- Email: [email protected]
A new method for heterotopic cardiac transplantation in the dog
JOURNAL
OF SURGICAL
32, 150- 153 ( 1982)
RESEARCH
A New Method
for Heterotopic
Cardiac
STUART W. JAMIESON, M.B., NELSON A. BURTON, M.D., BRUCE AND NORMAN E. SHUMWAY,
Transplantation
in the Dog
B.S., FRCS, A. REITZ, M.D., M.D., PH.D.
The Department of Cardiovascular Surgery, Stanford University School of Medicine, Stanford University Medical Center. Stanford, California 94305 Submitted
for publication
September 3, 1981
A new method of heterotopic cardiac transplantation in the dog is described. Transplantation is performed in the thorax using the left innominate artery as an arterial supply with venous drainage into the superior vena cava. Over 200 dogs have undergone heterotopic cardiac transplantation using this technique, which we consider superior to previously described methods in the neck or abdomen. There was no operative mortality and minimal morbidity. Serial electrocardiographic recordings were found to be a more reliable measure of rejection since the donor heart could be compared as a ratio to the voltage of the recipient heart. Biopsy is possible by passage of a tlexible cardiac bioptome through the right internal jugular vein and then into the right ventricle of the donor heart. The unpleasant sequelae or heterotopic transplantation in the neck or abdomen (torsion, hematoma, ileus, intestinal obstruction, and intussusception) are avoided.
INTRODUCTION
Heterotopic cardiac transplantation in the dog has provided a useful method of studying cardiac allograft rejection and the use of immunosuppressive drugs. Carrel and Guthrie reported cardiac transplantation in dogs in 1905, anastomosing the external jugular vein and carotid artery of the recipient to the aorta, pulmonary artery, vena cava, and one of the pulmonary veins of the donor heart [ 11. Subsequently, Mann and associates simplified these techniques by simply anastomizing the aorta to the internal carotid artery and the pulmonary artery to the external jugular vein [2]. Further studies of heterotopic cardiac transplantation were performed by Demikhov who devised a variety of methods for heterotopic cardiac transplantation including intrathoracic locations, such that the donor heart supported part or the whole of the recipient circulation [3]. In this institution both orthotopic and heterotopic transplant models have been studied extensively. The heterotopic cardiac transplant model has the advantage of minimal operative mortality and decreased cost, al0022-4804/82/020150-04$01.00/O Copyri&t 0 1982 by Acdanic All+lltSOtrspodvaiaill~yf~rosncd
Res
he.
though with the marked disadvantage that it does not support the circulation. This is probably not relevant in studies directed toward allograft histopathology and the modification of graft rejection using drugs. The two commonly used sites for heterotopic transplantation have been the neck and the abdomen. In the neck, the donor heart must be small in order to be accomodated within the subcutaneous tissue. Larger hearts in this location interfere with respiration and swallowing. Torsion may result because of the loose surrounding tissue and draining hematomas are common. Transplantation in the abdomen using the abdominal aorta as the arterial supply and inferior vena cava as the venous return results in disturbance of intraabdominal contents, with postoperative ileus, intestinal obstruction, and occasionally intussusception. This latter complication approaches 10% in most series and became nearly 100% in dogs that received preoperative total lymphoid irradiation for immunosuppressive purposes. For these reasons, alternative sites were sought. The technique which has proved most satisfactory is that of intrathoracic heterotopic transplantation. 150
JAMIESON
ET AL.: HETEROTOPIC
This procedure is quickly and easily performed with uniform survival and minimal morbidity. This report documents the operative method and its advantages for cardiac transplantation research. MATERIALS
Animals. Outbred mongrel dogs weighing between 12 and 20 kg were matched only for we!ght. Both dogs were anesthetized with intravenous sodium pentobarbital (26 mg/ kg) and ventilated through an endotracheal tube using a Bird pressure-cycled respirator and an FiOz of 50%. Operative technique. The chest of the recipient dog is entered through a left thoraRT. INNOMINATE
\
V.
I
A.
LT. INNOMINATE
I I
151
cotomy in the third intercostal space. The left innominate artery is exposed and the left vagus nerve is displaced anteriorly. The superior vena cara is dissected free by crossing the anterior mediastinum, protecting the right phrenic nerve which lies on its rightlateral aspect. The pericardium is not entered and the azygos vein is gently mobilized, but not divided. The exposure is shown in Fig. 1. A left thoracotomy is also made in the donor dog, entering the fifth intercostal space. Heparin is administered (3 mg/kg) and the donor superior vena cava and azygos veins are divided. The inferior vena cava is ligated at the diaphragm and divided proximally. The aorta and pulmonary artery are
AND METHODS
SUPERIOR INTERCOSTAL
CARDIAC TRANSPLANTATION
A.
LT. VAGUS N.
FIG. 1. Left tharaodany incision with subsequent exposure of the great vesse.lsof the recipient. Sites ofinckiomareshom.
152
JOURNAL OF SURGICAL RESEARCH: VOL. 32, NO. 2, FEBRUARY
1982
RECIPIENT LT. INNOMINATE A.
RIGHT ATRIUM
FIG. 2. (A) The pulmonary artery anastomcsis is constructed first, commencing posteriorly. The donor pulmonary artery is cut short to avoid kinking. (B) The donor aorta is anastomosed to the recipient left innominate artery.
then divided at the pericardial reflection. With the heart elevated, all the pulmonary veins are then tied “en masse” and divided. The heart is then placed in cold saline (4°C) and the aorta and pulmonary artery dissected free by electrocautery. The pulmonary artery is cut within 3 mm of the pulmonary valve commissures. An atria1 septal defect is made by opening the foramen ovale through the inferior vena cava. Following this, the inferior vena cava is closed with a ligature. A side biting vascular clamp is placed on the superior vena cava as shown in Fig. 2. A longitudinal incision is made in this vessel and the pulmonary artery sewn end-to-side
with 4-O Prolene using a continuous technique. Kinking of the pulmonary artery is prevented by its shortened length. After completion of this anastomosis a second clamp is placed on the left innominate artery and the donor aorta is sutured end-to-side to this vessel. Following completion of the anastomosis,both venous and arterial clamps are removed. The heart generally resumes normal sinus rhythm spontaneously; however, direct current shock may sometimes be necessary to reverse fibrillation. The recipient animal is not heparinized and bleeding is minimal. The completed operation is shown in Fig. 3. The apex of the left lung can be fully
JAMIESON
ET AL.: HETEROTOPIC
CARDIAC TRANSPLANTATION
153
AORTA
LEFT LUNG
FIG. 3. The position of the transplanted heart following completion of the anastomosis. In this position it does not compromise normal function of the recipient heart or left lung.
inflated and is not compromised by the position of the donor heart. The chest is then closed routinely with a single drainage tube. After awakening from anesthesia and resuming spontaneous respiration, the animal is extubated and the chest tube removed. Dogs tolerate thoracotomy well and are generally walking and drinking on the evening of surgery. DISCUSSION
This paper describes a method of heterotopic cardiac transplantation that we have found to be quickly and easily performed, and which carries minimal morbidity. The technique has several specific advantages over heterotopic transplant procedures in the neck or abdomen. Intraabdominal problems, including intussusception and intestinal obstruction, are avoided. Serial electrocardiographic recordings are a more reliable measure of allograft rejection inasmuch as the donor heart can be compared as a ratio to the total voltage of the recipient heart, and
thus factors other than rejection that affect total QRS voltage (such as fluid overload, pneumonia, increased chest wall impedance) are not confused with rejection. The donor heart may be biopsied by passageof the flexible cardiac bioptome under fluoroscopic control from the right internal jugular vein, through the superior vena cava, to the interior of the donor right ventricle. Biopsies can also be obtained from the recipient heart for comparison. We have used this method in more than 200 dogs for the study of various programs of immunosuppression, and consider it to be superior to previously described techniques. REFERENCES 1. Carrel, A., and Guthrie, C. C. The transplantation of veins and organs. Amer. J. Med. 10: 1101, 1905. 2. Mann, F. C., Priestly, J. R., Markowitz, J., and Yates, W. M. Transplantation of the intact mammalian heart. Arch. Surg. 26: 219, 1933. 3. Demikhov, V. P. Experimental Transplantation of Vital Organs (B. Haigh, trans.). Plenum, New York, 1962.
OF SURGICAL
32, 150- 153 ( 1982)
RESEARCH
A New Method
for Heterotopic
Cardiac
STUART W. JAMIESON, M.B., NELSON A. BURTON, M.D., BRUCE AND NORMAN E. SHUMWAY,
Transplantation
in the Dog
B.S., FRCS, A. REITZ, M.D., M.D., PH.D.
The Department of Cardiovascular Surgery, Stanford University School of Medicine, Stanford University Medical Center. Stanford, California 94305 Submitted
for publication
September 3, 1981
A new method of heterotopic cardiac transplantation in the dog is described. Transplantation is performed in the thorax using the left innominate artery as an arterial supply with venous drainage into the superior vena cava. Over 200 dogs have undergone heterotopic cardiac transplantation using this technique, which we consider superior to previously described methods in the neck or abdomen. There was no operative mortality and minimal morbidity. Serial electrocardiographic recordings were found to be a more reliable measure of rejection since the donor heart could be compared as a ratio to the voltage of the recipient heart. Biopsy is possible by passage of a tlexible cardiac bioptome through the right internal jugular vein and then into the right ventricle of the donor heart. The unpleasant sequelae or heterotopic transplantation in the neck or abdomen (torsion, hematoma, ileus, intestinal obstruction, and intussusception) are avoided.
INTRODUCTION
Heterotopic cardiac transplantation in the dog has provided a useful method of studying cardiac allograft rejection and the use of immunosuppressive drugs. Carrel and Guthrie reported cardiac transplantation in dogs in 1905, anastomosing the external jugular vein and carotid artery of the recipient to the aorta, pulmonary artery, vena cava, and one of the pulmonary veins of the donor heart [ 11. Subsequently, Mann and associates simplified these techniques by simply anastomizing the aorta to the internal carotid artery and the pulmonary artery to the external jugular vein [2]. Further studies of heterotopic cardiac transplantation were performed by Demikhov who devised a variety of methods for heterotopic cardiac transplantation including intrathoracic locations, such that the donor heart supported part or the whole of the recipient circulation [3]. In this institution both orthotopic and heterotopic transplant models have been studied extensively. The heterotopic cardiac transplant model has the advantage of minimal operative mortality and decreased cost, al0022-4804/82/020150-04$01.00/O Copyri&t 0 1982 by Acdanic All+lltSOtrspodvaiaill~yf~rosncd
Res
he.
though with the marked disadvantage that it does not support the circulation. This is probably not relevant in studies directed toward allograft histopathology and the modification of graft rejection using drugs. The two commonly used sites for heterotopic transplantation have been the neck and the abdomen. In the neck, the donor heart must be small in order to be accomodated within the subcutaneous tissue. Larger hearts in this location interfere with respiration and swallowing. Torsion may result because of the loose surrounding tissue and draining hematomas are common. Transplantation in the abdomen using the abdominal aorta as the arterial supply and inferior vena cava as the venous return results in disturbance of intraabdominal contents, with postoperative ileus, intestinal obstruction, and occasionally intussusception. This latter complication approaches 10% in most series and became nearly 100% in dogs that received preoperative total lymphoid irradiation for immunosuppressive purposes. For these reasons, alternative sites were sought. The technique which has proved most satisfactory is that of intrathoracic heterotopic transplantation. 150
JAMIESON
ET AL.: HETEROTOPIC
This procedure is quickly and easily performed with uniform survival and minimal morbidity. This report documents the operative method and its advantages for cardiac transplantation research. MATERIALS
Animals. Outbred mongrel dogs weighing between 12 and 20 kg were matched only for we!ght. Both dogs were anesthetized with intravenous sodium pentobarbital (26 mg/ kg) and ventilated through an endotracheal tube using a Bird pressure-cycled respirator and an FiOz of 50%. Operative technique. The chest of the recipient dog is entered through a left thoraRT. INNOMINATE
\
V.
I
A.
LT. INNOMINATE
I I
151
cotomy in the third intercostal space. The left innominate artery is exposed and the left vagus nerve is displaced anteriorly. The superior vena cara is dissected free by crossing the anterior mediastinum, protecting the right phrenic nerve which lies on its rightlateral aspect. The pericardium is not entered and the azygos vein is gently mobilized, but not divided. The exposure is shown in Fig. 1. A left thoracotomy is also made in the donor dog, entering the fifth intercostal space. Heparin is administered (3 mg/kg) and the donor superior vena cava and azygos veins are divided. The inferior vena cava is ligated at the diaphragm and divided proximally. The aorta and pulmonary artery are
AND METHODS
SUPERIOR INTERCOSTAL
CARDIAC TRANSPLANTATION
A.
LT. VAGUS N.
FIG. 1. Left tharaodany incision with subsequent exposure of the great vesse.lsof the recipient. Sites ofinckiomareshom.
152
JOURNAL OF SURGICAL RESEARCH: VOL. 32, NO. 2, FEBRUARY
1982
RECIPIENT LT. INNOMINATE A.
RIGHT ATRIUM
FIG. 2. (A) The pulmonary artery anastomcsis is constructed first, commencing posteriorly. The donor pulmonary artery is cut short to avoid kinking. (B) The donor aorta is anastomosed to the recipient left innominate artery.
then divided at the pericardial reflection. With the heart elevated, all the pulmonary veins are then tied “en masse” and divided. The heart is then placed in cold saline (4°C) and the aorta and pulmonary artery dissected free by electrocautery. The pulmonary artery is cut within 3 mm of the pulmonary valve commissures. An atria1 septal defect is made by opening the foramen ovale through the inferior vena cava. Following this, the inferior vena cava is closed with a ligature. A side biting vascular clamp is placed on the superior vena cava as shown in Fig. 2. A longitudinal incision is made in this vessel and the pulmonary artery sewn end-to-side
with 4-O Prolene using a continuous technique. Kinking of the pulmonary artery is prevented by its shortened length. After completion of this anastomosis a second clamp is placed on the left innominate artery and the donor aorta is sutured end-to-side to this vessel. Following completion of the anastomosis,both venous and arterial clamps are removed. The heart generally resumes normal sinus rhythm spontaneously; however, direct current shock may sometimes be necessary to reverse fibrillation. The recipient animal is not heparinized and bleeding is minimal. The completed operation is shown in Fig. 3. The apex of the left lung can be fully
JAMIESON
ET AL.: HETEROTOPIC
CARDIAC TRANSPLANTATION
153
AORTA
LEFT LUNG
FIG. 3. The position of the transplanted heart following completion of the anastomosis. In this position it does not compromise normal function of the recipient heart or left lung.
inflated and is not compromised by the position of the donor heart. The chest is then closed routinely with a single drainage tube. After awakening from anesthesia and resuming spontaneous respiration, the animal is extubated and the chest tube removed. Dogs tolerate thoracotomy well and are generally walking and drinking on the evening of surgery. DISCUSSION
This paper describes a method of heterotopic cardiac transplantation that we have found to be quickly and easily performed, and which carries minimal morbidity. The technique has several specific advantages over heterotopic transplant procedures in the neck or abdomen. Intraabdominal problems, including intussusception and intestinal obstruction, are avoided. Serial electrocardiographic recordings are a more reliable measure of allograft rejection inasmuch as the donor heart can be compared as a ratio to the total voltage of the recipient heart, and
thus factors other than rejection that affect total QRS voltage (such as fluid overload, pneumonia, increased chest wall impedance) are not confused with rejection. The donor heart may be biopsied by passageof the flexible cardiac bioptome under fluoroscopic control from the right internal jugular vein, through the superior vena cava, to the interior of the donor right ventricle. Biopsies can also be obtained from the recipient heart for comparison. We have used this method in more than 200 dogs for the study of various programs of immunosuppression, and consider it to be superior to previously described techniques. REFERENCES 1. Carrel, A., and Guthrie, C. C. The transplantation of veins and organs. Amer. J. Med. 10: 1101, 1905. 2. Mann, F. C., Priestly, J. R., Markowitz, J., and Yates, W. M. Transplantation of the intact mammalian heart. Arch. Surg. 26: 219, 1933. 3. Demikhov, V. P. Experimental Transplantation of Vital Organs (B. Haigh, trans.). Plenum, New York, 1962.