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* From the Department of Cardiothoracic Surgery, Kinki University, School of Medicine, Osaka, Japan.
Correspondence to: Masaki Otaki, MD, Department of Cardiothoracic Surgery, Kinki University School of Medicine, Ohno-Higashi, Osaka-Sayama, Osaka 589, Japan
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Abstract |
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Methods: The following model was developed in our laboratory to investigate the feasibility of performing an orthotopic heart and bilateral lung transplantation without performing a cardiopulmonary bypass. Nineteen transplants were attempted using 19 pairs of mongrel dogs. The recipient dog (mean weight, 23 kg) was anesthetized, and the ascending aorta, the superior vena cava (SVC), the inferior vena cava (IVC), and the main bronchus were dissected. Then, the donor dog (mean weight, 20 kg) was anesthetized, and the heart and lung block was prepared and explanted from the chest under cardioplegic arrest. A Gore-tex shunt (W. L. Gore; Flagstaff, AZ) was placed side-to-side between the recipient IVC and SVC, and then the donor right atrium was anastomosed to the Gore-tex shunt. The donor ascending aorta was anastomosed to the recipient ascending aorta with a partial clamp. On completion of these anastomoses, the donor heart was reperfused by the recipient heart and allowed to beat. When hemodynamic conditions were stable with double hearts, the recipient SVC and IVC were ligated just proximal to the venous anastomosis and the recipient aorta was ligated proximal to the anastomotic site. The recipient trachea was anastomosed to the donor trachea with an end-to-end anastomosis. Finally, the recipient heart and lungs were removed from the chest and the sternum was closed.
Results: Four of the 19 transplants failed. Three died due to left ventricular dysfunction, and one died due to bleeding. Mean (± SD) ischemic time was 67 ± 11 min with a mean (± SD) anastomotic time of 54 ± 12 min. The 15 survivors were hemodynamically stable with or without the minimal use of inotropic support (dopamine, 2 to 3 µg/kg/min) 6 h after grafting, with normal cardiac output, satisfactory oxygenation, and normal wall motion. The sternotomy was repaired without loss of cardiopulmonary function.
Conclusions: On the basis of our experiences, the experimental model of orthotopic heart and bilateral lung transplantation completed "off pump" can be technically feasible without the loss of cardiac and pulmonary functions.
Key Words: experimental orthotopic transplantation • heart and lung transplantation • off pump
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Introduction |
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Since this report was published, several experimental methods have been attempted using cardiopulmonary bypass,2 3 4 but they have not been developed because of the disadvantages associated with cardiopulmonary bypass. Some of these disadvantages are related to disturbances in coagulation, vascular tone, capillary permeability, fluid balance, and organ function, especially lung. Therefore, easily reproducible canine models of orthotopic heart and lung transplantation with good survival have been sought.
The purposes of our set of experiments were the following: (1) to develop a new technique of orthotopic heart and lung transplantation; (2) to assess the feasibility in performing transplantation without using cardiopulmonary bypass; and (3) to evaluate cardiac performances before and after heart and lung transplantation with the echocardiogram.
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Materials and Methods |
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Experimental Procedures
Donor Animal: The donor animal was anesthetized,
intubated, and ventilated, and arterial monitors were placed. The
standard median sternotomy was performed, and the great vessels were
dissected along with the main bronchus and trachea. The carotid,
vertebral, and subclavian vessels were dissected, and the pericardium
was opened. A perfusion catheter was placed in the carotid artery. A
two-dimensional echocardiogram of the donor heart was obtained, and the
inferior vena cava (IVC) and the superior vena cava (SVC) were clamped
along the aorta. The trachea was subsequently clamped and transected,
and the right atrium was opened. The heart was then flushed with 400 mL
of cold crystalloid cardioplegia, and the donor heart and lung were
removed en bloc. This block was then transferred to cold
storage, and the vessels were prepared for subsequent transplantation.
Recipient Animal: The recipient animal was simultaneously anesthetized with sodium pentobarbital and intubated and ventilated, and arterial monitors were placed. The standard median sternotomy in the recipient dog was performed, and the great vessels and trachea were dissected from the chest cavity. In our earlier series of animal heart and lung transplantation (unpublished data), the direct end-to-side anastomoses between the donor and recipient IVC and SVC was performed, but due to increased tension on the anastomoses, the venous return to the donor heart was considered inadequate. In this series of transplantation, a Gore-tex shunt (W. L. Gore; Flagstaff, AZ) was placed side-to-side between the recipient IVC and SVC, and then the donor right atrium was anastomosed to the Gore-tex shunt.
Anastomoses: An end-to-side Gore-tex shunt to the recipient IVC was anastomosed together followed by an end-to-side Gore-tex shunt to the recipient SVC. Then, the donor right atrium was anastomosed to an opening in the Gore-tex graft (Fig 1 ). An arterial connection was created by anastomosing the donor descending aorta and the recipient ascending aorta using partial occlusion of the recipient vessel (Fig 2 ).
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Parallel Circuits: Double hearts and double bilateral lungs were created, and the simultaneous function of both hearts and lungs was demonstrated. The grafts were essentially piggy-backed, with the recipient heart initially responsible for systemic perfusion. An example of a pressure tracing showing donor-recipient combined heart beats is shown in Figure 3 .
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Results were interpreted with regard to the possibility or technical feasibility of the procedure. Criteria for short-term survivorship were based on the following: (1) chest closed; (2) mean systemic pressure > 75 mm Hg without inotropics or with minimal doses of inotropics (dopamine, 2 to 3 µg/kg/min); and (3) PaO2 > 85 mm Hg on room air.
The Guide for the Care and Use of Laboratory Animalsfollowed carefully during these experiments.5
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Results |
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Fifteen animals were hemodynamically stable 6 h after grafting without inotropic support or with a minimal dose of the inotropic support (dopamine, 2 to 3 µg/kg/min). A two-dimensional echocardiogram revealed normal wall motion of the donor heart, demonstrating a mean (± SD) functional shortening of 0.23 ± 0.04 before transplantation and 0.21 ±0.03 after transplantation (p = not significant [NS]). Oxygenation was demonstrated by blood gases with a mean (± SD) PO2 of 89.6 ± 2.9 mm Hg on room air before transplantation and 87.8 ± 3.4 mm Hg after transplantation (p = NS). The sternotomy was closed without loss of cardiac function, demonstrating a mean (± SD) arterial pressure of 98 ± 11 mm Hg before closure and 93 ± 15 mm Hg after sternal repair; and a mean (± SD) left atrial pressure of 12 ± 4 mm Hg before sternal closure and 14 ± 3 mm Hg after sternal repair (both p = NS).
Twelve animals awoke enough for the spontaneous ventilation to separate from the ventilator within 6 h after transplantation. Three animals remained anesthetized but awoke and obtained the spontaneous breath 10 h after transplantation.
Comments
The first experiments in heart and heart and lung orthotopic
transplantations were performed in dogs by Demikhov in the
1940s.1
However, experimental studies regarding canine
heart and lung transplantation have been limited because most
experimental studies of easily orthotopic graft rejection are
complicated by an inability to separate rejection-specific inflammatory
mediators from nonspecific cardiopulmonary bypass effects, and
cardiopulmonary bypass-related disturbances appear to lead to
respiratory failure.2
3
4
Experimental studies of orthotopic transplantation without cardiopulmonary bypass-related complications have been required despite the increased costs of and difficulties in maintaining these animals. Therefore, as Schäfers et al6 described, an experimentally reproducible canine model in orthotopic heart and lung transplantation without cardiopulmonary bypass has been desirable.
Additionally, the procedure of heart and lung transplantation gained renewed interest in the late 1980s when cyclosporine was induced in clinical and animal experiments conducted at Stanford University Medical Center.7 Essentially, the current method of human heart and lung transplantation involves the orthotopic en bloc transplantation of the trachea, pulmonary artery, left atrium, pulmonary veins, and aorta. Similar experimental models of heart and lung transplantation with a cost-effective procedure were also needed to evaluate the hemodynamic or immunologic condition of the transplanted organs for further studies of transplantation.
Recently, several canine models of heart and lung transplantation have been proposed, but survival was limited either because of respiratory failure or because of increased operative mortality associated with cardiopulmonary bypass. Among those studies, Kawaguchi et al2 proposed a new orthotopic heart and unilateral lung transplantation model using cardiopulmonary bypass. As they described, their model may be suitable for further studies of immunologic problems in cardiopulmonary transplantation, but this procedure needs cardiopulmonary bypass, and the recipient lung was preserved to avoid respiratory failure. Ertel et al8 presented similar models, but these models were achieved heterotopically with the heart and right lung of the recipient preserved. In order to obviate the need for cardiopulmonary bypass and preserve normal respiratory function, Schäfers et al6 presented an encouraging canine model without cardiopulmonary bypass during the operation. The donor heart and left lung were transplanted heterotopically with the preservation of the recipient heart and right lung. Actually, Schäfers et al6 have offered the advantages of preserving the normal respiratory gas exchanging function, which avoids the need of cardiopulmonary bypass, and the survival achieved in their study compares favorably with other surgical models. However, their model was achieved heterotopically with an en bloc heart and left donor lung transplantation. Therefore, their surgical procedure does not necessarily substitute a working cardiopulmonary unit that allows hemodynamic and respiratory studies after orthotopic cardiopulmonary transplantation.
The techniques we present in this article offer several advantages of completely replacing the total heart and bilateral lungs with donor organs and obviating the need for cardiopulmonary bypass. The essential step of this procedure requires a heterotopic implant of a ventilated heart and lung block, using partial occlusion clamps on target vessels. Once the second organs are in place, circulation and ventilation can be transferred gradually from the recipient to the donor, and then the native recipient organs can be resected, thereby leaving only the donor organ block to support the systemic circulation. The approach is greatly facilitated by placing a shunt between the recipient vena cavae, which greatly reduces technical barriers and reduces both ischemic and anastomotic time to < 1 h. The cardiac performance of the transplanted heart, such as cardiac output and left ventricular wall motion and oxygenation of the transplanted lungs, are preserved, at least acutely.
The surgical transplantation model in this article has several advantages. The procedure in our laboratory can do the following: (1) create a cardiopulmonary unit for hemodynamic, respiratory and immunologic studies in the orthotopic position of the donor organs; (2) be performed cost-effectively without cardiopulmonary bypass; (3) separate rejection-specific inflammatory mediators relating to cardiopulmonary bypass; and (4) acutely obtain stable hemodynamic and respiratory function of the transplanted organs and expect long-term survival. This report demonstrates the technical feasibility of orthotopic heart and lung transplantation without cardiopulmonary bypass using an acute animal model. Ongoing trials for achieving the chronic model are being conducted to evaluate the long-term hemodynamics and chronic heart and lung rejection of the transplanted organs.
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Footnotes |
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Received for publication September 4, 1998. Accepted for publication June 4, 1999.
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References |
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