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Right arrow Lung - transplantation

Ann Thorac Surg 2006;81:1205-1213
© 2006 The Society of Thoracic Surgeons

Original article: General thoracic

Ex Vivo Evaluation of Human Lungs for Transplant Suitability

Thomas M. Egan, MD, MS a , * , John A. Haithcock, RRT b , William A. Nicotra, BS b , Giovanna Koukoulis, MD a , Hidetoshi Inokawa, MD, PhD a , Mayura Sevala, PhD a , Paul L. Molina, MD a , William K. Funkhouser, MD, PhD a , Burton J. Mattice, MBA c

a School of Medicine, University of North Carolina, Chapel Hill
b UNC Hospitals, University of North Carolina, Chapel Hill
c Carolina Donor Services, Durham, North Carolina

Accepted for publication September 15, 2005.

* Address correspondence to Dr Egan, Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, CB 7065, 3040 Burnett Womack Building, Chapel Hill, NC 27599-7065 (Email: ltxtme{at}med.unc.edu).

Presented at the Basic Science Forum of the Fifty-second Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 10–12, 2005.


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: If lungs could be retrieved from non-heart-beating donors, the critical shortage of lungs for transplant could be alleviated. An obstacle to this approach is the inability to predict these lungs' suitability for transplant. We used human lungs deemed unsuitable for transplant to develop a method to perfuse and ventilate human lungs ex vivo to assess gas exchange and vascular resistance, and to perform bronchoscopic inspection and radiographic evaluation.

METHODS: Lungs were retrieved from six brain-dead organ donors after cold Perfadex (Vitrolife, Kungsbacka, Sweden) flush, stored cold for 6 to 13 hours (mean, 8.7 hours) then perfused and rewarmed in a modified cardiopulmonary bypass circuit. Circuit perfusate was buffered colloid-crystalloid containing type-specific leukocyte-filtered blood (hematocrit of 10%–12%), circulated through a membrane oxygenator ventilated with CO2 and nitrogen to deoxygenate it. Lungs were ventilated with fraction of inspired oxygen (FIO 2) 0.5 when 32°C was reached. Gas exchange and vascular resistance was assessed at 5 L/minute flow at 37°C, FIO 2 0.5 and 1.0. Bronchoscopy, plain radiographs, and spiral computed tomographic (CT) scans were performed. Lung biopsies were obtained pre- and post-reperfusion.

RESULTS: Ex vivo perfusion did not cause increased wet to dry ratio, or major abnormalities by microscopy but was associated with elevated tissue levels of conjugated dienes. The alveolar-arterial difference in partial pressure of oxygen (PaO 2)/FIO 2 ratio in the ex vivo circuit was generally higher than in the six donors. Ex vivo radiographs and CT scans were abnormal in all lungs, confirming unsuitability of these lungs for transplant.

CONCLUSIONS: Ex vivo evaluation of human lungs is feasible and may be useful to evaluate transplant suitability of lungs retrieved after circulatory arrest from non-heart-beating donors.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Lung transplantation (LTX) is a successful therapy that palliates patients with a variety of end-stage lung diseases [1]. Unfortunately, access to LTX is severely limited by an inadequate number of suitable lungs from conventional donors. In the last five years, fewer than 920 isolated lung transplants were performed annually in the United States, compared with 2,200 heart and 4,600 liver transplants. Currently, almost 4,000 patients in the US are listed for LTX and face annual increases in waiting time and wait-list mortality. During the last 5 years, more than 2,500 patients listed for LTX died waiting [2]. However, these figures grossly underrepresent the extent of the demand for lungs for transplant, because the shortage of lungs has led to extremely strict listing criteria [3]. If the supply of lungs were unlimited, many more patients' lives might be extended or improved by transplant.

Donor lungs are far scarcer than any other solid organ for transplant, because lung function in the donor frequently does not meet established criteria for transplant [4], due to neurogenic pulmonary edema [5], pneumonia (with or without aspiration) [6], and adult respiratory distress syndrome (ARDS) in ventilated trauma victims.

Normally, organs for transplant are retrieved from a brain-dead donor after controlled cardiac arrest in an operating room; this is a "conventional" donor. There has been some interest in non-heart-beating donors (NHBDs) as a source of organs for transplant [7–9], but enthusiasm has been hampered by the requirement to minimize graft ischemic time [10]. A non-heart-beating donor is an individual who has sustained a cardiac arrest and has died in the field or in an emergency room. Among transplanted organs, the lung may be ideally suited to retrieval from NHBDs because the lung is the only solid organ transplanted that does not rely on perfusion for oxygenation. Respiration for lung parenchymal cells occurs via air spaces, and perfusion of the pulmonary capillary bed may represent an "oxygen steal." Thus, lung tissue remains viable for substantial periods of time after circulatory arrest, in contrast to other solid organs, and lungs may be suitable for transplant even if recovered from donors hours after circulatory arrest and death [11, 12]. This hypothesis is supported by the observation that pulmonary epithelial cells can be cultured from morgue specimens [13] and considerable experimental data, reviewed in a recent article [14]. If lungs from NHBDs could be transplanted successfully, then the lung donor shortage could be eliminated.

Steen and colleagues [15] developed a method to evaluate gas exchange function of lungs retrieved from porcine NHBDs, later transplanting these lungs to demonstrate suitable function. They used the identical system to evaluate lungs retrieved from a human NHBD and subsequently transplanted one of the lungs with good early function [16]. Because of the myriad ways in which humans die, and the variability in warm ischemic time among NHBDs, there is a pressing need for a reliable means of lung assessment to minimize the risk of graft failure if transplantation of lungs from NHBDs is an option for patients with end-stage lung disease. We used human lungs from conventional donors deemed unsuitable for transplant to develop such a system.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Organ Retrieval
Organ donors were identified and organs assessed for transplant suitability by staff at Carolina Donor Services (organ procurement organization [OPO] based in Durham, NC) and by physicians and surgeons at affiliated transplant programs. Lungs determined unsuitable were obtained for this study at the time of multiorgan retrieval in the identical manner of retrieval for clinical transplant [17]. After administration of 500 µg of PGE-1 (Alprostadil, Bedford Labs, Bedford, OH) into the donor pulmonary artery (PA), and arrest by aortic cross clamp, the lungs were flushed antegrade into the PA and retrograde with 5.6 liters of cold Perfadex (Vitrolife, Kungsbacka, Sweden). The trachea was divided at the thoracic inlet with a TA-stapling device with the lungs inflated with 100% oxygen. The double lung block was removed and immersed in cold Perfadex in a plastic bag, and transported on ice to Carolina Donor Services. After a minimum of six hours of cold storage (to mimic the time required to obtain serologies in the scenario of lung retrieval from a NHBD), the lungs were prepared for ex vivo assessment in a laminar flow hood (Sterilgard III Advance laminar flow hood; Baker Co., Sanford, ME) under sterile conditions.

An umbilical tape secured to the cephalad tracheal staple line at the time of retrieval was buttressed to the staple line with heavy silk sutures. A hard nylon barbed "T" connector with a short length of 3/8'' Tygon (Norton Performance Plastics, Wayne, NJ) tubing attached was secured into the right and left PAs with silk ligatures. A 16 gauge angiocath was inserted through a purse string suture into the right PA for PA pressure monitoring.

The Perfusion-Ventilation Circuit
A Biomedicus (Medtronic, Minneapolis, MN) pump was used to circulate fluid through 3/8" Tygon tubing and an Affinity (Medtronic) membrane oxygenator with integral heat exchanger (Fig 1). One lung block was studied in a sterile Plexiglas lung evaluation box (Vitrolife, Kungsbacka, Sweden), while the other seven were suspended into an open sterile Medtronic cell saver bag that served as a reservoir in the circuit, with a dependent outlet connected to 3/8'' circuit tubing. To prime the circuit, the inflow (PA) perfusion line was temporarily positioned in the reservoir cell saver bag. The perfusate (800 mL Ringer's lactate, 400 mL 25% human albumin, 20 mEq bicarbonate of soda (NaHCO3), 2 mL 50% dextrose, 1,000 units heparin, 1 gm ceftazidime, and 80 mg tobramycin) was circulated to prime the membrane oxygenator before adding a unit of type-specific, leukocyte-filtered packed red blood cells to produce a solution with a hematocrit of 12% to 15%, (confirmed with a Fisher hematocrit microcentrifuge [Fisher Scientific, Hampton, NH]) and an albumin concentration of 5 to 6 gm/100 cc.


Figure 1
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  		Fig 1. (A) Photograph of ventilation-perfusion circuit with human lungs (LU) suspended into opened Medtronic cell saver bag. (B = Medtronic Biomedicus pump; M = Medtronic Affinity oxygenator; T = Terumo CDI-500 display; V = Siemens C900 ventilator.) (B) Schematic of ex vivo ventilation-perfusion circuit.

 
Flow was interrupted and the lung block was positioned into the opened cell saver bag, suspended from the umbilical tape secured to the trachea. After a brief period of retrograde perfusion to remove air from the tubing in the PA of the lung block, the tubing was attached to the perfusion circuit. Perfusion was initiated at room temperature slowly (at 100 mL/minute). The PA pressure was monitored by a Transpac IV (Abbott Laboratories, Abbott Park, IL) disposable pressure transducer, attached to a 4-channel amplifier (National Instruments, Austin, TX) connected by a shielded cable to a personal computer (Gateway, Irvine, CA) equipped with a National Instruments I/O card and software for continuous online data acquisition.

Ex Vivo Lung Assessment
Perfusion flow rate was gradually increased maintaining PA pressure less than 20 mm Hg during warming, accomplished with the integral heat exchanger in the oxygenator by a heater-cooler (Hemotherm, Cincinnati, OH). The oxygenator was initially ventilated with 20%O2/5%CO2/75%N2. When perfusion temperature reached 32°C, a No. 8 Portex (Smiths Medical, Kent, UK) endotracheal tube (ET) was inserted into the trachea, and pressure-controlled lung ventilation was initiated with 50% oxygen with a pressure limit of 10 cm H2O above 5 cm H2O positive end expiratory pressure (PEEP) using a Siemens C900 ventilator (Siemens, Erlangen, Germany) through a disposable ventilator circuit. The pressure limit was gradually increased to 20 cm H20, or until tidal volume was 10 cc/kg donor weight. When ventilation of the lungs was initiated, the membrane oxygenator was ventilated with 8%CO2/95% N2 to load CO2 and deoxygenate the perfusate pumped into the PA. Rewarming continued and flow was gradually increased until 37°C was obtained and flow of 5 L/minute was established. Arterial blood gases (ABGs) were documented on FIO 2 0.5, then ventilation with 100% oxygen was initiated to obtain ABGs analogous to those obtained in a conventional brain-dead donor on 100% O2 with 5 cm H2O PEEP, referred to as the "O2 challenge test."

A CDI-500 system (Terumo Corp, Tokyo, Japan) continuously monitored temperature, pH, partial pressure of oxygen (PO 2), partial pressure of carbon dioxide (PCO 2), O2 saturation, hematocrit, K+, and bicarbonate concentrations on both sides of the lung perfusion circuit. Blood gas values were calibrated by withdrawing samples using an i-STAT blood gas machine (Abbott Laboratories), which also monitored glucose levels. The pH was adjusted by the addition of bicarbonate into the reservoir and glucose was added as needed to keep glucose levels greater than 100 mg/dL.

Parameters Collected, Bronchoscopy
Fiberoptic bronchoscopy was performed to inspect the airway and collect bronchial washings. Lung biopsies (@ 4 cm3) were obtained from accessible portions of the midlung block using a surgical stapling device (U.S. Surgical, Norwalk, CT), prior to commencement of perfusion, and after the lung block was rewarmed and perfused at full flow (post-reperfusion). Biopsies were partitioned; one portion was fixed in formalin, and other portions flash frozen and stored at –80°C. Lungs were then transported to UNC Hospitals (UNCH) for radiographic studies.

Radiologic Assessment
Plain anteroposterior (AP) radiographs and spiral computed tomographic (CT) scans were obtained on all specimens. In 3 cases, lungs were transported with low flow perfusion and ventilation with 100% O2. In the 3 other cases, lungs were cooled in the circuit to room temperature (20°C), flushed antegrade with 2.8 L cold Perfadex, and transported immersed in cold Perfadex for radiologic assessment. All radiographs were interpreted by one of us (PM).

Analytical Assessments: Wet to Dry (W/D)
A portion of each frozen biopsy was weighed, then dried in a 60°C oven for 48 hours and reweighed to determine W/D ratio.

Adenosine Monophosphate (AMP), Adenosine Diphosphate (ADP), and Adenosine Triphosphate (ATP) Analysis by High Performance Liquid Chromatography (HPLC)
Lung tissue levels of AMP, ADP, and ATP were determined as described previously by HPLC [18]. Total adenine nucleotide levels (TAN) were defined as TAN = AMP + ADP + ATP, and are expressed as µmoles/gm dry weight.

Conjugated Dienes
Lung conjugated dienes were determined as a surrogate for free radical mediated tissue damage [19]. Frozen lung tissue (50–75 mg) was homogenized in distilled water (5 mL/g tissue) for 1 minute. The homogenate was extracted in a mix of chloroform to methanol 2:1 (v/v), vortexed, and centrifuged at 1,000 x g for 10 minutes. The lower organic layer was washed twice with 0.003M HCl and centrifuged again. The final organic layer was dried under rotary evaporation and resuspended in 1.5 mL heptane. Concentration of conjugated dienes was detected spectrophotometically at 234 nm using a Beckman DU-6 UV-Visible spectrophotometer (Beckman Instruments Inc, Fullerton, CA) against a heptane blank. Results are expressed as units of optical density per mg dry weight of lung tissue.

Histologic Analysis
Lung pieces were fixed in 10% buffered formalin, and paraffin-embedded sections were prepared using standard techniques, stained with hematoxylin and eosin. Specimens were evaluated by one of us (WF) in a masked manner to assess the degree of reperfusion injury and lung architecture.

Statistics
Results are presented as mean ± standard error of the mean. Comparisons were made between pre- and postreperfusion samples using paired t tests. Differences were considered significant if p was less than 0.05.

This study was approved by the University of North Carolina's Biomedical Institutional Review Board on March 5, 2003, and renewed Dec. 21, 2004. Consent for use of human organs for research was obtained from next-of-kin by Carolina Donor Services staff.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Eight human lung blocks were available for this study. Donor characteristics and reason for refusal are outlined in Table 1. Technical problems precluded completion of evaluation of two lung blocks. A preperfusion lung biopsy was not obtained in one specimen. One donor, with a greater than 40-pack-year smoking history, was found to have an incidental non-small cell lung cancer at the apex of the right lung, which precluded the use of all other organs.


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  		Table 1. Donor Characteristics and Reason for Refusal
 
Results of ex vivo perfusion and ventilation of six human lung blocks are summarized in Table 2. Cold ischemic time varied from 6 to 13 hours (mean 522.3 ± 56.1 minutes, or 8.7 hours). A 5 L/minute flow was achieved in all lung blocks; in two of six, this resulted in mean PA pressure in excess of 25 mm Hg, implying pulmonary vascular resistance greater than 5 Wood units. Wet to dry weight ratios decreased in 4 lung blocks and increased in one (p = not significant [NS]) as a result of reperfusion, but tissue levels of conjugated dienes increased significantly after reperfusion, implying some effects of oxygen free radicals on cell membranes due to reperfusion. For technical reasons, AMP and ADP levels were only available in 4 lung blocks. The AMP and ADP levels were less after reperfusion, but these differences did not reach statistical significance. Total adenine nucleotides did not differ significantly between pre- and post-reperfusion samples, but ATP levels were modestly but significantly increased after reperfusion. Data from analysis of histologic specimens are summarized in Table 2. There was no difference between pre- and post-reperfusion samples with respect to evidence of edema or injury.


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  		Table 2. Results of Ex-Vivo Perfusion and Ventilation of Six Human Lung Blocks
 
Gas exchange documented in the donor and in the ex vivo circuit is presented in Table 3 along with radiographic findings. Figure 2 shows comparison of PaO 2/FIO 2 in the circuit with FIO 2 0.5 and 1.0 compared with PaO 2/FIO 2 in the donor. We assessed gas exchange at two different FIO 2 because of our anecdotal observation that PaO 2 in conventional donors on FIO 2 of 1.0 does not always reflect PaO 2 measured at lower FIO 2. In general, PaO 2/FIO 2 in the ex vivo circuit was better than PaO 2/FIO 2 documented in the donor. We did not correct donor PaO 2 for temperature because donor temperature was not routinely available. Assuming donor temperature was greater than 33°C, corrected donor PaO 2 was within 85% of reported values [20]. The impact of mild hypothermia in the donors on PaO 2 was probably not as relevant as temperature correction for hemoglobin saturation at lower FIO 2 and PaO 2 [21].


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  		Table 3. Gas Exchange and Radiographic Findings in Donor and in Ex-Vivo Circuit
 

Figure 2
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  		Fig 2. (A) PaO 2/FIO 2 in the circuit with FIO 2 1.0 compared with PaO 2/FIO 2 in the donor. (B) PaO 2/FIO 2 in the circuit with FIO 2 0.5 compared with PaO 2/FIO 2 in the donor. The PaO 2/FIO 2 ratio in the donor was determined only on FIO 2 1.0, and when more than one PaO 2 was available on FIO 2 1.0, the average was used, as reported in Table 3. There was a better correlation between PaO 2/FIO 2 assessed in the circuit with PaO 2/ FIO 2 in the donor when lungs were ventilated ex vivo with FIO 2 0.5. The reason for this is unclear. (FIO 2 = fraction of inspired oxygen; PaO 2 = partial pressure of oxygen.)

 
Bronchoscopy was easily performed and all segments visualized. Bronchial washings were obtained, but not analyzed in the interest of cost. All six evaluated lungs showed abnormalities on spiral CT scans consistent with lung pathology, confirming the clinical impression that these lungs were not suitable for transplantation. In five cases, the plain radiograph showed parenchymal abnormalities that were subsequently amplified by CT scan. Ex vivo radiographic images from one of the lung blocks are presented in Figure 3.


Figure 3
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  		Fig 3. Ex vivo plain radiograph and computed tomographic scan images of donor lung No. 1 showing bilateral lower lobe consolidation consistent with bilateral lower lobe pneumonia. This donor had good arterial blood gases but bilateral purulent bronchoscopy resulted in a determination that the lungs were not suitable for transplant.

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
The shortage of suitable lungs for transplant is a serious impediment to more widespread availability of LTX to palliate patients with end-stage lung disease. Although bilateral lower lobe transplants from living donors can be performed with acceptable morbidity and mortality [22], there are often size constraints and other impediments to this approach [23]. Increasingly, so-called "marginal" donors are being used in LTX, but this may result in poorer post-transplant survival or reduced long-term graft function [24, 25].

We have postulated that lungs might be suitable for transplant even if retrieved hours after circulatory arrest and death [11]. This innovative approach to the lung donor shortage may be ideally and uniquely suited to the lung. There is a small but encouraging experience using lungs retrieved after life support was withdrawn [26] (also personal communication from GA Patterson, May 2005) but the practicality of this is limited by the number of suitable lungs in this small population of potential organ donors.

The interest in the use of NHBDs as a source of donor organs has prompted a classification of non-heart-beating donors [27]. It is the possibility of retrieving lungs for transplant from class I donors (uncontrolled arrest resulting in donors dead on arrival to hospital) that has been the focus of our laboratory investigations. Steen and colleagues [16] reported a successful human LTX after retrieval from a NHBD following ex vivo gas exchange assessment in a modified cardiopulmonary bypass circuit. Varela [28] reported outcomes using lungs from donors dying in the emergency room that were equivalent to outcomes using conventional donors after in vivo gas exchange assessment.

It is unknown how many human lungs might be suitable for transplant following recovery after circulatory arrest but data from the CDC's National Vital Statistics Reports [29] summarized in Table 4 suggest that the impact may be huge. In the age range from 15 to 64 years, there were more than 25,000 suicides in 2002 (more than half using firearms) and more than 16,000 homicides (with two-thirds due to firearms). Although not all of the 66,000 accidental deaths would be appropriate for donation, many of these deaths are sudden and could provide potential NHBDs for evaluation.


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  		Table 4. Causes of Death by Age, 2003
 
Before transplantation of lungs retrieved from NHBDs becomes routine, there is a pressing need for a reliable means of assessment to reduce the risk of graft failure after transplantation. Using an isolated perfused rat lung preparation, Tremblay and colleagues [30] demonstrated the deleterious effect of premortem hypotension due to exsanguination on subsequent lung function. The perfusion circuit we described allows for reliable assessment of the human lung's response to perfusion and ventilation at physiologic levels. Although we used lungs that were judged unsuitable a priori, these organs allowed us to develop methods that can be used to assess lungs from NHBDs where premortem indices of pulmonary function are unknown. We showed slightly better gas exchange characteristics of many of the lungs we evaluated compared with gas exchange in the donor, despite CT scan evidence of significant parenchymal disease. Perhaps perfusion with a higher hematocrit solution might demonstrate poorer oxygenation in the lungs evaluated.

The cold ischemic time experienced by the lungs in our study is a realistic and practical range to obtain necessary serologies on NHBDs before transplanting these organs. Pre-evaluation assessment of serologies would reduce exposure risk to OPO personnel performing the evaluation, and would be more cost efficient.

We measured tissue adenine nucleotide levels because levels of total adenine nucleotides (TAN = AMP + ADP + ATP) correlated with lung viability (assessed by trypan blue exclusion) [31] and filtration coefficient, a measure of capillary endothelial function in an isolated perfused rat lung model [32]. We are not aware that TAN in normal human lung has been reported, but the levels we measured were less than normal levels measured in rat lung (@ 10 µmoles/gm dry weight) [18]. We documented increased conjugated diene levels, implying elaboration of free radicals, despite little evidence of significant injury by histology or development of pulmonary edema as evidenced by wet to dry weight ratio. If these measurements are found to be useful predictors of graft suitability in future studies, then their determination noninvasively may supplant the need for more resource intensive evaluation.

We performed bronchoscopy to demonstrate feasibility and visualize the quality of secretions. Bronchoscopic washings were obtained but were not routinely analyzed in the interest of cost. Plain radiographs and CT scans were feasible ex vivo, and provided a means to diagnose infiltrates and other abnormalities that might exclude lungs retrieved from NHBDs from being considered appropriate for transplantation. Thus, we consider radiographic assessment, especially by CT scan, to be a potentially important adjunct to the ex vivo evaluation of lungs for transplant suitability.

It is intriguing to speculate that lungs retrieved from NHBDs and assessed in an ex vivo circuit may function better than lungs retrieved from conventional donors. Lungs retrieved after sudden death will not have been subjected to the deleterious effects of brain death [33, 34], which is associated with apoptosis in livers [35]. Lower levels of intracellular adhesion molecule one (ICAM-1) were detected in livers retrieved from human NHBDs compared with conventional organ donors, suggesting less exposure to inflammatory mediators in NHBDs [9]. Slow rewarming and gradual increasing of perfusion flow rates as we did is analogous to controlled reperfusion of ischemic lung tissue, which has been shown to be beneficial in conventional lung transplantation [36], as has reperfusion with leukocyte-free reperfusate [37, 38], another feature of our circuit. Perfusion with rewarming, followed by a second interval of cold ischemia, is also analogous to ischemic preconditioning, wherein protective mechanisms are up-regulated to minimize the deleterious effects of reperfusion of ischemic tissue [39, 40].

Ex vivo assessment of gas exchange has been demonstrated to predict subsequent gas exchange function after transplant in sheep [41] and pigs [15]. With this study, we document the feasibility of ex vivo human lung assessment using conventional cardiopulmonary bypass equipment. We plan to test the hypothesis that this system can be used to predict function of human lungs retrieved from NHBDs. In the future, retrieval of lungs from NHBDs with ex vivo evaluation by OPOs or shipment to one of several evaluation centers may make lung transplant from NHBDs practical on a large scale.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This work was supported by a grant from the Cystic Fibrosis Foundation and by donations-in-kind from: Cincinnati Sub-Zero, Cryolife, Ethicon, Medtronic, Olympus, Pilling Surgical, Portex, Terumo, US Surgical and Vitrolife. The authors wish to acknowledge the advice and technical assistance of Stig Steen, MD, PhD, of the University of Lund, Sweden; the editorial assistance of Margaret A. Cloud in preparation of this manuscript; and the technical assistance of Kimberlie Burns for preparation of histologic specimens.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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