h y p e r f o r m e d 1 day to 5 m o n t h s p o s t o p e r a tively, showing successful revascularization in 50 (in 1 after reoperation for anastomotic occlusion) and failed revascularization in 3 (including the 2 patients in the early series). Nine of 10 patients not examined by arter i o g r a p h y for various reasons h a d normal bronchial healing, w h e r e a s 1 had poor bronchial healing, suggesting failed revascularization. Sixteen patients have been reexa m i n e d after 2 years, showing 100% long-term patency of the bronchial artery revascularization. Using the KaplanMeier m e t h o d (and the International Society for Heart and Lung Transplantation working formulation [40]), the proportion of patients having double lung transplantation with bronchial artery revascularization who were free from bronchiolitis obliterans s y n d r o m e after 1, 2, a n d 3 years was, respectively, 85%, 82%, a n d 67%. O n e of 6 patients having single lung transplantation with bronchial artery revascularization h a d bronchiolitis obliterans s y n d r o m e after 12 months. None of our 9 patients having heart lung transplantation with bronchial artery revascularization have so far d e v e l o p e d bronchiolitis obliterans syndrome. Table 1 s u m m a r i z e s the p u b l i s h e d results of lung transplantation with bronchial artery revascularization. Comment Because of lack of interest a n d methodologic p r o b l e m s due to the a w k w a r d location of the bronchial arteries, only a few facts about these arteries have b e e n established from humans. From the work p e r f o r m e d on exp e r i m e n t a l animals by several authors, as described earlier, we have l e a r n e d that the bronchial arteries seem to play an i m p o r t a n t role in the response of the lungs and airways to m a n y physiologic and pathologic conditions. It is difficult not to be i m p r e s s e d by the high flow a n d the reactivity of the bronchial arteries. The possible impact of direct bronchial artery revascularization in lung transplantation is interesting. In a g r e e m e n t with the experi-
mental studies [30, 31], we have been i m p r e s s e d by the absence of e d e m a early after operation in the majority of the lungs t r a n s p l a n t e d with bronchial artery revascularization. W e expect the revascularized lungs to be m o r e resistant to infection, as indicated b y the study of lung abscesses in sheep [32]. That revascularization might have an i m p a c t on obliterative bronchiolitis s y n d r o m e r e m a i n s speculative. The evidence against such a relation, however, [34] is not impressive. The e x p e r i m e n t s in this study [34] were of autotransplantation, a n d the authors did not d o c u m e n t that airway ischemia was actually p r e s e n t after the operation. It m a y f u r t h e r m o r e be a r g u e d that the 3.5 m o n t h s of follow-up m a y be too short to find any signs of obliterative bronchiolitis. O u r interpretation of available studies is that it s e e m s unlikely that the bronchial arteries can be neglected d u r i n g t r a n s p l a n t a t i o n without adverse consequences, ie, the recipient will have lungs with a severed physiologic response to pathologic conditions as a result of the absence of the bronchial artery blood supply. In the early era of lung transplantation, healing of the airway anastomosis was a major concern. The m e t h o d used for anastomotic protection a n d airway revascularization in the first successful h u m a n lung t r a n s p l a n t a tions, single as well as en bloc double, was to w r a p the airway anastomosis with o m e n t u m [41]. W r a p p i n g the anastomosis with o m e n t u m has b e e n shown to enhance early ingrowth of vessels a r o u n d the airway anastomosis [42]. For single-lung transplantation, this m e t h o d prod u c e d g o o d early results, w h e r e a s double lung transplantation p e r f o r m e d en bloc with a tracheal anastomosis was still associated with a high incidence of tracheal anastomosis a n d bronchial p r o b l e m s [43]. Based on these o b s e r v a t i o n s - - s u g g e s t i n g that the i n t r a p u l m o n a r y part of the bronchial tree is less d e p e n d e n t on the arterial blood s u p p l y than are the main bronchi and t r a c h e a - - t h e technique of p e r f o r m i n g d o u b l e - l u n g t r a n s p l a n t a t i o n as sequential bilateral lung t r a n s p l a n t a t i o n was i n t r o d u c e d [44[. This m e t h o d has been associated with a low rate of bronchial complications a n d good early results [45]. With i m p r o v e d technique, the incidence of airway p r o b l e m s today is very, low, even without w r a p p i n g the bronchial
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anastomoses. This m e t h o d is, however, associated with a p r o l o n g e d ischemic time, especially for the second lung. A l t h o u g h the logical m e t h o d to prevent bronchial and lung i s c h e m i a - - d i r e c t bronchial artery revascularizat i o n - - w a s i n t r o d u c e d experimentally by Metras already in 1950 [5] a n d clinically b y C o u r a u d a n d associates [11, 39] in 1992, the Harefield group in 1993 [12], the Mayo Clinic in 1994 I15[, a n d the C o p e n h a g e n group in 1994 [13, 141, most lung t r a n s p l a n t surgeons have not yet decided to use the method. The main a r g u m e n t s for not performing bronchial artery, revascularization have b e e n as follows: (1) good early results without bronchial artery revascularization, (2) lack of evidence of the effectiveness of the method, (3) p r o l o n g e d operation time a n d prolonged ischemic time, and (4) increased risk of bleeding. Until this publication, 33 en bloc d o u b l e - l u n g a n d 11 single-lung transplantations with bronchial artery, revascularization have been published. Concerning early results and effectiveness of the method, 28 of 33 r e p o r t e d patients with bronchial artery revascularization d u r i n g en bloc double lung t r a n s p l a n t a t i o n s were s t u d i e d by angiography. Twenty-three showed good revascularization of the bronchial arteries, a n d none of these patients h a d airwav healing problems. In 5, the bronchial artery revascularization h a d failed; 3 of these h a d airway healing p r o b l e m s including necrosis, and 2 h a d s u b s e q u e n t d e v e l o p m e n t of severe bronchial stenosis. As m e n t i o n e d earlier, we can a d d 31 en bloc d o u b l e lung transplantation patients, in w h o m a n g i o g r a p h y verified successful revascularization in 30 a n d failure in 1. This failure was in a r e t r a n s p l a n t a t i o n patient who d i e d of p n e u m o n i a 30 days postoperatively. Ten of the 11 r e p o r t e d patients with single lung transplantations were checked by arteriography. Two revascularization p r o c e d u r e s h a d failed. All patients h e a l e d their bronchial a n a s t o m o s e s without complications. W e can a d d five single-lung procedures, with successful revascularization verified by a n g i o g r a p h y in four. In the last patient, a n g i o g r a p h y was not performed. All patients h e a l e d without airway complications. We also have a d d e d nine bronchial artery revascularizations in heart lung transplantations. Successful revascularization was verified b y a r t e r i o g r a p h y in six. Arter i o g r a p h y was not p e r f o r m e d in the r e m a i n i n g three. Tracheal anastomosis healing was n o r m a l in all. Prolongation of the ischemic time r e q u i r e d for performing the bronchial artery revascularization has b e e n 20 to 60 minutes, d e p e n d i n g on the m e t h o d used. With our method, the ischemic time is shortened rather than p r o l o n g e d because early bronchial artery reperfusion is allowed. W h e n calculating the ischemic time involved in performing bronchial artery revascularization, it is necessary to c o m p a r e the time used for this p r o c e d u r e with the increased surgical t r a u m a and the potential risk of abd o m i n a l complications involved with w r a p p i n g the anastomosis with o m e n t u m . Bilateral sequential lung transplantation using a clamshell incision takes longer than en bloc d o u b l e - l u n g t r a n s p l a n t a t i o n including bronchial artery revascularization. Postoperative b l e e d i n g as a consequence of bronchial
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artery revascularization has been rare, and in all instances has b e e n controllable.
Conclusion A l t h o u g h the initial series of patients u n d e r g o i n g lung transplantation with bronchial artery revascularization have b e e n s m a l l the results have b e e n good, a n d the correlation b e t w e e n healing of the airway anastomosis and the function of the bronchial artery revascularization has b e e n convincing. This m e t h o d is the obvious choice for achieving good healing of the airway anastomosis in en bloc d o u b l e - l u n g transplantation. W e conclude that reliable bronchial artery revascularization is possible. W h e n using the m a m m a r y artery as conduit, long-term patency can be expected. However, airway healing is not the only issue. Longterm results after lung t r a n s p l a n t a t i o n are still not convincing, and the early results after a t t e m p t e d direct bronchial artery revascularization are definitely g o o d enough to justify, its use in large series to allow studies of long-term results.
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