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Heart and unilateral lung transplantation in the dog
Volume 91,
April 1986
Number 4
THORACIC AND CARDIOVASCULAR SURGERY The Journal
J
THORAC CARDIOVASC SURG
of
91:485-489, 1986
Original Communications
Heart and unilateral lung transplantation in the dog A technique is presented fortransplantation of theheart and leftlung enbloc inthedog. In contrast to the erratic respiratory pattern that occurs in subprimate animals after total cardiopulmonary denervation, preservation of innervation to the native right lung results in a normal respiratory pattern in the dogand has allowed survival of one animal for 68 days. This model is proposed as potentiaUy suitable for physiologic and immunologic studies of cardiopulmonary transplantation in the dog.
Akira Kawaguchi, M.D. (by invitation), Paul D. Hirsh, M.D. (by invitation), Timothy C. Wolfgang, M.D. (by invitation), A. Scott Mills, M.D. (by invitation), and Richard R. Lower, M.D., Richmond, Va.
Long-term laboratory studies of heart-lung transplantation have been few because total cardiopulmonary denervation seems to preclude prolonged survival in animals lower than primates." It has been suggested that retaining a part of the pulmonary innervation would preserve the normal respiratory pattern.' Therefore, a new procedure has been devised to study heart-lung transplantation in the dog. It involvesorthotopic grafting of the heart and left lung, which preserves innervation of the autologous right lung, to enhance long-term survival. Because even human transplant recipients may not be totally free from the problems derived from complete respiratory denervation, the present technique might prove useful in selected patients. From the Divisions of Cardiothoracic Surgery, Cardiology, and Pathology, Medical College of Virginia, Richmond, Va. Read at the Sixty-fifth Annual Meeting of The American Association for Thoracic Surgery, New Orleans, La., April 29-May I,
Ins.
Address for reprints: Richard R. Lower, M.D., P.O. Box 68, MeV Station, Richmond, Va. 23298.
Methods A recipient mongrel dog weighing 18 to 25 kg is anesthetized with intravenous pentobarbital (30 mgjkg) and prepared for cardiopulmonary bypass as previously described.' The left lung is excised through a left thoracotomy and a broadly based pericardiaI pedicle flap is created without detaching the phrenic nerve from the pericardium (Fig. 1, a). Care is taken to leave the main bronchus as long as possible with minimal proximal dissection of the pleura. The heart and left lung are procured from a size-matched donor dog with cardioplegic protection. The pulmonary artery and superior vena cava are ligated. The left main bronchus is trimmed to leave one cartilage proximal to the bifurcation to the superior lobe. The left atrium is entered along the junction with the right pulmonary veins and the right atrium is opened from the inferior vena cava to the appendage, the sinus node being avoided (Fig. 1, b). A cardiectomy is performed on the recipient, now stabilized on bypass. Enough atrial and arterial tissue is left for later anastomosis (Fig. 1, c). The graft is implanted by first approximating the left
485
4 8 6 Kawaguchi et al.
The Journal of Thoracic and Cardiovascular Surgery
Fig. 1. The operative technique for transplantation of the heart and left lung. See text for details. a, Left pneumonectomy in the recipient and preparation of the pericardial pedicle. b, The donor heart and left lung have been prepared. c, The bronchial anastomosis. d, Coverage of the bronchial anastomosis with the pericardial pedicle. e. The left atrial anastomosis after the heart had been passed under the phrenic tvsvc.f, Left atrial, right atrial, and aortic anastomoses completed and pulmonary artery anastomosis carried end to side.
main bronchus with interrupted sutures. The anastomosis is wrapped with pericardium by inverting the preserved pedicle back around the bronchus (Fig. 1, d). Several anchoring stitches are placed to reinforce the buttress and prevent dislocation. The donor heart is passed under the phrenic nerve into the pericardial well
and the remaining anastomoses are performed in the order of left and right atria, aorta, and pulmonary artery with continuous sutures (Fig. 1, e). The graft pulmonary trunk is incised and anastomosed to that of the recipient in an end-to-side fashion (Fig. 1, f). The heart is "debubbled,' defibrillated, and allowed to beat under
Volume 91 Number 4 April, 1986
Heart-lung transplantation
487
decompression with inotropic support until ready to take over the circulation. The chest is closed in layers with a tube left for drainage. The dog is removed from the respirator as soon as spontaneous respiration occurs. Surviving animals are immunosuppressed with cyclosporine alone (20 rug/kg) for the initial 2 weeks and low-dose steroid is added thereafter. Surviving animals are monitored with electrocardiograms twice daily and chemical profiles, blood cell counts, chest roentgenograms, and arterial blood gas analyses twice weekly during the quiescent period. When rejection or infection is suspected, these tests are repeated more frequently and intravenous methylprednisolone is used for antirejection therapy. Results The survival and causes of failure are listed in Table I.
All animals were successfully weaned from cardiopulmonary bypass with an average graft ischemia time of 148 ± 19 minutes. Because a normal respiratory pattern resumed immediately in all dogs, respiratory support could be terminated within 1 hour of chest closure. Intractable bleeding was responsible for the failures that occurred within the first 24 hours. Poor myocardial protection, graft size mismatch, traumatic manipulation of the graft lung, incomplete bronchial hemostasis, and bleeding diathesis continued to complicate the intermediate course up to 2 days. In some experiments phrenic nerve injury led to graft lung atelectasis and consequent respiratory insufficiency, which prompted a change in the procedure to preserve the phrenic nerve on the pericardium. That two survivors died of bronchial anastomotic disruption at 3 days and 4 days prompted us to reinforce the bronchial anastomosis with a pericardial wrap. Thus, modifications have been made to reach the procedure described herein, and one animal survived for 68 days after this operation. This 68 day survivor had a normal exercise tolerance and a normal respiratory response to exercise. After initial full recovery, the dog underwent a period of illness with reduced oxygenation during the second postoperative week. When compared to the autologous right lung, the graft left lung had a subtle but diffuse hazy density on roentgenograms. The episode was interpreted as "reimplantation response" when it subsided spontaneously. Because of apathy, coughing, tachypnea, and reduced arterial oxygenation, two episodes of acute rejection were diagnosed in the third and fifth weeks and were successfully reversed with intravenous methylprednisolone without detectable residual by subsequent endomyocardial biopsy. Electrocardiograms revealed occa-
Fig. 2. Chest x-ray film of the recipient dog.
sional atrial and ventricular premature beats and reduced total QRS voltages during the presumed episodes of rejection. Although biopsy was not done during these episodes, endomyocardial arterial blood gases appeared to be a sensitive indication of graft dysfunction by reduction in oxygen and carbon dioxide tensions. Even during the suspected rejection episodes, chest roentgenograms remained clear bilaterally (Fig. 2). The hemodynamic data obtained on the first postoperative day showed normal right heart pressures. Pulmonary angiograms demonstrated decreased blood flow to the superior lobe of the allografted lung. This observation was confirmed by a radionuclide pulmonary perfusion study on postoperative day 46 (Fig. 3). The dog died of bilateral bronchopneumonia on postoperative day 68 despite intensive antibiotic therapy and reduction of immunosuppressive therapy. At autopsy all lobes of both lungs showed patchy consolidation with various degrees and stages of bronchopneumonia. The severe inflammatory reaction precluded any assessment of rejection. There was partial torsion of the left upper lobe caused by a chest wall adhesion, which explained the abnormalities seen earlier on the perfusion scan and arteriogram. The bronchial anastomosis with its pericardial wrap was completely
The Journal of Thoracic and Cardiovascular Surgery
4 8 8 Kawaguchi et al.
Fig. 3. Pulmonary angiography and technesium perfusion study show reduced flow to the left upper lung field.
Table I. Results of heart and left lung transplantation in the dog Animal No.
CPB (min)
Ischemia (min)
Survival (hr)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mean SD
203 180 185 218 162
168 177 170 193 157 160 141 149 146 133 117 134 132 137 135 135 135 148 19
25 26 26 4 days 18 2 days 17 20 34 28 29 27 28 2 days 3 days 31 68 days
I7l 164 183 184 157 121 165 133 158 203 152 147 170 25
Cause offailure LV failure, pulmonary edema Bleeding, filaria is Bleeding, atelectasis Bronchial disruption Bleeding, filariasis Atelectasis, bleeding Bleeding, filariasis Bleeding, filariasis LV failure Bleeding, filariasis Seizure Atelectasis, phrenic palsy Atelectasis, size mismatch Atelectasis, phrenic palsy Bronchial disruption Aspiration Pneumonia, filariasis
Legend; CPB, Cardiopulmonary bypass. LV, Left ventricular. SD. Standard deviation.
healed without stenosis (Fig. 4). Histologic sections of the heart were normal except for two microscopic foci of myocytolysis associated with localized mononuclear cell infiltrate in the interventricular septum. Discussion This preliminary investigation of heart and unilateral lung transplantation in the dog suggests that this model may be suitable for further studies of the physiologic and immunologic problems in cardiopulmonary transplantation. Preserving innervation to the native lung clearly results in resumption of a normal respiratory
pattern by the recipient dog. This response is in marked contrast to that previously seen in subprimate animals with total cardiopulmonary denervation, wherein erratic respiratory patterns are thought to limit survival. The previous longest survival of a subprimate animal after cardiopulmonary transplantation was reported by Grinnan and associates" and was 10 days in one dog. The survival of one animal in this study for 68 days illustrates that prolonged survival is indeed possible in the dog if partial innervation is retained. Retention of one native lung also provides a useful control for investigating the reimplantation response and
Volume 91 Number 4 April, 1986
Heart-lung transplantation
48 9
autonomic reinnervation of the cardiac graft. Sympathetic and parasympathetic reinnervation has been irrefutably demonstrated in dogs several months after either autotransplantation or allotransplantation of the heart," whereas reinnervation in human beings has never been documented even years after heart transplantation. It will be of interest to determine whether this species difference also applies to lung denervation and whether in either human or in canine survivors pulmonary autonomic reinnervation occurs. REFERENCES
Fig. 4. The bronchial anastomosis at autopsy on day 68 shows excellent healing.
2 3 4
rejection, much as in single lung transplantation, while permitting comparison of various immunosuppressive regimens on heart and lung transplantation in the same recipient. The presence of the native lung may also provide important support for the animal during episodes of severe rejection or reimplantation response and thereby may enhance survival. Thus, the canine model, which is less expensive than the primate, may be more useful for laboratory studies of cardiopulmonary transplantation than previously concluded. Management of the bronchial anastomosis that evolved in this study involves protection by a pericardial pedicle. It would appear that this maneuver may reduce the risk of bronchial disruption, which has been a major problem in other studies," If sufficient numbers of long-term survivors can be achieved, studies of coronary to bronchial collaterals'? in this model may be of interest. In the human and subhuman primate experience with total cardiopulmonary transplantation, the long range effects of total cardiopulmonary denervation have not been completely studied. 11, 12 The question may be raised concerning the possible clinical application of this procedure, since it would be beset with the same disadvantages as single lung transplantation, namely ventilationperfusion mismatch and cross contamination. Whether there are instances in which these disadvantages would beoutweighed by the advantage of retained innervation and lack of immunologic damage to the native lung is conjectural. One of the mysteries that remain in cardiac transplantation is the species difference with regard to
5
6
7
8
9
10
11
12 13
Neptune WB, Cookson BA, Barley CP, Appler R, Rajkowski F: Complete homologous heart transplantation. Arch Surg 66:174-178,1953 Webb WR, Howard HS: Cardia-pulmonary transplantation. Surg Forum 8:313-319,1958 Blanco G, Adam A, Rodriguez-Perez 0, Fernandez A: Arch Surg 76:20-23, 1958 Lower RR, Stofer RC, Hurley EJ, Shumway NE: Complete homograft replacement of the heart and both lungs, Surgery 50:842-845, 1961 Nakae S, Webb WR, Theodorides T, Sugg WL: Respiratory function following cardiopulmonary denervation in dog, cat, and monkey. Surg Gynecol Obstet 125:12851292,1967 Grinnan GLB, Graham WH, Childs JW, Lower RR: Cardiopulmonary homotransplantation. J THORAC CAR. D10YASC SURG 60:609-615, 1970 Castaneda AR, Arnar 0, Schmidt-Habelbaum P, Moller JH, Zamora R: Cardiopulmonary autotransplantation in primates, J Cardiovasc Surg 37:523-531, 1972 Reitz BA, Burton NA, Jamieson SW, Bieber CP, Pennock JL, Stinson EB, Shumway NE: Heart and lung transplantation. Autotransplantation and allotransplantation in primates with extended survival. J THoRAc CARDIOYASC SURG 80:360-371, 1980 Veith FJ, Kamholz SL, Mollenkopf FP, Montefusco CM: Lung transplantation 1983. Transplantation 35:271-278, 1983 Guthaner OF, Wexler L, Sadeghi AM, Blank NE, Reitz BA: Revascularization of tracheal anastomosis following heart-lung transplantation. Invest Radiol 18:500-503, 1983 Jamieson SW, Stinson EB, Oyer PE, Reitz BA, Baldwin J, Modry 0, Dawkins K, Theodore J, Hunt S, Shumway NE: Heart-lung transplantation for irreversible pulmonary hypertension. Ann Thorac Surg 38:554-562, 1984 Jamieson SW: Recent developments in heart and heartlung transplantation. Transplant Proc 17:199-203, 1985 Kontos HA, Thames MD, Lower RR: Responses to electrical and reflex autonomic stimulation in dogs with cardiac transplantation before and after reinnervation. J THoRAc CARDlOYASC SURG 59:382-392, 1970
April 1986
Number 4
THORACIC AND CARDIOVASCULAR SURGERY The Journal
J
THORAC CARDIOVASC SURG
of
91:485-489, 1986
Original Communications
Heart and unilateral lung transplantation in the dog A technique is presented fortransplantation of theheart and leftlung enbloc inthedog. In contrast to the erratic respiratory pattern that occurs in subprimate animals after total cardiopulmonary denervation, preservation of innervation to the native right lung results in a normal respiratory pattern in the dogand has allowed survival of one animal for 68 days. This model is proposed as potentiaUy suitable for physiologic and immunologic studies of cardiopulmonary transplantation in the dog.
Akira Kawaguchi, M.D. (by invitation), Paul D. Hirsh, M.D. (by invitation), Timothy C. Wolfgang, M.D. (by invitation), A. Scott Mills, M.D. (by invitation), and Richard R. Lower, M.D., Richmond, Va.
Long-term laboratory studies of heart-lung transplantation have been few because total cardiopulmonary denervation seems to preclude prolonged survival in animals lower than primates." It has been suggested that retaining a part of the pulmonary innervation would preserve the normal respiratory pattern.' Therefore, a new procedure has been devised to study heart-lung transplantation in the dog. It involvesorthotopic grafting of the heart and left lung, which preserves innervation of the autologous right lung, to enhance long-term survival. Because even human transplant recipients may not be totally free from the problems derived from complete respiratory denervation, the present technique might prove useful in selected patients. From the Divisions of Cardiothoracic Surgery, Cardiology, and Pathology, Medical College of Virginia, Richmond, Va. Read at the Sixty-fifth Annual Meeting of The American Association for Thoracic Surgery, New Orleans, La., April 29-May I,
Ins.
Address for reprints: Richard R. Lower, M.D., P.O. Box 68, MeV Station, Richmond, Va. 23298.
Methods A recipient mongrel dog weighing 18 to 25 kg is anesthetized with intravenous pentobarbital (30 mgjkg) and prepared for cardiopulmonary bypass as previously described.' The left lung is excised through a left thoracotomy and a broadly based pericardiaI pedicle flap is created without detaching the phrenic nerve from the pericardium (Fig. 1, a). Care is taken to leave the main bronchus as long as possible with minimal proximal dissection of the pleura. The heart and left lung are procured from a size-matched donor dog with cardioplegic protection. The pulmonary artery and superior vena cava are ligated. The left main bronchus is trimmed to leave one cartilage proximal to the bifurcation to the superior lobe. The left atrium is entered along the junction with the right pulmonary veins and the right atrium is opened from the inferior vena cava to the appendage, the sinus node being avoided (Fig. 1, b). A cardiectomy is performed on the recipient, now stabilized on bypass. Enough atrial and arterial tissue is left for later anastomosis (Fig. 1, c). The graft is implanted by first approximating the left
485
4 8 6 Kawaguchi et al.
The Journal of Thoracic and Cardiovascular Surgery
Fig. 1. The operative technique for transplantation of the heart and left lung. See text for details. a, Left pneumonectomy in the recipient and preparation of the pericardial pedicle. b, The donor heart and left lung have been prepared. c, The bronchial anastomosis. d, Coverage of the bronchial anastomosis with the pericardial pedicle. e. The left atrial anastomosis after the heart had been passed under the phrenic tvsvc.f, Left atrial, right atrial, and aortic anastomoses completed and pulmonary artery anastomosis carried end to side.
main bronchus with interrupted sutures. The anastomosis is wrapped with pericardium by inverting the preserved pedicle back around the bronchus (Fig. 1, d). Several anchoring stitches are placed to reinforce the buttress and prevent dislocation. The donor heart is passed under the phrenic nerve into the pericardial well
and the remaining anastomoses are performed in the order of left and right atria, aorta, and pulmonary artery with continuous sutures (Fig. 1, e). The graft pulmonary trunk is incised and anastomosed to that of the recipient in an end-to-side fashion (Fig. 1, f). The heart is "debubbled,' defibrillated, and allowed to beat under
Volume 91 Number 4 April, 1986
Heart-lung transplantation
487
decompression with inotropic support until ready to take over the circulation. The chest is closed in layers with a tube left for drainage. The dog is removed from the respirator as soon as spontaneous respiration occurs. Surviving animals are immunosuppressed with cyclosporine alone (20 rug/kg) for the initial 2 weeks and low-dose steroid is added thereafter. Surviving animals are monitored with electrocardiograms twice daily and chemical profiles, blood cell counts, chest roentgenograms, and arterial blood gas analyses twice weekly during the quiescent period. When rejection or infection is suspected, these tests are repeated more frequently and intravenous methylprednisolone is used for antirejection therapy. Results The survival and causes of failure are listed in Table I.
All animals were successfully weaned from cardiopulmonary bypass with an average graft ischemia time of 148 ± 19 minutes. Because a normal respiratory pattern resumed immediately in all dogs, respiratory support could be terminated within 1 hour of chest closure. Intractable bleeding was responsible for the failures that occurred within the first 24 hours. Poor myocardial protection, graft size mismatch, traumatic manipulation of the graft lung, incomplete bronchial hemostasis, and bleeding diathesis continued to complicate the intermediate course up to 2 days. In some experiments phrenic nerve injury led to graft lung atelectasis and consequent respiratory insufficiency, which prompted a change in the procedure to preserve the phrenic nerve on the pericardium. That two survivors died of bronchial anastomotic disruption at 3 days and 4 days prompted us to reinforce the bronchial anastomosis with a pericardial wrap. Thus, modifications have been made to reach the procedure described herein, and one animal survived for 68 days after this operation. This 68 day survivor had a normal exercise tolerance and a normal respiratory response to exercise. After initial full recovery, the dog underwent a period of illness with reduced oxygenation during the second postoperative week. When compared to the autologous right lung, the graft left lung had a subtle but diffuse hazy density on roentgenograms. The episode was interpreted as "reimplantation response" when it subsided spontaneously. Because of apathy, coughing, tachypnea, and reduced arterial oxygenation, two episodes of acute rejection were diagnosed in the third and fifth weeks and were successfully reversed with intravenous methylprednisolone without detectable residual by subsequent endomyocardial biopsy. Electrocardiograms revealed occa-
Fig. 2. Chest x-ray film of the recipient dog.
sional atrial and ventricular premature beats and reduced total QRS voltages during the presumed episodes of rejection. Although biopsy was not done during these episodes, endomyocardial arterial blood gases appeared to be a sensitive indication of graft dysfunction by reduction in oxygen and carbon dioxide tensions. Even during the suspected rejection episodes, chest roentgenograms remained clear bilaterally (Fig. 2). The hemodynamic data obtained on the first postoperative day showed normal right heart pressures. Pulmonary angiograms demonstrated decreased blood flow to the superior lobe of the allografted lung. This observation was confirmed by a radionuclide pulmonary perfusion study on postoperative day 46 (Fig. 3). The dog died of bilateral bronchopneumonia on postoperative day 68 despite intensive antibiotic therapy and reduction of immunosuppressive therapy. At autopsy all lobes of both lungs showed patchy consolidation with various degrees and stages of bronchopneumonia. The severe inflammatory reaction precluded any assessment of rejection. There was partial torsion of the left upper lobe caused by a chest wall adhesion, which explained the abnormalities seen earlier on the perfusion scan and arteriogram. The bronchial anastomosis with its pericardial wrap was completely
The Journal of Thoracic and Cardiovascular Surgery
4 8 8 Kawaguchi et al.
Fig. 3. Pulmonary angiography and technesium perfusion study show reduced flow to the left upper lung field.
Table I. Results of heart and left lung transplantation in the dog Animal No.
CPB (min)
Ischemia (min)
Survival (hr)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mean SD
203 180 185 218 162
168 177 170 193 157 160 141 149 146 133 117 134 132 137 135 135 135 148 19
25 26 26 4 days 18 2 days 17 20 34 28 29 27 28 2 days 3 days 31 68 days
I7l 164 183 184 157 121 165 133 158 203 152 147 170 25
Cause offailure LV failure, pulmonary edema Bleeding, filaria is Bleeding, atelectasis Bronchial disruption Bleeding, filariasis Atelectasis, bleeding Bleeding, filariasis Bleeding, filariasis LV failure Bleeding, filariasis Seizure Atelectasis, phrenic palsy Atelectasis, size mismatch Atelectasis, phrenic palsy Bronchial disruption Aspiration Pneumonia, filariasis
Legend; CPB, Cardiopulmonary bypass. LV, Left ventricular. SD. Standard deviation.
healed without stenosis (Fig. 4). Histologic sections of the heart were normal except for two microscopic foci of myocytolysis associated with localized mononuclear cell infiltrate in the interventricular septum. Discussion This preliminary investigation of heart and unilateral lung transplantation in the dog suggests that this model may be suitable for further studies of the physiologic and immunologic problems in cardiopulmonary transplantation. Preserving innervation to the native lung clearly results in resumption of a normal respiratory
pattern by the recipient dog. This response is in marked contrast to that previously seen in subprimate animals with total cardiopulmonary denervation, wherein erratic respiratory patterns are thought to limit survival. The previous longest survival of a subprimate animal after cardiopulmonary transplantation was reported by Grinnan and associates" and was 10 days in one dog. The survival of one animal in this study for 68 days illustrates that prolonged survival is indeed possible in the dog if partial innervation is retained. Retention of one native lung also provides a useful control for investigating the reimplantation response and
Volume 91 Number 4 April, 1986
Heart-lung transplantation
48 9
autonomic reinnervation of the cardiac graft. Sympathetic and parasympathetic reinnervation has been irrefutably demonstrated in dogs several months after either autotransplantation or allotransplantation of the heart," whereas reinnervation in human beings has never been documented even years after heart transplantation. It will be of interest to determine whether this species difference also applies to lung denervation and whether in either human or in canine survivors pulmonary autonomic reinnervation occurs. REFERENCES
Fig. 4. The bronchial anastomosis at autopsy on day 68 shows excellent healing.
2 3 4
rejection, much as in single lung transplantation, while permitting comparison of various immunosuppressive regimens on heart and lung transplantation in the same recipient. The presence of the native lung may also provide important support for the animal during episodes of severe rejection or reimplantation response and thereby may enhance survival. Thus, the canine model, which is less expensive than the primate, may be more useful for laboratory studies of cardiopulmonary transplantation than previously concluded. Management of the bronchial anastomosis that evolved in this study involves protection by a pericardial pedicle. It would appear that this maneuver may reduce the risk of bronchial disruption, which has been a major problem in other studies," If sufficient numbers of long-term survivors can be achieved, studies of coronary to bronchial collaterals'? in this model may be of interest. In the human and subhuman primate experience with total cardiopulmonary transplantation, the long range effects of total cardiopulmonary denervation have not been completely studied. 11, 12 The question may be raised concerning the possible clinical application of this procedure, since it would be beset with the same disadvantages as single lung transplantation, namely ventilationperfusion mismatch and cross contamination. Whether there are instances in which these disadvantages would beoutweighed by the advantage of retained innervation and lack of immunologic damage to the native lung is conjectural. One of the mysteries that remain in cardiac transplantation is the species difference with regard to
5
6
7
8
9
10
11
12 13
Neptune WB, Cookson BA, Barley CP, Appler R, Rajkowski F: Complete homologous heart transplantation. Arch Surg 66:174-178,1953 Webb WR, Howard HS: Cardia-pulmonary transplantation. Surg Forum 8:313-319,1958 Blanco G, Adam A, Rodriguez-Perez 0, Fernandez A: Arch Surg 76:20-23, 1958 Lower RR, Stofer RC, Hurley EJ, Shumway NE: Complete homograft replacement of the heart and both lungs, Surgery 50:842-845, 1961 Nakae S, Webb WR, Theodorides T, Sugg WL: Respiratory function following cardiopulmonary denervation in dog, cat, and monkey. Surg Gynecol Obstet 125:12851292,1967 Grinnan GLB, Graham WH, Childs JW, Lower RR: Cardiopulmonary homotransplantation. J THORAC CAR. D10YASC SURG 60:609-615, 1970 Castaneda AR, Arnar 0, Schmidt-Habelbaum P, Moller JH, Zamora R: Cardiopulmonary autotransplantation in primates, J Cardiovasc Surg 37:523-531, 1972 Reitz BA, Burton NA, Jamieson SW, Bieber CP, Pennock JL, Stinson EB, Shumway NE: Heart and lung transplantation. Autotransplantation and allotransplantation in primates with extended survival. J THoRAc CARDIOYASC SURG 80:360-371, 1980 Veith FJ, Kamholz SL, Mollenkopf FP, Montefusco CM: Lung transplantation 1983. Transplantation 35:271-278, 1983 Guthaner OF, Wexler L, Sadeghi AM, Blank NE, Reitz BA: Revascularization of tracheal anastomosis following heart-lung transplantation. Invest Radiol 18:500-503, 1983 Jamieson SW, Stinson EB, Oyer PE, Reitz BA, Baldwin J, Modry 0, Dawkins K, Theodore J, Hunt S, Shumway NE: Heart-lung transplantation for irreversible pulmonary hypertension. Ann Thorac Surg 38:554-562, 1984 Jamieson SW: Recent developments in heart and heartlung transplantation. Transplant Proc 17:199-203, 1985 Kontos HA, Thames MD, Lower RR: Responses to electrical and reflex autonomic stimulation in dogs with cardiac transplantation before and after reinnervation. J THoRAc CARDlOYASC SURG 59:382-392, 1970