Ann Thorac Surg 1996;62:1418-1423
© 1996 The Society of Thoracic Surgeons
Original Article: Cardiovascular
Controlled Reperfusion of Cardiac Grafts From Non—Heart-Beating Donors
Jeffrey T. Cope, MD,
Michael C. Mauney, MD,
David Banks, BS,
Oliver A. R. Binns, MD,
Nuno F. De Lima, MD,
Scott A. Buchanan, MD,
Kimberly S. Shockey, MS,
Shawn W. Wilson, BS,
Irving L. Kron, MD,
Curtis G. Tribble, MD
Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia Health Sciences Center, Charlottesville, Virginia
Accepted for publication June 16, 1996.
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Abstract
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Background. Hearts harvested from non–heart-beating donors sustain severe injury during procurement and implantation, mandating interventions to preserve their function. We tested the hypothesis that limiting oxygen delivery during initial reperfusion of such hearts would reduce free-radical injury.
Methods. Rabbits sustained hypoxic arrest after ventilatory withdrawal, followed by 20 minutes of in vivo ischemia. Hearts were excised and reperfused with blood under conditions of high arterial oxygen tension (PaO2) (approximately 400 mm Hg), low PaO2 (approximately 60 to 70 mm Hg), high pressure (80 mm Hg), and low pressure (40 mm Hg), with or without free-radical scavenger infusion. Non–heart-beating donor groups were defined by the initial reperfusion conditions: high PaO2/high pressure (n = 8), low PaO2/high pressure (n = 7), high PaO2/low pressure (n = 8), low PaO2/low pressure (n = 7), and high PaO2/high pressure/free-radical scavenger infusion (n = 7).
Results. After 45 minutes of reperfusion, low PaO2/high pressure and high PaO2/low pressure had a significantly higher left ventricular developed pressure (63.6 ± 5.6 and 63.1 ± 5.6 mm Hg, respectively) than high PaO2/high pressure (40.9 ± 4.5 mm Hg; p < 0.0000001 versus both). However, high PaO2/high pressure/free-radical scavenger infusion displayed only a trend toward improved ventricular recovery compared with high PaO2/high pressure.
Conclusions. Initially reperfusing nonbeating cardiac grafts at low PaO2 or low pressure improves recovery, but may involve mechanisms other than decreased free-radical injury.
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Introduction
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Although the number of patients in need of cardiac transplantation in the United States continues to rise, the number of heart transplantations actually performed in this country each year has remained at a plateau over the past several years [1]. In response to the serious deficit of cardiac homografts available from brain-dead donors, the concept of transplanting organs from non–heart-beating donors (NHBDs) has been resurrected. Potential NHBDs include neurologically devastated patients who cannot be declared legally brain-dead but who become eligible organ donors after declaration of death by cardiopulmonary criteria, as in apneic, vegetative patients from whom mechanical ventilatory support is withdrawn. The procurement of hearts from such donors after natural cessation of ventilation would greatly expand the limited donor pool for cardiac transplantation.
However, as demonstrated by recent work from our laboratory, the consecutive periods of global myocardial hypoxia and warm in vivo ischemia inherent to an NHBD harvest markedly impair recovery of cardiac graft function and combine to produce an injury that is of greater severity than an equivalent duration of warm ischemia alone [2]. As a result, measures specifically designed to protect non–heart-beating cardiac grafts against the severe myocardial injury incurred during harvest and implantation will be critical to ensure the feasibility of using such grafts for human cardiac transplantation. Although a handful of recent investigations in animal models have reported successful transplantations of hearts from asystolic donors, the successful outcomes of these experiments are attributable to the application of multiple cardioprotective pretreatments and interventions at several times during harvest and implantation [3–6]. It is impossible to ascertain from these studies which of these multiple interventions improved the function of the implanted graft. In contrast, the current study focuses on the effects of specific cardiac resuscitative measures used at a single, discrete time after implantation.
It is well documented in other models of myocardial ischemia that the initial few minutes of reperfusion account for a disproportionately large amount of the damage incurred by the myocardium, and there is a wealth of evidence implicating oxygen free radicals in such injury [7, 8]. In addition, it is believed that when the antecedent ischemic period is severe and the heart has sustained profound metabolic depletion-as is certainly the case of hypoxia-induced arrest and the subsequent warm in vivo myocardial ischemia that characterize an NHBD harvest-the ensuing reperfusion injury is even greater [9]. Because the presence of an adequate concentration of molecular oxygen is a prerequisite to free-radical formation in biologic systems [10], our hypothesis in the current study was that minimizing oxygen delivery during the early period of reperfusion of non–heart-beating cardiac explants would reduce oxygen-derived free-radical generation and thus improve recovery of graft function. To test this hypothesis, we studied ex vivo cardiac graft function on a blood-perfused, isolated rabbit heart apparatus after asystolic death due to asphyxiation. Because myocardial oxygen delivery is a function of perfusate oxygen tension (PaO2), hemoglobin concentration, and coronary flow (which is in turn dependent upon perfusion pressure), we endeavored to investigate the effects of controlling reperfusion by maintaining a low perfusate PaO2 with or without low pressure during the first 10 minutes of reperfusion. In addition, the independent effects of infusion of a free-radical scavenger during the same time interval were studied to ascertain the relative degree of damage attributable to reactive oxygen metabolites in the NHBD model of myocardial injury.
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Material and Methods
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Adult New Zealand white rabbits of either sex were used for all protocols in this study. The Animal Review Committee of the University of Virginia reviewed and approved the protocols for this study. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH publication 86-23, revised 1985).
Preparation of Hearts from Non–Heart-Beating Donors
New Zealand white rabbits (2.8 to 3.0 kg) of either sex were anesthetized with intramuscular xylazine and ketamine, followed by tracheostomy and volume ventilation (12 mL/kg) with 100% oxygen. An 18-gauge femoral artery catheter was placed to monitor blood pressure and to identify the onset of pulseless cardiac arrest. Intravenous metocurine (0.2 mg/kg) was given to achieve pharmacologic paralysis. Termination of mechanical ventilation in these apneic animals initiated a period of systemic hypoxia, which ended in cardiac arrest within 5 to 10 minutes, indicated by loss of the femoral arterial pressure waveform. Heparin sodium (2,000 U intravenously) was administered at the time of cardiac arrest and circulated with 2 minutes of external cardiac massage. This practice was based on the policy of our institution's medical ethics committee, which forbids prearrest heparin treatment in the clinical setting, as it could be argued that systemic anticoagulation in a patient with a sublethal brain injury could provoke brain death through intracranial hemorrhage, thus hastening the donor's death.
After the onset of hypoxic cardiac arrest, all NHBD groups were subjected to a 20-minute period of warm in vivo global myocardial ischemia to approximate the amount of time needed in the clinical setting of a non–heart-beating harvest to perform a sterile sternotomy and explant the donor heart. Just before the end of the 20-minute ischemic period, a sternotomy was performed, a left atrial blood gas sample was collected, and a saline-filled glass cannula was inserted into the ascending aorta of the donor heart. At 20 minutes of ischemia, NHBD hearts were excised and immediately reperfused ex vivo in the Langendorff mode under the various conditions described later. The blood-perfused, isolated heart circuit depicted in Figure 1
was assembled in essentially the same manner as described in a recent study from our laboratory [2]. We used a support rabbit system for the continuous provision of fresh, oxygenated arterial blood to the perfusion circuit.
Experimental Design
Six groups of rabbits were studied. Five groups of NHBDs were prepared as described in the previous section. Each group of NHBDs was defined by the conditions under which the isolated hearts were perfused during the first 10 minutes of the reperfusion period. Hearts harvested from NHBDs were initially reperfused at high pressure (80 mm Hg, Hipress) or low pressure (40 mm Hg, Lopress), in combination with high PaO2 (approximately 350 to 400 mm Hg, HiO2) or low PaO2 (approximately 60 to 70 mm Hg, LoO2). The different perfusion pressures were obtained by adjusting the perfusion column to the appropriate height. It should be noted that 80 mm Hg is considered a normal perfusion pressure for a rabbit heart under physiologic conditions. High perfusate oxygen tensions were obtained simply by ventilating the support rabbit with 100% oxygen and using femoral arterial blood from this animal as the perfusate, after transfusion of the support animal with 150 to 200 mL of blood harvested from another blood-donor rabbit. In contrast, low PaO2 blood was harvested into a separate Viaflex (Baxter Healthcare Corp, Deerfield, IL) bag from another rabbit undergoing ventilation with room air. This blood reservoir was then suspended at the appropriate height in the perfusion column to achieve the desired pressure. We used hypoxic blood perfusate from a separate blood donor instead of using arterial blood from the support rabbit while undergoing ventilation at a low inspired oxygen fraction because the latter practice makes it difficult to maintain survival of the support animal and still obtain a consistent range of low PaO2. However, other than differences between perfusate PaO2 and pressure, the blood perfusates were identical in composition between the groups.
The above-mentioned combinations of reperfusion conditions yielded the following four groups: HiO2/Hipress (n = 8), LoO2/Hipress (n = 7), HiO2/lopress (n = 8), and LoO2/lopress (n = 7). A fifth group of NHBD cardiac explants was initially reperfused at high pressure and high PaO2, but in addition the free-radical scavenger N-2-mercaptopropionylglycine (MPG) was infused directly into the coronary circulation through the side-port in the aortic cannula, at a rate of 10 mg•kg-1•h-1 for 10 minutes (HiO2/Hipress/MPG, n = 7). We selected this particular free-radical scavenger based on its characteristics as a scavenger of the potent hydroxyl anion and because this agent is effective both intracellularly and extracellularly [8]. After the initial 10 minutes, all hearts were perfused at high pressure and high PaO2 for the remainder of the 45-minute reperfusion period. A nonischemic control group (n = 8) underwent paralysis, systemic heparin treatment (2,000 U intravenously), cannulation of the ascending aorta, and immediate ex vivo perfusion at high pressure and high PaO2 for the entire 45-minute reperfusion period.
Data Acquisition During Reperfusion of Isolated Hearts
Just before the initiation of reperfusion, a sample of blood was collected from the perfusion column for determination of hemoglobin (Hgb), PaO2, and oxygen saturation (SaO2). Coronary flow (CF) was measured continuously with an inline ultrasonic flow probe (Transonic Systems, Inc, Ithaca, NY), which was positioned just above the aortic cannula. The highest CF rate attained during the initial 10 minutes, termed "peak CF," was recorded for each heart. From these data, we calculated the highest rate of oxygen delivery to each heart ("peak DO2") according to the equation: Peak DO2 (mL O2•min-1•g-1 dry left ventricle) = Peak CF x CaO2, where CaO2 = coronary arterial perfusate oxygen content = (1.34 x Hgb x SaO2) + (0.003 x PaO2). Left ventricular developed pressure, myocardial oxygen consumption (MVO2), coronary vasodilator responsiveness, and myocardial water content were measured exactly as described previously [2]. The indices of oxygen delivery and consumption were expressed as milliliters of oxygen per minute per gram of dry left ventricle (LV) to normalize for differences in LV weight. Coronary vasodilator responses were reported as peak increases in CF (mL• min-1•g-1 dry LV) over baseline. Comparisons were made among hearts with regard to left ventricular developed pressure, CF, MVO2, coronary vasodilator responsiveness, and percentage myocardial water content after 45 minutes of reperfusion.
Statistical Analysis
All results are expressed as mean ± standard error of the mean. Data were analyzed for between-group differences using analysis of variance (ANOVA) and the post hoc test of Tukey's multiple comparisons. Significant differences were identified with a confidence level of p < 0.05.
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Results
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As outlined in Table 1, the time required to produce hypoxic cardiac arrest after withdrawal of ventilation was not statistically different among the 5 groups of NHBDs. In addition, left atrial blood gases collected 20 minutes after arrest were similar among these groups and emphasized the severe hypoxia, hypercarbia, and acidemia that characterize cardiac arrest from asphyxiation.
The mean reperfusate hemoglobin concentration and PaO2 during the first 10 minutes of reperfusion are presented in Table 2. Although the hemoglobin concentration was similar among all groups (p = not significant), both LoO2/Hipress and LoO2/Lopress were exposed to a significantly lower mean PaO2 (p < 0.0000001 by ANOVA) than their counterparts initially undergoing reperfusion at a high oxygen tension.
Peak CF data for the five groups of NHBDs are depicted in Figure 2. Initial reperfusion at a combined high PaO2 and high pressure resulted in the highest peak CF, whether in the absence (HiO2/Hipress, 34.7 ± 1.7 mL•min-1•g-1 dry LV) or presence of a free-radical scavenger (HiO2/Hipress/MPG, 30.5 ± 2.4 mL•min-1• g-1 dry LV). However, when compared with HiO2/Hipress, modifying the initial reperfusion conditions with either low PaO2 or low pressure resulted in a significant reduction of peak CF in LoO2/Hipress (25.5 ± 2.7 mL•min-1•g-1 dry LV; p < 0.01 by ANOVA) and HiO2/Lopress (18.2 ± 2.0 mL•min-1•g-1 dry LV; p < 0.01 by ANOVA). Similarly, as Figure 3 indicates, initial reperfusion at both a high PaO2 and pressure resulted in the highest calculated peak DO2 (HiO2/Hipress, 5.06 ± 0.33 mL O2•min-1•g-1 dry LV and HiO2/Hipress/MPG, 5.0 ± 0.30 mL O2•min-1•g-1 dry LV). However, decreasing either the initial reperfusate PaO2 or pressure yielded intermediate levels of peak DO2 in LoO2/Hipress (3.42 ± 0.31 mL O2•min-1•g dry LV-1) and HiO2/Lopress (3.06 ± 0.40 mL O2•min-1•g-1 dry LV). A combination of these two reperfusion modifications (LoO2/Lopress) produced an extremely low peak DO2 (1.83 ± 0.26 mL O2•min-1•g-1 dry LV).
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Fig 2. . Peak coronary flow of non–heart-beating cardiac grafts during initial 10 minutes of reperfusion. (HiO2 = high partial pressure of oxygen in arterial blood; hipress = high pressure; LoO2 = low partial pressure of oxygen in arterial blood; lopress = low pressure; LV = left ventricle; MPG = N-2-mercaptopropionylglycine; *p < 0.01 vs all except HiO2/Hipress/MPG; **p < 0.01 vs all except HiO2/Hipress; #p < 0.01 vs LoO2/Lopress [all by analysis of variance].)
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Fig 3. . Peak myocardial oxygen delivery to non–heart-beating cardiac grafts during initial 10 minutes of reperfusion. (Abbreviations as in legend to Figure 1 ; *p < 0.01 versus all except HiO2/Hipress/MPG; **p < 0.01 vs all except HiO2/Hipress; #p < 0.01 versus LoO2/Lopress [all by analysis of variance].)
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After 45 minutes of reperfusion, all groups of cardiac explants from NHBDs had a significantly lower mean left ventricular developed pressure than nonischemic controls (p < 0.0000001 by ANOVA) (Fig 4), thus highlighting the severity of myocardial injury incurred during a non–heart-beating harvest. However, initiating reperfusion of such explants at a low oxygen content yielded a significant improvement in LV functional recovery compared with hearts reperfused under the conditions of high PaO2 and high pressure (LoO2/Hipress versus HiO2/Hipress, 63.6 ± 5.6 versus 40.9 ± 4.5 mm Hg, respectively; p < 0.0000001 by ANOVA). Similarly, a reduced initial reperfusion pressure significantly enhanced recovery of LV function (HiO2/Lopress versus HiO2/Hipress, 63.1 ± 5.6 versus 40.9 ± 4.5 mm Hg, p < 0.0000001 by ANOVA). In contrast, a combination of these two reperfusion modifications was associated with poor LV recovery (LoO2/Lopress, 33.7 ± 2.9 mm Hg). Infusion of MPG yielded only a trend toward improved LV recovery over HiO2/Hipress (HiO2/Hipress/MPG, 56.0 ± 7.1 mm Hg; p = 0.4 by Tukey's test of multiple comparisons versus HiO2/Hipress).
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Fig 4. . Left ventricular developed pressure for all groups after 45 minutes of reperfusion. (NC = nonischemic controls; other abbreviations as in legend to Figure 1; *p < 0.0000001 versus all others; **p < 0.0000001 versus HiO2/Hipress and LoO2/Lopress [all by analysis of variance].)
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Table 3 outlines mean MVO2 and myocardial water content data for all groups after 45 minutes of reperfusion. Although not statistically significant, all NHBD groups except for LoO2/Lopress had a higher mean MVO2 than the nonischemic controls, which is consistent with recovery from reversible injury. Conversely, LoO2/Lopress exhibited a decidedly lower MVO2 than all others, suggesting the presence of a component of irreversible myocardial damage in this group. Nonischemic controls sustained a lower mean myocardial water content than all NHBD groups, achieving statistical significance when compared with HiO2/Hipress, HiO2/Lopress, and LoO2/Lopress (p = 0.003 by ANOVA). Although HiO2/Hipress sustained the highest myocardial water content, this was not significantly different from that in any of the other NHBD groups.
Mean values for baseline CF and coronary vasodilator responsiveness are presented in Table 4. As indicated, there were no statistically significant differences with regard to the coronary endothelial-dependent response to bradykinin or endothelial-independent response to bradykinin or endothelial-independent response to sodium nitroprusside. The group HiO2/Hipress had a significantly higher baseline CF after 45 minutes of reperfusion compared with nonischemic controls and HiO2/Hipress/MPG (p = 0.003 by ANOVA versus both).
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Comment
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The worsening mismatch between the stagnant supply of hearts from brain-dead donors and the increasing demand from the growing population of patients in need of cardiac transplantation has prompted clinicians to reevaluate the potential procurement of cardiac homografts from NHBDs. As demonstrated by recently completed work from our laboratory [2] as well as the current study, such grafts sustain profound injury during harvest. The magnitude of this injury has heretofore confounded any clinical attempts to transplant nonbeating hearts. If the use of these hearts for transplantation is ever to achieve clinical fruition, specific cardioprotective interventions must be identified and applied to enable the donor heart to overcome these severe insults during harvest and implantation. In this study, we have demonstrated two such protective interventions: initiating reperfusion of non–heart-beating cardiac grafts with either a low reperfusate PaO2 or low pressure. Clearly, a combination of these two reperfusion conditions exacerbates myocardial injury, as manifested by poor LV recovery and reduced MVO2. This finding is most likely attributable to an inadequate supply of oxygen to sustain cellular reparative processes during the early reperfusion period. Because reperfusion under the condition of low PaO2 or low pressure significantly reduced oxygen delivery to the heart early in the reflow phase, it is tempting to ascribe the benefits of these reperfusion modifications to decreased oxygen free-radical damage. However, it is somewhat surprising that infusion of the hydroxyl radical scavenger MPG produced only a modest trend toward improved LV recovery. Because hydroxyl anion is the most potent biologically active free radical known [11] and the MPG dose that we used is well within the range shown to scavenge hydroxyl anion effectively and preserve postischemic cardiac function in other models of myocardial ischemia-reperfusion [8, 12], we speculate that reactive oxygen metabolites produced during reperfusion may assume a less important overall role in the complex NHBD model of myocardial injury than they do in other models of ischemia-reperfusion. However, we cannot rule out the possibility that other free radicals, such as superoxide anion or hydrogen peroxide, are involved in this injury process. Nevertheless, our results lead us to conclude that mechanisms other than reduced free-radical formation contribute to the beneficial effects of either low pressure or low PaO2 reperfusion.
Most previous studies have cited decreased myocardial edema formation and improved coronary endothelial preservation as the dominant mechanisms underlying the enhanced cardiac recovery associated with controlled low-pressure reperfusion [13–15]. In the current study, we failed to detect any differences among groups with regard to the coronary endothelial-dependent vasodilator response to bradykinin. Although hearts reperfused at both high pressure and high PaO2 suffered the highest degree of myocardial edema, it was not significantly greater than that in the group undergoing isolated low-pressure reperfusion. Although the reasons for these disparities remain unclear, they may reflect differences between the types of injuries produced by the novel NHBD model and the more traditional models of myocardial ischemia-reperfusion in the previous studies. In two previous investigations of nonbeating hearts, a low antegrade [3] or retrograde [4] perfusion pressure was used during the early phase of reperfusion. However, the authors of these studies did not ascertain whether these modifications were beneficial to cardiac recovery or what mechanisms might be involved. A possible alternative explanation for the advantages of low-pressure reperfusion in our model may involve reduced nitric oxide (NO) production during the early phase of reperfusion. This theory is supported by the fact that NO is a rather potent negative inotrope [16] and is released in large quantities by the endothelium in states of increased shear stress [17], such as in high-pressure reperfusion. It is conceivable that the significantly reduced early hyperemic response of the group reperfused at a low pressure may be directly attributable to a marked reduction of endothelial NO production. A similar mechanism may underlie the reduction in peak CF with low PaO2 reperfusion in our model, as it is well established that oxygen is an essential substrate for NO synthesis. Depressed NO production may also account for the functional benefits of low PaO2 reperfusion in our model. A similar phenomenon has been described in recent studies involving controlled reoxygenation of the hypoxic neonatal heart [18, 19].
In summary, the current study demonstrates that injury to non–heart-beating cardiac grafts can be partially overcome by initially reperfusing these hearts with either a low reperfusate PaO2 or low pressure. These reperfusion modifications, if applied in conjunction with other cardioprotective interventions, may prove vital to achieving clinical success in transplanting hearts from such donors. Future studies should focus on the mechanisms accounting for the advantages of controlled reperfusion of nonbeating cardiac grafts, such as decreased NO production.
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Acknowledgments
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This work was supported by a National Research Service Award (fellowship no. 1 F32 HL09065-01A2) from the National Institutes of Health.
We thank Mr. Anthony J. Herring for his invaluable technical assistance.
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Footnotes
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Address reprint requests to Dr Tribble, Department of Surgery, University of Virginia Health Sciences Center, Box 181-95, Charlottesville, VA 22908.
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Abstract
Introduction
