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Ann Thorac Surg 1996;62:54-61
© 1996 The Society of Thoracic Surgeons
Department of Surgery, University of Virginia School of Medicine, Charlottesville, Virginia
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Abstract |
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Methods. Rabbit hearts and lungs were procured from separate donors and placed on isolated blood perfusion circuits. Controls were excised and perfused without ischemia. Hearts from NHBDs underwent either prearrest hypoxic perfusion alone or consecutive periods of prearrest hypoxic perfusion and 20 minutes of postarrest warm ischemia. A third group of hearts underwent 30 minutes of warm, global ischemia alone. Two groups of pulmonary allografts were studied using similar hypoxic perfusion/20-minute ischemia and 30-minute ischemia donors.
Results. Prearrest hypoxic perfusion clearly causes significant dysfunction of cardiac allografts from NHBDs compared with nonischemic controls. Prearrest hypoxic perfusion combined with postarrest ischemia results in an additive degree of dysfunction more severe than a similar period of warm ischemia alone. Both groups of experimental lungs displayed function similar to that of nonischemic controls in terms of pulmonary hemodynamics, airway resistance, and oxygenation potential.
Conclusions. We conclude that prearrest hypoxic perfusion significantly contributes to the dysfunction of NHBD cardiac allografts. Pulmonary allografts may be more amenable to procurement of NHBDs.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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Transplantation has become the treatment of choice for end-stage cardiopulmonary disease. However, the number of patients receiving transplants each year has plateaued while the number of patients eligible for transplants has continued to grow [1]. The major obstacle to wider application of transplantation for end-stage cardiopulmonary disease continues to be a critical shortage of organs. Currently in the United States, all thoracic allografts are obtained from brain-dead, heart-beating donors maintained on life support systems. Despite an estimated 10,000 to 12,000 potential brain-dead donors per year in the United States [2], only 10% to 20% of these eventually become cardiac donors [3] and even fewer become lung donors. As a result, 10% to 40% of all thoracic transplant candidates at major transplant centers die waiting for their new organ [4, 5].
One solution to the critical organ shortage is the use of non–heart-beating donors (NHBDs). Non–heart-beating donors are patients who become eligible for donation after declaration of death by cardiopulmonary criteria instead of brain death criteria. One group of potential NHBD candidates includes patients with terminal brain injuries who do not meet all the criteria for brain death but from whom the family and physicians have decided to withdraw life support. After consent for donation is obtained, ventilatory support would be withdrawn in the controlled environment of the operating room and hypoxic cardiac arrest would ensue. Upon declaration of death by cardiopulmonary criteria, rapid procurement of organs from the NHBD could then begin.
Although NHBDs have been used clinically for nonthoracic organs, cardiac and pulmonary transplantation with NHBD allografts has not proceeded beyond the laboratory. The NHBD allograft is exposed to several different mechanisms of injury during procurement that are absent in a heart-beating donor procurement including hypoxic perfusion before arrest and an indeterminant but inevitable period of warm ischemia after arrest before the allograft can be explanted and flush preserved. This study was designed to determine what effect a clinically relevant period of hypoxic perfusion and in vivo warm ischemia would have on isolated cardiac and pulmonary allografts obtained from an animal model of an NHBD.
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Material and Methods |
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Isolated, Blood-Perfused Rabbit Hearts
PREPARATION OF BLOOD-PERFUSED ISOLATED HEART PERFUSION CIRCUIT.
New Zealand white rabbits (3.5 to 4 kg) were used as support animals to provide blood perfusate for the isolated heart perfusion circuit. Under intramuscular xylazine (5 mg/kg) and ketamine (50 mg/kg) anesthesia, a tracheostomy was performed for continuous ventilation with a halothane/100% O2 mixture. The marginal ear vein was cannulated for continuous administration of heparin (800 U • kg-1 • h-1) in 3 mL • kg-1 • h-1 lactated Ringer's solution. An 18-gauge angiocatheter was placed in the left femoral artery for continuous measurement of mean arterial pressure. The contralateral femoral artery and vein were likewise cannulated with 18- and 16-gauge angiocatheters, respectively, the former for supply of arterial blood to the perfusion circuit and the latter for receiving recirculated blood after exiting the perfused heart. A schematic of the perfusion circuit is depicted in Figure 1
. Before the controlled exsanguination of arterial blood into the circuit, the support animal was transfused with 150 to 200 mL of blood harvested from a second rabbit (4 to 4.5 kg). Arterial blood from the support rabbit was circulated through Tygon tubing (Norton Performance Plastics, Akron, OH) with a roller pump and warmed to 37°C by passage through a heat exchanger. The perfusion circuit was equipped with two 40-µm blood filters (4C7732; Baxter Healthcare Corporation, Deerfield, Illinois) to collect any microaggregates before perfusing the isolated heart and before return to the support rabbit via the femoral vein.
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PREPARATION OF ISOLATED HEART DONORS.
Intramuscular xylazine/ketamine was administered to adult (2.8 to 3.0 kg) New Zealand white rabbits of either sex. All animals underwent tracheostomy and volume ventilation (12 mL/kg) with 100% O2 followed by placement of a femoral artery catheter (18-gauge) for transduction of the arterial pressure waveform. After systemic heparinization (2,000 units intravenously), intravenous metocurine (0.2 mg/kg) was given to achieve pharmacologic paralysis.
HEART DONOR PROTOCOLS.
Four groups of cardiac donors were studied: one nonischemic control group, two groups undergoing hypoxic arrest with or without additional warm ischemia, and one group undergoing global, no-flow warm ischemia. The nonischemic control group underwent median sternotomy and isolation of the ascending aorta immediately after heparinization and paralysis. Without any antecedent hypoxia or ischemia the ascending aorta was cannulated and the beating heart was excised and placed on the perfusion circuit within 60 seconds (control, n = 8). In all donors a glass cannula filled with saline solution was inserted into the ascending aorta and tied into place such that its tip was situated well above the coronary ostia and aortic valve, taking care to avoid injuring the valve or introducing air into the coronary circulation. Two groups of donors underwent hypoxic perfusion (HP) and cardiac arrest after withdrawal of mechanical ventilation. Hypoxic arrest was identified by the absence of the femoral artery pressure waveform for at least 30 seconds. One group of hypoxic arrest donors underwent rapid sternotomy, aortic cannulation, explantation, and immediate reperfusion within 2.6 to 3.0 minutes (HP, n = 7). A second group of hypoxic arrest donors was subjected to 20 minutes of warm, in vivo ischemia after arrest before explantation and perfusion (HP/20WI, n = 8). A 20-minute period of in vivo ischemia was chosen to approximate the amount of time needed in the clinical setting of an NHBD harvest to perform a sterile sternotomy and explant the heart. Previous authors have used 15 and 30 minutes for similar reasons [6, 7]. Both groups of donors undergoing hypoxic arrest had left atrial blood gases drawn at the time of explantation just before reperfusion. After heparinization and paralysis a fourth group underwent a median sternotomy while on the ventilator. The aorta was cannulated without any antecedent hypoxia or ischemia. The heart was excised and replaced in the mediastinum for 30 minutes of warm in vivo ischemia before reperfusion (30WI, n = 8). Left atrial blood gases were not drawn in this group because the heart had been completely excised 30 minutes before reperfusion. A schematic for the heart donor protocols is depicted in Figure 2.
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A side-port in the aortic cannula was used for the direct intracoronary administration of drugs to assess vasodilator responsiveness. Coronary endothelium-dependent and endothelium-independent relaxation were assessed by the peak coronary flow responses to 2-minute infusions of bradykinin (5 x 10-7 M/min; Sigma Chemical Co, St. Louis, MO) and sodium nitroprusside (5 x 10-5 M/min; Sigma Chemical Co), respectively. Coronary vasodilator responses were reported as percent increases in coronary flow over baseline.
Left ventricular developed pressure and CF were recorded continuously by customized digital data acquisition software (Workbench PC; Strawberry Tree, Inc, Sunnyvale, CA) and recorded on computer disk. Myocardial oxygen consumption and coronary vasodilator responses were assessed after 45 minutes of reperfusion. Comparisons were made between hearts with regard to left ventricular developed pressure, CF, MVO2, and percent coronary vasodilator responsiveness after 45 minutes of reperfusion. At the conclusion of each experiment, each heart was flushed with 30 mL of 0.9% saline solution and trimmed free of both atria and the right ventricular free wall. The isolated LV specimen was immediately weighed (wet weight) and allowed to undergo passive desiccation to a stable weight (dry weight). Percent myocardial water content was calculated using the formula: % myocardial water content = [1 - (dry weight/wet weight)] x 100%.
Isolated, Blood-Perfused Rabbit Lungs
PREPARATION OF THE BLOOD-PERFUSED, ISOLATED LUNG PERFUSION CIRCUIT.
Unlike the isolated heart perfusion circuit, the isolated lung perfusion circuit could not be adequately maintained with a support rabbit due to the markedly greater blood flows required to reproduce normal rabbit pulmonary artery flow rates. Hence a recirculating circuit using pooled venous whole blood was designed. The circuit has been described in detail in a previous article from this laboratory [10] and is outlined in the schematic in Figure 3.
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LUNG DONOR PROTOCOLS.
A hypoxic perfusion-only group similar to the cardiac donor HP group could not be studied due to the significantly greater amount of dissection required to rapidly procure a lung from an arrested, closed-chest animal and place it on the perfusion apparatus. Preliminary studies demonstrated that the minimum time needed was in excess of 5 minutes compared with the 2.5 to 3.0 minutes needed for the hearts.
After heparinization rabbits underwent randomization to one of three groups: nonischemic controls, NHBDs, and warm ischemic controls. Nonischemic controls underwent a median sternotomy and thymectomy. The superior and inferior venae cavae were loosely encircled with ligatures and the pericardium was opened. Both the pulmonary artery and the aorta were dissected free and similarly encircled. A pursestring suture was then placed in the free wall of the right ventricle. The venae cavae were ligated, the pulmonary artery was then cannulated through a right ventriculotomy in the center of the pursestring, and both the right ventricular and pulmonary arterial ligatures were tied around the cannula. After the left ventricle was vented through a left ventriculotomy and the aorta was ligated, the left atrium was cannulated through the left ventriculotomy and a second pursestring was tied around the cannula. A second catheter was placed in the left atrium to directly transduce left atrial pressures. The pulmonary arterial and left atrial cannulas were clamped. Care was taken to leave the pleurae intact during the harvest. The heart block was excised and placed on the perfusion circuit with a total ischemic time of less than 90 seconds.
Donors randomized to the non–heart-beating group were disconnected from the ventilator and allowed to undergo hypoxic arrest (HP/20WI). Criteria for hypoxic arrest were the same as in the heart donors, namely, pulselessness for 30 seconds. After arrest the animals underwent an additional 15 minutes of in vivo warm ischemia before a sternotomy was performed for cannulation and explantation of the heart-lung block in a manner identical to the control groups. The warm ischemic group underwent median sternotomy while on the ventilator (30WI). After cannulation of the pulmonary artery and left atrium in a manner identical to the control group, the heart-lung blocks were excised but replaced in the chest of the donor animal for an additional 30 minutes before transfer to the isolated lung perfusion circuit. A schematic of the lung donor protocols is outlined in Figure 4.
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Statistical Analyses
All results are expressed as the mean ± standard error of the mean. Data were analyzed for between-group differences using analysis of variance and Tukey's multiple comparison test. Significant differences were defined by p less than 0.05.
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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outlines the average time to arrest, the timing of left atrial blood gases relative to discontinuation of ventilation, and the left atrial blood gas determinations at that time for the two groups of cardiac donors undergoing hypoxic arrest. HP hearts underwent reperfusion 10.1 ± 0.1 minutes after ventilator withdrawal, which was an average of 2.8 minutes after pulselessness. HP/20WI hearts underwent reperfusion 27.2 ± 0.3 minutes after ventilator support was withdrawn. HP/20WI hearts were exposed to a significantly greater acidotic perfusate before explantation and reperfusion.
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illustrates the composition of the isolated heart perfusate at the end of 45 minutes of reperfusion for all groups of donor hearts. There were no significant differences in terms of pH, hemoglobin concentration, or supraphysiologic oxygen partial pressures.
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outlines the results after 45 minutes of reperfusion for all four groups of cardiac donors. All three experimental groups displayed significantly impaired ventricular function compared with controls. In addition, the HP/20WI hearts demonstrated significantly worse ventricular function compared with HP and 30WI hearts. All three groups of experimental hearts had higher baseline coronary flows compared with controls, although this was only of statistical significance for 30WI hearts. With regard to postischemic myocardial metabolism only the HP and 30WI hearts demonstrated significantly greater myocardial oxygen consumptions compared with controls. Endothelial dependent vasodilatation to bradykinin was slightly depressed in all three experimental groups compared with controls, but this did not reach statistical significance for any group. However, endothelium-independent vasodilatation to sodium nitroprusside was significantly impaired in the 30WI group. There were no statistically significant differences in wet/dry ratios between the three experimental groups: control, 78.7 ± 0.3; HP, 79.4 ± 0.3; HP/20WI, 81.4 ± 0.3; and 30WI, 81.2 ± 0.5.
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illustrates the results after 45 minutes of reperfusion for the three groups of donor lungs. There were no statistically significant differences between any of the groups in terms of baseline pulmonary artery pressure or pulmonary vascular resistance, decline in airway compliance during the reperfusion period, or oxygenation potential at the end of reperfusion.
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Comment |
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Investigators in the 1960s proved the feasibility of cardiac transplantation using NHBDs, coinciding with the emergence of the debate over brain death [6, 15]. Nevertheless the concept of NHBDs for cardiac transplantation was eventually abandoned due to the marginal results of these experiments and the legal recognition of brain death. In addition, the burgeoning field of myocardial protection had identified irreversible myocardial injury after as little as 20 minutes of warm ischemia and reperfusion [16].
However, the current critical shortage of organs has rekindled interest in NHBD cardiac allografts and has inspired a handful of new investigations to reconsider the potential use of these organs. Gundry and associates [7, 17] have successfully transplanted neonatal lamb hearts procured from donors 30 minutes after either hypoxic or hypovolemic arrest. These authors successfully expanded the limits of cardiac allograft viability by employing a number of cardioprotective techniques before, during, and after procurement including (1) pharmacologic pretreatment of the donor, (2) cold preservation of donor hearts in a University of Wisconsin-like solution before implantation, and (3) modified reperfusion of the allograft. Similarly, Egan's group has demonstrated the feasibility of non–heart-beating donation for lung transplantation using ventilation of the lung with 100% oxygen during the warm ischemic interval [18] and the addition of free radical inhibitors to the pulmonary flush during the harvest [19]. A recent study from our laboratory demonstrated no difference in function between porcine pulmonary allografts undergoing 30 minutes of postarrest in vivo warm ischemia and those grafts harvested immediately after arrest [20].
Clearly, these studies demonstrate that viable thoracic allografts can be obtained from NHBDs. However, several important questions are raised by these reports. To what extent is Gundry and associates' success due to the donor pretreatment, cold cardioplegic storage, and modified reperfusion? Could 30 minutes of warm ischemia be tolerated without these adjunctive measures? Similarly, is Egan and associates' success due to the addition of postarrest ventilation and free radical scavengers or, as the report from our laboratory suggests, are pulmonary allografts from the NHBD more tolerant of hypoxic arrest and in vivo warm ischemia than cardiac allografts? We sought to answer two questions in this study. First, is the period of warm ischemia the most important determinant of viability in cardiac allografts procured from NHBDs? Second, are pulmonary allografts as susceptible to injury from NHBD procurement as cardiac allografts?
This study suggests that the period of prearrest hypoxic perfusion in the NHBD is as important in determining cardiac allograft viability as the postarrest period of in vivo warm ischemia. In an animal model of NHBDs, cardiac arrest from hypoxic perfusion in the absence of significant postarrest warm ischemia is associated with a significantly impaired left ventricular function compared with nonischemic controls after reperfusion. The 40% reduction in left ventricular developed pressures compared with nonischemic controls after an average of only 7.3 minutes of hypoxic perfusion is indistinguishable from a similar reduction after 30 minutes of global, no-flow warm ischemia.
Several explanations for this significant injury associated with hypoxic arrest can be found. The agonally arrested heart is metabolically depleted [21] and more vulnerable to subsequent ischemia and reperfusion [22]. This latter observation is supported by our study, which demonstrated significantly lower left ventricular function in hearts undergoing hypoxic arrest and only 20 minutes of warm ischemia compared with hearts exposed to 30 minutes of warm ischemia. Although it did not reach statistical significance, the HP/20WI hearts displayed a blunted increase in MVO2 compared with the 30WI and HP hearts, suggesting an impaired recovery of metabolic function. Severe hypoxic stress has been shown to deplete aspartate and glutamate stores by 50% [23]. Additionally, diffusible substrate precursors such as adenosine may be washed out before arrest, thereby mandating the replenishment of substrate during resuscitation and reperfusion. Both animals undergoing hypoxic arrest were found to have profound hypercarbia, a known myocardial depressant [24]. Finally, acute hypoxia and hypovolemia causes release of systemic inflammatory mediators known to have a myocardial depressant effect [25].
The myocardial injury associated with hypoxic arrest appears to be related more to myocyte function than to coronary vasomotor activity. There was no significant reduction in endothelial-dependent vasodilatation in any of the experimental donor hearts. This was surprising at first given the abundance of literature demonstrating the sensitivity of the endothelium to ischemia. The endothelium has been shown to be injured by as a little as 10 minutes of ischemia in an in vitro crystalloid-perfused model [26]. However, a similar period of ischemia in the blood-perfused open chest of anesthetized pigs failed to elicit a decrease in endothelial-dependent vasodilatation [27]. These disparate results may be related to the differences between crystalloid- and blood-perfused hearts, as suggested by the recent report by Deng and colleagues [28], who demonstrated no decline in endothelium-dependent vasodilatation in blood-perfused rabbit hearts compared with a significant decline in endothelium-dependent vasodilatation in the crystalloid perfused hearts. Interestingly, endothelium-independent vasodilatation was significantly depressed in the 30WI group but not in either of the hypoxic arrest groups. The observation of increased baseline coronary flows in all of the experimental groups compared with the nonischemic controls is in agreement with several other blood-perfused rabbit heart models that found flows to be 136% to 151% of baseline 30 and 60 minutes after warm ischemia, respectively [29, 30].
With regard to the second question, the results of this study seem to suggest that, given an identical period of hypoxic arrest and in vivo warm ischemia as was used for the HP/20WI cardiac allografts, pulmonary allografts demonstrate no significant reduction in oxygenation potential, airway compliance, or pulmonary vascular function when compared with nonischemic controls. The fact that no injury was seen in either experimental group compared with controls was surprising. The data for the control lungs in this study correlated well with other nonischemic control groups from published studies by our laboratory [31], thereby eliminating the possibility of artificially lower functional indices in the controls. From the results of this study, coupled with the documented viability of porcine lung transplants procured from NHBDs undergoing 30 minutes of postarrest warm ischemia, we conclude that pulmonary allografts are more resistant to the injury associated with NHBDs. Perhaps their immunity to injury is in part due to the fact that the lung, compared with the heart, has a substantially lower substrate demand and is barely more than a skeletal collection of pulmonary vascular endothelium and bronchial epithelium.
Certainly there are limitations to our NHBD model that deserve mention. First, no effort was made to simulate a terminal brain injury, a condition known to affect potential allograft function. Second, we deliberately omitted two mechanisms of potential injury to the NHBD allograft to eliminate their effects on outcome: (1) lack of systemic anticoagulation at the time of arrest and (2) cold ischemic time. An additional difference between the brain dead, heart-beating donor and the NHBD is the fact that the NHBD cannot be anticoagulated until after the time of arrest because the donor is not legally "dead" at the time of withdrawal of ventilatory support. Anticoagulation of a terminally brain-injured but not yet brain-dead patient could be interpreted as hastening the demise of the donor. This leaves the possibility for diffuse microvascular thrombosis of the allograft. All of the harvested organs in this study underwent immediate reperfusion after explantation without any cold storage time, a scenario not encountered clinically. Third, as we were interested in the effects of the agonally arresting donor's circulation on the potential allograft, the isolated organ could not be excised, perfused to a baseline level of function, and used as its own control before the contrived insult as other isolated organ studies allow. We relied on our immediately reperfused nonischemic controls to serve as baseline for comparison. Finally, these experiments demonstrated allograft viability in the acute phase only and did not look at long-term allograft viability in a survival model of transplantation.
In conclusion, we believe that NHBDs are a feasible alternative for increasing the donor pool for thoracic transplantation. This study represents a systematic approach to studying the injury associated with reperfusion of cardiac and pulmonary allografts obtained from NHBDs. The results suggest that pulmonary allografts may well function better than cardiac allografts when reperfusion is not delayed, a condition that could be met with the controlled withdrawal of support of a terminally brain-injured, same-institution donor. Although cardiac allografts are resuscitatable after NHBD procurement, new preservation techniques will be required to achieve sustainable function. This study demonstrated that the period of hypoxic arrest is responsible for a significant degree of the injury associated with NHBD cardiac allografts and represents a key area for development of newer preservation techniques.
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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Address reprint requests to Dr Tribble, Department of Surgery, University of Virginia Health Sciences Center, Box 181, Charlottesville, VA 22908.
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