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Ann Thorac Surg 1999;68:1605-1611
© 1999 The Society of Thoracic Surgeons
a Division of Cardiothoracic Surgery, Duke University Medical Center, Durham, North Carolina, USA
Address reprints request to Dr Biswas, Division of Cardiothoracic Surgery, Duke University Medical Center, PO Box 31044, Durham, NC 27710
e-mail: ssb1{at}acpub.duke.edu
Presented at the Poster Sessions of the Thirty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 25–27, 1999.
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Abstract |
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Methods. A canine donor model of brain death and a monocrotaline pyrrole-induced chronic pulmonary hypertension recipient model were established, and used for 30 orthotopic bicaval cardiac transplantations divided into three groups: Controls (group A, normal donor/recipient), group B (brain-dead donors/normal recipient), and group C (normal donor/recipients with pulmonary hypertension). Right ventricular function was measured before transplant and brain death, 4 hours after brain death, and after transplant (1 hour off bypass) by load-independent means plotting stroke work versus end-diastolic volume during caval occlusion. Right ventricular total power and pulmonary vascular impedance were determined by Fourier analysis.
Results. In comparison to the control group right ventricular preload-recruitable stroke work and total power decreased significantly after brain death and transplant in group B (from 22.7 x 103 erg (±1.2) at baseline to 15.6 x 103 (±0.9) after brain death and to 11.3 x 103 (±0.9) after transplant). In group C there was a significant increase in pulmonary artery pressure, impedance, right ventricular preload-recruitable stroke work, total power after transplant.
Conclusions. Normal donor hearts adapt acutely to the recipient’s elevated pulmonary vascular resistance by increasing right ventricular power output and contractility. Brain death caused significant right ventricular dysfunction and power loss, which further deteriorated after graft preservation and transplantation. The effects of donor brain death on myocardial function contribute to right ventricular dysfunction after cardiac transplantation.
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Introduction |
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Material and methods |
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Experimental groups
Twenty mongrel adult dogs served as controls. The cardiac grafts were retrieved from normal donors and transplanted into normal recipients after a hypothermic preservation time of 4 hours. In the second group of animals (group B, n = 20) the effects of brain death on myocardial performance and cardiopulmonary hemodynamics were assessed over a period of 4 hours after brain death and after 4 hours of cardiac graft hypothermic preservation, subsequent transplantation and weaning off bypass. In the third group (group C, n = 20) the hearts were harvested from normal donors and transplanted into adult mongrel dogs with persistent pulmonary hypertension and significantly increased right ventricular afterload.
Assessment of donor and recipient cardiac function
A standard median sternotomy and an anterior pericardiotomy were performed to expose the heart. An ultrasonic flow meter (T208X; Transonic Systems Inc, Ithaca, NY) was applied around the pulmonary trunk to measure right ventricular output. Hemispheric ultrasonic dimension transducers (1.5 mm outer diameter; No. 1-1015-5A; Vernitron, Bedford, OH) were positioned across the base–apex major axis, anteroposterior minor axis diameters of the left ventricle, and the septal-free wall minor axis diameters of both the right and left ventricles to measure left and right ventricular cavitary volumes. Millar pressure catheters (MPC-500; Millar Instruments Inc, Houston, TX) were placed into the right and left ventricle, left atrium, and pulmonary artery for continuous pressure recording of right and left ventricular pressure, end-diastolic right and left ventricular pressure, left atrial pressure, and pulmonary artery pressure. Dynamic right ventricular volume was measured according to the ellipsoidal shell subtraction method [8]. Right ventricular end-systolic pressure volume and stroke work/end-diastolic volume relations as well as end-diastolic segment length or chamber volume were then evaluated. The relationship between stroke work and either end-diastolic segment length or chamber volume was quantified by the highly linear relationship of slope and x-intercept during vena caval occlusion [9]. The slope (preload-recruitable stroke work) and x-intercept (volume) of these linear regressions represent load-independent indices of ventricular systolic function and myocardial contractility.
The interactions of the right ventricle and its afterload, the pulmonary vasculature and left atrial pressure were assessed by measurements of pulmonary vascular energetics and their oscillatory nature using the ultrasonic flow probe and micromanometers. These high-fidelity phasic measurements allow Fourier analysis of the waveforms to define pulmonary vascular input resistance, a measure of resistance to mean blood flow. Pulmonary vascular resistance was calculated by standard formula applying mean pulmonary pressure, cardiac output, as well as end-diastolic right ventricular pressure.
Induction, diagnosis, and validation of brain death
A previously introduced validated model of canine brain death was used and is described elsewhere [10]. In brief, brain death was induced by an intracranial pressure increase through inflation of a subdurally placed balloon that caused global brain and brainstem ischemia and herniation. Analgesic and anesthetic agents were discontinued after brain death was induced.
Establishment of chronic pulmonary hypertension
Recipient animals received an injection of 3 mg/kg monocrotaline pyrrole 4 months before transplantation. Monocrotaline pyrrole was artificially synthesized as described by Chen and colleagues in 1997 [11] and subsequently injected directly into the pulmonary artery during right heart catheterization. Hemodynamic measurements were collected in recipients at baseline and 4 months after injection on the day of transplantation. Monocrotaline pyrrole injection leads to an increase in pulmonary hemodynamic indexes over a 4- to 8-week period and is caused by vascular remodeling after endothelial injury at the level of the small- and medium-sized pulmonary arterioles. The endothelial cell degeneration and hyperplasia as well as smooth muscle hypertrophy and medial thickening occurs gradually and microscopic changes produced in the small- and medium-sized pulmonary arterioles resemble those observed in the pulmonary circulation of patients with chronic and fixed pulmonary hypertension secondary to end-stage heart disease.
Donor management
The micromanometers and flow probes were removed after data collection while the ultrasonic dimension transducers remained attached to the epicardium, but disconnected from the sonomicrometer and protected from immersion. The animals were fully anticoagulated with systemic injection of 350 IU/kg heparin (Elkins-Sinn Inc). The inferior vena cava was distally ligated at its emergence from the diaphragm followed promptly by cross-clamping of the ascending aorta at the origin of the brachiocephalic artery. One liter of St. Thomas cardioplegia (Plegisol; Abbott Laboratories, North Chicago, IL) at 40°C was infused into the aortic root through a 16-gauge cannula, and the heart was vented by incising the superior vena cava and right pulmonary veins distally. Topical normal saline at 40°C was applied to the surface of the heart and immersed in this solution. Transsection of the superior and inferior vena cava was done as distally as possible and the ascending aorta was transected just proximally to the aortic cross-clamp. The left and right pulmonary veins were transected at their pleural aspect outside the pericardium. The heart was then stored and protected in 40°C preservation solution based on an extracellular preparation of high osmolality (420 mOsm/L, sodium chloride 138 mEq/L, potassium chloride 25 mEq/L, calcium chloride 0.7 mEq/L, magnesium chloride 7.56 mEq/L, glucose 15 g/L, mannitol 20 g/L, hetastarch 6%, tromethamine to pH 7.4 to 7.5) formulated at the Duke University Medical Center Pharmacy.
Preparation of the recipient
Each recipient received triple immunosuppression therapy 2 hours before transplantation consisting of 10 mg/kg of oral cyclosporin (Sandoz Pharmaceutical Corp, East Hannover, NJ), 2 mg/kg of oral azathioprine (Burroughs Welcome, Research Triangle Park, NC), and 25 mg/kg of intravenous methylprednisolone (Upjohn Company, Kalamazoo, MI). After anticoagulation with 350 IU/kg of heparin, a 16F arterial cannula was inserted into the femoral artery and venous drainage was performed through bicaval cannulation using a 28F cannula for the inferior and a right angled 24F cannula for the superior vena cava, both inserted as distally as possible in preparation of cardiopulmonary bypass (Sarns 5000 heart- lung machine; Sarns Corp, Ann Arbor, MI; Cobe VPCML membrane oxygenator; Cobe Laboratories Inc, Lakewood, CO). On bypass the core temperature was reduced to 32°C, before rewarming was initiated during anastomosis of the pulmonary artery. The flow rate was kept between 80 and 100 mL · kg-1 · min-1 and mean arterial pressure maintained in the range of 60 to 70 mm Hg.
A bicaval orthotopic cardiac transplantation technique was used as described previously [12]. In brief, all the anastomoses were sutured with 4-0 Prolene suture in a continuous fashion and executed in the following order: left pulmonary veins, right pulmonary veins, inferior vena cava, pulmonary artery, aorta, and superior vena cava. The last anastomosis was performed after having de-aired the heart and the aortic cross-clamp released.
Data acquisition and analysis
Data were collected at baseline in every donor animal as well as 120 and 240 minutes after brain death and 60 minutes after cardiac transplantation and weaning off cardiopulmonary bypass. Functional and hemodynamic data were digitized on-line, collected, and stored on a microprocessor (PDP 11/23; Digital Equipment Corp, Maynard, MA). Pressure data and cardiac output were analyzed with software developed in our laboratory and is described elsewhere [9]. Briefly, all data were digitized at 500 Hz and filtered by a 50-Hz low-pass filter, stored on magnetic media, and analyzed on a Zenith Z-386/20 (Zenith Data Systems Corp, St. Joseph, MI).
Experimental approval and animal rights
The experimental set-up and procedures conformed to the guidelines established by the American Physiological Society and the National Institute of Health ("Guide for the Care and Use of Laboratory Animals," National Institutes of Health publication 85-23, revised 1985). The experiments were approved by the Duke University Institutional Animal Care and Use Committee (DUIACUC Registry A477-93-10R3).
Statistical analysis
Statistical analysis of data taken before and after brain death was performed on an IBM personal computer using commercially available software (SAS Institute, Inc, Statistical Software Package, Cary, NC). First, a linear multivariate analysis of repetitive measurements was used to test for an overall effect or trend over time. Because the analysis of repetitive measurements does not indicate which periods differ, follow-up paired Student’s t tests were used to compare baseline values with data after brain death and transplant. F tests were used to compare the means at each data point after brain death with baseline data. Each animal was used as its own control. Bonferroni’s method was used to compensate for the increased risk of a type I error with multiple comparisons. The results are expressed as mean ± standard error of the mean. A difference was considered statistically significant at p less than 0.05.
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Results |
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After the induction of chronic pulmonary hypertension 4 months after monocrotaline pyrrole injection in group C the mean pulmonary artery pressure increased by more than 100% associated with a significant increase in pulmonary vascular resistance and impedance (see Table 1). No significant differences were observed in pulmonary vascular blood flow and left atrial pressure before (1,340 ± 118 mL/min and 6.1 ± 0.5 mm Hg) and after the establishment of pulmonary hypertension in the recipient (1,589 ± 128 mL/min and 5.9 ± 0.5 mm Hg). After cardiac transplantation and weaning off bypass there was a further significant increase in pulmonary artery pressure, vascular resistance, and impedance, associated with a significant increase in total power and contractility (see Table 2 and Fig 1).
A fourth type of transplantation experiments were attempted and the hearts from brain dead donors were implanted into recipients with established pulmonary hypertension; however, these experiments were aborted after a series of three subsequent failures. In one experiment unsalvageable pulmonary artery hemorrhage occurred and in two other experiments weaning off cardiopulmonary bypass was unsuccessful secondary to severe right ventricular dilatation and sustained ventricular tachycardia and fibrillation. Three animals of group C died after transplantation due to acute right ventricular failure. The mean pulmonary artery pressure and pulmonary vascular resistance in these animals before death were 34.7 ± 3.9 mm Hg and 1,628 ± 422 dynes · s-1 · cm-5, respectively. The right ventricles in these three hearts were grossly distended, cyanotic, and hypocontractile. These animals were eliminated from the data analysis.
Weaning from cardiopulmonary bypass
Weaning from cardiopulmonary bypass was done gradually while monitoring left atrial and systemic pressures. Mean systemic pressures more than 50 mm Hg in combination with a mean left atrial pressures of 3 to 12 mm Hg were acceptable. The average total cardiac graft ischemic times and cardiopulmonary bypass times of the animals in groups A and B were different (236 ± 4/72 ± 3 minutes and 232 ± 2/68 ± 3 minutes) compared to 126 ± 6/97 ± 6 minutes in group C. The majority of the hearts required a direct current transmyocardial shock to convert ventricular fibrillation to the underlying rhythm. All transplanted hearts resumed stable sinus rhythm after weaning off cardiopulmonary bypass (heart rate between 125 and 135 beats/min) and only five animals required atrial pacing for rate control.
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentReferences |
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It was the aim of this experimental study to investigate the performance of the right ventricle after orthotopic cardiac transplantation in the setting of donor brain death and recipient pulmonary hypertension. Using load-insensitive measurements to objectively analyze myocardial performance in a previously validated donor canine brain death and recipient pulmonary hypertension model, this study demonstrated that brain death has a significant impact on right ventricular function in the donor as well as in the recipient after transplantation. After brain death, right ventricular systolic function and contractility, expressed by the linear relationship and regression of load-independent recruitable stroke work, was significantly decreased.
The brain death model described in this study may not reflect every clinical situation of brain death. There are other mechanisms of brain death in the organ donor population that do not involve a sudden increase in intracranial pressure with marked elaboration of endogenous catecholamines. It does replicate the clinical scenario in most patients who suffer brain death due to a sudden increase in intracranial pressure caused by acute intracranial hemorrhage or head trauma. In fact, severe head injury is the cause of death in 56% to 77% of actual organ donors. The importance of this catecholamine storm and the associated Cushing hyperdynamic response lies in its potential to cause cardiopulmonary damage. Presumably, cardiac injury occurred during the hyperdynamic response when systolic blood pressure increased to more than 350 mm Hg while systemic as well as pulmonary vascular resistance doubled leading to a mechanical impact on the myocardium and ventricular distention. At the cellular level, the sarcomere units were stretched beyond their normal working range resulting in the disengagement of actin filaments from the M-band and a reduction in the number of possible cross-bridge interactions [15].
No significant functional changes were observed in the control group where normal hearts were subjected to 4 hours of hypothermic cardiac preservation followed by subsequent transplantation. A significant additive effect exits between brain death and prolonged cardiac graft preservation on cardiac function after transplant. In the brain dead donor group right ventricular function decreased further by 28% after preservation and subsequent transplantation.
The preload recruitable stroke work relationship revealed that monocrotaline pyrrole-induced recipient pulmonary hypertension (group C) led to significantly increased right ventricular function after cardiac transplantation. The preload recruitable stroke work relationship represents a highly sensitive and previously well-validated model of evaluating intrinsic myocardial mechanics and function, independent of any changes in ventricular loading conditions that may occur in the setting of recipient pulmonary hypertension. This technique thus allows for reliable in vivo estimation of dynamic right ventricular volumes and subsequent assessment of right ventricular performance. Thus, significant augmentation of donor right ventricular function occurred in response to the increased afterload. The significant increases in right ventricular preload recruitable stroke work and hydraulic power occurring after cardiac transplantation suggest that, in the setting of recipient chronic pulmonary hypertension, the donor right ventricle was able to adapt to the increased afterload without evidence of cardiac failure.
These results were, admittedly, surprising and may initially appear to contradict several well-documented clinical reports and investigations that have clearly shown that an elevated pulmonary vascular resistance represents a known risk factor for acute right ventricular failure and early death. It is important to keep in mind, however, that the donor hearts used in this group were not subjected to either brain death-related cardiac injury or an extended period of hypothermic arrest and graft preservation, and had essentially normal function at the time of implantation. Therefore, an acute right ventricular adaptation to the suddenly exposed elevated afterload condition may have occurred. The ability of the right ventricle adapting to increased afterload was demonstrated in previous studies when right ventricular function increased over the period of 4 to 8 weeks after monocrotaline pyrrole injection and development of chronic pulmonary hypertension [16]. Hsieh and colleagues [17] described pulmonary hypertension with pulmonary artery banding that led to reversible right ventricular failure in a canine model of increased pulmonary vascular afterload. Right heart failure developed after 2 months of banding and was adapted initially by the generation of right ventricular hypertrophy.
Right ventricular hydraulic power was significantly increased after cardiac transplantation compared to the control animals and brain death group where right ventricular power was significantly decreased. However, the ratio of the components of total or hydraulic power, mean power, the energy required to wave blood forward at a steady state and oscillatory power, the energy wasted in oscillatory accelerations of the blood and eventually disseminated into the vessel walls, remained unchanged. In addition, there was a slight decrease in the pulmonary blood flow. A significant decrease in the pulmonary blood flow was observed in the brain dead donor group. These results indicate that a significantly larger amount of energy is expended by the right ventricle to maintain the relatively same amount of pulmonary blood flow in the setting of monocrotaline pyrrole-induced recipient chronic pulmonary hypertension. Presumably, a greater energy requirement was necessary to support pulmonary blood flow due to the significantly higher right ventricular afterload to which transplanted hearts were exposed after cardiopulmonary bypass. Once again, the right ventricle adapted acutely to this increase in afterload, suggesting an important power reserve to sustain pulmonary blood flow. This power reserve was not observed in the control group and the brain dead donor hearts after transplantation. A similar observation was made in a previous study in which the ability of the brain dead donor right ventricle was investigated to pump blood against an acute increase in pulmonary vascular resistance established through a snare applied on the proximal pulmonary artery [18]. In this study, the response to increased pulmonary vascular afterload and impedance was abolished significantly compared with baseline and control animals, suggesting a significant loss of compensatory power and impaired right ventricular power reserve to sustain pulmonary vascular blood flow in the brain dead organ donor.
Hemodynamic assessment of the pulmonary vasculature revealed a significant increase in impedance and pulmonary vascular resistance after transplantation and weaning off cardiopulmonary bypass compared to baseline data and even a further increase in the animals with pulmonary vascular hypertension, which is probably related to the increased susceptibility to lung injury and inflammatory reaction in dogs to cardiopulmonary bypass. Dreyer and colleagues [19] demonstrated neutrophil sequestration and pulmonary dysfunction in a canine model of open heart operations with cardiopulmonary bypass and evidence for a CD18-dependent mechanism. Furthermore, cardiopulmonary bypass is associated with release of numerous vasoactive substances that may alter normal vascular smooth muscle and endothelial cell function [20]. In response to such an injury, endothelial cells not only loose their ability to promote vasodilation, but also produce potent vasoconstrictor substances, such as endothelin, thromboxane A2, and angiotensin II, which can eventually lead to a net shift of pulmonary vascular smooth muscle tone toward vasoconstriction. Presumably these well-known deleterious effects of cardiopulmonary bypass compounded the preexistent state of monocrotaline pyrrole-induced endothelial cell injury in this report and led to the additional significant increase in recipient pulmonary hemodynamic indices after transplantation.
To mimic the clinical setting and gain further insight into the adaptive mechanisms of the acutely transplanted right ventricle in the setting of recipient pulmonary hypertension, studies were attempted to use donor hearts for transplantation that were subjected to brain death as well as longer periods of hypothermic graft preservation. These experiments failed primarily due to acute right ventricular failure and inability to wean these hearts off cardiopulmonary bypass secondary to severe right ventricular distention and malignant arrhythmias. This further suggests that donor brain death leads to more deleterious effects on right ventricular function than an elevated pulmonary vascular resistance and afterload.
To summarize, in a canine model of donor brain death and monocrotaline pyrrole-induced chronic pulmonary hypertension and orthotopic cardiac transplantation, a significant decrease in right ventricular function was observed after transplantation in those hearts retrieved from a brain dead donor. Right ventricular function was maintained or increased after transplantation of normal hearts into recipients with chronic pulmonary hypertension suggestive for that right ventricular dysfunction after cardiac transplantation is primarily related to the status of the donor heart.
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