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Back to Annual Meeting Program
WEDNESDAY MORNING, MAY 1, 1996
7:00 a.m. FORUM SESSION II - GENERAL THORACIC SURGERY Room 6C/F, San Diego Convention Center
Moderators: Keith S. Naunheim, M.D. Larry R. Kaiser, M.D.
F9. REGULATORY EFFECTS OF INTERLEUKIN-10 ON LUNG ISCHEMIA-REPERFUSION INJURY. Michael J. Eppinger, M.D.*, Peter A. Ward, M.D.*, Steven F. Bolling, M.D. and G. Michael Deeb, M.D. Ann Arbor, Michigan
Lung reperfusion injury may predispose the transplanted lung to poor function and early rejection. Interleukin-10 (IL-10), a cytokine with primarily anti-inflammatory effects, was studied to determine its effects on the development of early lung reperfusion injury.
Adult male rats underwent clamping of the left bronchus, pulmonary artery, and pulmonary vein for 90 minutes of ischemia, followed by 4 hours of reperfusion (controls, n=6). Time-matched shams underwent hilar dissection but not lung ischemia (n=4). Lung injury was measured by vascular permeability to 125I-BSA (cpm/g lung tissue/ml blood). To evaluate the effect of exogenous IL-10, additional animals (n=4) received 10 μg IL-10 intravenously prior to ischemia. To assess the role of endogenous IL-10, animals received 200 μg of either rabbit anti-mouse IL-10 IgG or pre-immune IgG (n=5 each) prior to ischemia. Compared to shams, controls demonstrated significantly more lung injury (permeability index 0.358±0.035 vs. 0.102±0.009, p<0.01). Animals receiving IL-10 had significantly less lung injury compared to controls (0.167±0.028, p<0.01). Animals receiving IgG against IL-10 had significantly more lung injury than animals receiving pre-immune IgG (0.411±0.056 vs 0.237±0.044, p<0.05). Alveolar macrophages from animals after 90 minutes of lung ischemia produced more TNF-a in culture than unstimulated macrophages; this production was reduced significantly by the addition of IL-10 to the culture medium. Northern blot analysis of whole lung RNA demonstrated that the reduction in TNF-a occurred at the mRNA level.
We conclude that endogenous IL-10 has a protective effect against lung reperfusion injury during this early phase; and that IL-10 administration can reduce lung reperfusion injury, at least in part through its ability to reduce production of TNF-a by alveolar macrophages.
*By invitation F10. CHANGES IN LUNG COMPLIANCE AFTER VOLUME REDUCTION SURGERY IN A RABBIT MODEL OF BULLOUS EMPHYSEMA. Fernando E. Kafie, M.D.*, Matthew Brenner, M.D.*, John C. Chen, M.D.*, Edward A. Stemmer, M.D., Michael Budd, B.S.* and Michael W. Berns, M.D.* Orange, California
Purpose: Staple lung volume reduction surgery has recently been described for treatment of emphysema resulting in improvement in Forced Expiratory Volume (FEV1). Little is known regarding physiologic mechanisms of response in surgically treated emphysema patients. We hypothesized that volume reduction surgery in animals with pulmonary bullous emphysema would result in decreased lung compliance. Reduction in compliance may decrease airway resistance and improve Forced Expiratory Volume.
Methods: Seventeen New Zealand (NZ) white rabbits were induced with emphysema according to our previously published model with sephadex beads and carrageenan. This animal model has been previously used to study surgical treatments for emphysema. Pressure-volume relationships were measured at 60, 40 and 20 cc inflation pre- and post-operatively in anesthetized animals. Thoracoscopy was performed prior to thoracotomy to document bullae formation. A mini-thoracotomy was performed on the side of bullae formation. Resection of areas with emphysema was accomplished with a standard pediatric multirow surgical stapler.
Results: Comparison of pressure-volume curves pre- and post-op demonstrate significant decrease in static compliance.
Conclusion: Lung compliance is decreased following lung volume reduction surgery in New Zealand White rabbits. This finding suggests that increased elastic recoil and airway support may contribute to the mechanism of improved function following lung volume reduction surgery.
*By invitation F11. GENETICALLY ENGINEERED PORCINE LUNGS IN A HUMAN XENOTRANSPLANTATION MODEL. Casey W. Daggett, M.D.*, Mark Yeatman, FRCS*, Andrew J. Lodge, M.D.*, JeffH. Lawson, M.D.*, Edward P. Chen, M.D.*, Meera Srinivasan, B.A.*, Peter Van Trigt, M.D., Gerry Byrne, Ph.D.*, John Logan, Ph.D.*, Jeff L. Platt, M.D.* and Robert D. Davis, M.D.* Durham, North Carolina
Pulmonary xenotransplantation is currently limited by an abrupt rise in pulmonary vascular resistance, capillary leak, loss of compliance, and poor gas exchange. Complement activation is believed to be a central event in this process. The human complement regulatory proteins, decay accelerating factor (hDAF) and CD59 (hCD59), inhibit both the classical and the alternative pathways. Using an ex vivo model has made it possible to study specific aspects of acute pulmonary dysfunction in an heterologous combination. The pulmonary function of swine expressing hDAF/hCD59 (n=7) was compared to that of the lungs from farm bred animals (n=6) while the lungs were perfused with human fresh frozen plasma (FFP). Lungs from adult swine were isolated and preserved with Euro-Collins solution. The perfusate consisted of freshly thawed, heparinized, pooled O+FFP reconstituted in 40% Lactated Ringer's solution. Perfusion fluid was delivered to the pulmonary artery at 37°C via a gravity reservoir and recirculated by a roller pump. The lungs were ventilated with 60% oxygen and the tidal volume was controlled to keep the peak airway pressure between 35-40 cm H2O. After two hours of perfusion the control lungs had lost an average of 74 ± 16% of their static pulmonary compliance versus a 6 ± 17% loss by the transgenic lungs (p<0.001). The controls had an average transalveolar capillary leak of 561.7 ml compared to 5.9 ml by transgenic lungs (p<0.05). The control lungs achieved an oxygen concentration in the perfusate of 259 ± 42 mmHg compared to 383 ± 42 mmHg in transgenic lungs (p<0.001). The pulmonary vascular resistance was 20.3 ± 12.6 mmHg/L/min in controls and 10.9 ±2.0 mmHg/L/min in transgenic lungs (p = 0.17).
In conclusion, the lungs from swine expressing hDAF/hCD59 demonstrated superior pulmonary function compared to lungs from farm bred swine when perfused with human plasma. The compliance, capillary leak, oxygenation, and pulmonary vascular resistance were all significantly improved in the transgenic lungs as compared to controls. These data indicate that complement activation is in part responsible for acute pulmonary dysfunction in xenotransplantation and that inhibiting complement function with hDAF and hCD59 can improve several aspects of pulmonary function in porcine-to-human pulmonary transplantation.
*By invitation F12. ISOLATED LUNG PERFUSION WITH MELPHALAN FOR TREATMENT OF METASTATIC PULMONARY SARCOMA. Sumihiko Nawata, M.D.*, Howard M. Ross, M.D.*, Nuno Abecasis, M.D.*, Komal S. Sachar, B.S.*, Huiming Cheng, M.A.* and Michael E. Hurt, M.D., Ph.D. New York, New York
Introduction: Metastatic pulmonary sarcoma remains a significant clinical problem with systemic chemotherapy offering little hope for cure. Isolated lung perfusion (ILP) avoids systemic chemotherapeutic toxicity, but the most efficacious agent remains unknown. Melphalan (MN) is active in the treatment of extremity sarcoma via isolated limb perfusion and therefore MN activity in a pulmonary sarcoma metastases model was investigated.
Methods: Toxicity Study: Nineteen F344 rats underwent left ILP with MN at total doses of 20 mg (n=2), 5 mg (n=6), 2 mg (n=6), or buffered hespan (BH) (n=5). Rats underwent contralateral pneumonectomy on day 21 post-perfusion to evaluate left lung toxicity. Efficacy Study: On day 0, 41 F344 rats were injected with 5x106 MCA sarcoma cells via the external jugular vein. On day 7, rats received either 2 mg MN i.v. (n=10), 1 mg MN i.v. (n=8), or underwent ILP with MN (2 mg) (n=12) or BH (n=11). On day 14, rats were sacrificed and lung sarcoma nodules were counted. Statistical analysis was performed with ANOVA and Student T test.
Results: Toxicity: All rats perfused with 20 mg or 5 mg of MN died perioperatively. Rats perfused with 2 mg of MN or BH survived contralateral pneumonectomy at rates of 67% and 80%, respectively. Efficacy: The number of left lung lesions decreased significantly in the animals receiving MN via ILP as compared to all the other groups (p<0.05). In addition, MN ILP resulted in significant reduction of tumor nodules in treated lung as compared to right lung (p<0.02). All rats that received MN 2 mg i.v. died within 5 days of injection.
Conclusion: Melphalan ILP is well-tolerated at a dose that leads to 100% mortality intravenously. Melphalan ILP significantly decreased the number of metastatic pulmonary nodules compared to i.v. treatment. Melphalan can be considered an effective agent for ILP of metastatic sarcoma and studies evaluating Melphalan by ILP in man are warranted.
*By invitation F13. GENE THERAPY FOR LUNG CANCER: ENHANCEMENT OF TUMOR SUPPRESSION BY A COMBINATION OF SYSTEMIC CISPLATINUM AND ADENOVIRUS-MEDIATED P53 GENE TRANSFER. Dao M. Nguyen, M.D., FRCSC*, Sandra A. Weihle, B.Sc.*, Patricia E. Koch, M.Sc.*, Richard J. Cristiano, Ph.D.* and Jack A. Roth, M.D. Houston, Texas
Mutations of the p53 tumor suppressor gene occur in up to 70% of human non-small cell lung cancers. Restoration of the normal p53 function by gene replacement therapy in cancer cells with an abnormal p53 gene leads to G1cell cycle arrest or apoptosis (programmed cell death). We observed that brief exposure of H1299 lung cancer cells (deleted p53) to low doses of cisplatinum (CDDP) prior to gene transfer resulted in a 2-fold elevation of reporter gene expression. To determine if such treatment would potentiate the tumor suppression effect of the AdV-CMV-p53 (recombinant adenovirus carrying the p53 gene driven by the cytomegalovirus [CMV] enhancer/promoter), H1299 cells were treated with CDDP (0.062 μg/ml x 24 hrs) 2 days prior to transfection with AdV-CMV-p53 at multiplicities of infection (MOI) of 1 and 5 viral particles per cell (n=6 per group). Prior exposure to CDDP resulted in a 35% (MOI = 1) to 61% (MOI = 5) enhanced inhibition of tumor cell proliferation 3 and 5 days after AdV-CMV-p53 transfection as compared to that of similarly treated cells without prior CDDP exposure. In vitro transfection of CDDP-treated cells with AdV-CMV-p53 led to earlier, higher levels of p53 gene expression as well as increased apoptosis. Subcutaneous H1299 tumors were created in irradiated nude mice. A combination of sequential intraperitoneal CDDP (5 μg/g of body weight) and injections of AdV-CMV-p53 (5x109 viral particles/injection) into H1299 tumors (200 mm3) 2, 4, 6 days following CDDP administration resulted in a profound and prolonged inhibition of tumor growth of H1299 tumors in nude mice (n=5 per group). While systemic administration of CDDP had a small effect on H1299 tumor growth (3000±218 mm3) compared to saline-injected tumors (3550±240 mm3, 20 days after injection), tumors treated by a combination of CDDP and AdV-CMV-p53 were significantly smaller (1570±140 mm3) than those treated with AdV-CMV-p53 alone (3100±260 mm3, 32 days after treatment, p<0.0001). The timing of systemic CDDP administration relative to gene transfer was identified to be critical as simultaneous intraperitoneal CDDP and intratumoral AdV-CMV-p53 injections were less effective than sequential treatment (2300±196 mm3 vs 1570±140 mm3, p<0.001). A second cycle of combined CDDP and gene therapy given 10 days after completion of the first one led to further suppression of tumor growth (679±89 mm3 vs 1570±140 mm3, p<0.001). In conclusion, the combination of sequential systemic CDDP and intratumoral injection of AdV-CMV-p53 results in a superior tumor suppression effect. Inhibition of tumor growth can be maintained by repeated cycles of gene therapy. This gene therapy strategy has been incorporated into a phase I clinical trial for the treatment of lung cancer and provides the basis for the development of improved therapeutic protocols.
*By invitation F14. THE DUAL FACES OF INHALED NITRIC OXIDE: IMPROVED LUNG PRESERVATION WITH EXOGENOUS NITRIC OXIDE GIVEN AT THE TIME OF HARVEST BUT NOT WHEN GIVEN DURING REPERFUSION. Yoshifumi Naka, M.D., Ph.D.*, Dilip K. Roy, M.D.*, Hui Liao, M.D.*, David M. Stern, M.D.*, Arthur J. Smerling, M.D.*, Robert E. Michler, M.D., David J. Pinsky, M.D.* and Mehmet C. Oz, M.D.* New York, New York
Although inhaled nitric oxide (NO) lowers pulmonary vascular resistance in ARDS, its usefulness in the setting of lung transplantation remains controversial. We hypothesized that NO may have either beneficial or harmful effects depending upon the circumstances in which it is given. If NO given to the pulmonary donor raises endogenous (tissue) cGMP levels, this should benefit lung preservation by promoting vascular function, as cGMP analog supplementation is known to do. NO administered during reperfusion may rapidly combined with superoxide to become either ineffective or toxic (forming peroxynitrite and hydroxyl radical). Using an orthotopic rat left lung transplant model in which hemodynamics and functional parameters can be measured independent of the native lung [following ligation-of the right pulmonary artery (PA)], 4 experimental groups were established using male Lewis rats: (1) no supplemental gas given (No NO); (2) NO given at the time of harvest (65 ppm measured by chemiluminescence, Harvest NO); (3) supplementation of the preservation solution with a membrane permeable cGMP analog 8-Bromo-cGMP under No NO conditions (500 nM, cGMP); and (4) NO given during reperfusion (65 ppm, Reperfusion NO). For all groups, lungs were preserved for 6 hours at 4°C in Euro-Collins solution. Thirty minutes following ligation of the native PA, PA flow (ml/min), arterial oxygenation (pO2, mmHg), graft neutrophil infiltration (myeloperoxidase activity, MPO, Δabsorbance/min at 460 nm), and recipient survival were determined.
To explore potential mechanisms underlying these beneficial effects of Harvest NO, and knowing that NO stimulates the soluble guanylate cyclase to produce endogenous cGMP, we determined (by ELISA) that Harvest NO increases endogenous pulmonary cGMP (by 38% vs No NO, p<0.05). These data suggest that stimulating the NO/cGMP pathway (such as by Harvest NO or by supplementing the preservation solution with a cGMP analog) is beneficial. We conclude that inhaled NO can be either beneficial or neutral, depending upon the circumstances in which it is given.
Robert E. Gross Research Scholar *By invitation F15. MITIGATION OF INJURY IN CANINE LUNG GRAFTS BY EXOGENOUS SURFACTANT THERAPY. Ken E. Gehman, M.D.*, Richard J. Novick, M.D., Andrea A. Gilpin, HBSc.*, Imtiaz S. AH, M.D.*, Ruud A.W. Veldhuizen, Ph.D.*, Jenifer Duplan, AHT*, Lynn Denning, AHT*, Fred Possmayer, Ph.D.* and James F. Lewis, M.D.* London, Ontario and Edmonton, Alberta, Canada
We have previously demonstrated alterations in endogenous surfactant after lung transplantation and improved pulmonary function after 36 hour preservation of normal canine lung grafts using donor bovine lipid extract surfactant (bLES) therapy. The objective of the current study was to determine whether exogenous bLES can mitigate the damage in lung grafts induced by high volume ventilation before procurement. Five control donor dogs were subjected to 8 hours of mechanical ventilation using a tidal volume of 45 ml/kg. This produced a significant decrease in PO2 values (p<0.01) and significant increases in bronchoalveolar lavage (BAL) neutrophil count (p = 0.05), BAL protein concentration (p<0.01) and the ratio of poorly-functioning small surfactant aggregates (SA) to superior-functioning large aggregates (LA, p = 0.02) [see Table 1]. Animals (n=5) given instilled bLES (100 mg/kg) and subsequently ventilated with a tidal volume of 45 ml/kg demonstrated no significant change in PO2 values over 8 hours and a decrease in BAL protein concentration (p = 0.04 versus control) and SA/LA ratio (p = 0.01 versus control).
All 10 lung grafts were then flushed with 60 ml/kg modified Euro-Collins solution and stored for 18 hours at 4°C. Left lungs were transplanted into recipient dogs and reperfused for 6 hours. No additional bLES therapy was used. Results after 6 hours of reperfusion, including SA/LA in whole lung lavages from transplanted grafts, are shown in Table 2 (Recipient Animal data):
We conclude that instillation of exogenous bLES prior to 8 hours of high volume ventilation decreased protein leak, decreased surfactant SA/LA ratio and prevented the subsequent deterioration of PO2 values in donor animals. Moreover, when these lungs were transplanted into recipients, bLES-treated grafts had superior PO2 values, improved ventilation efficiency and a higher proportion of superior-functioning surfactant aggregate forms in the alveolar space than control grafts. bLES therapy can thus protect lung grafts from ventilation-induced injury and may offer a promising means to expand the donor pool.
*By invitation F16. EXOGENOUS SURFACTANT TREATMENT BEFORE AND AFTER 16-HOUR ISCHEMIA IN EXPERIMENTAL LUNG TRANSPLANTATION. Bernard Hausen, M.D.*, Wolfgang Bernhard*, Charles Hewitt, M.D., Ph.D.*, Frank Schroder*, Maike Beuke* and Hans-Joachim Schafers, M.D.* Hannover, Germany and Camden, New JerseySponsored by: Hans-George Borst, M.D., Hannover, Germany
Severe alterations in surfactant content of lung grafts occur following extended ischemia. A syngeneic, acute, in situ transplant model in the rat was used to determine the impact of exogenous surfactant treatment. Double lung blocs were flush perfused and preserved for 16 hours and then reperfused for 120 minutes. Group I received intratracheal surfactant (200 mg/kg; Curosurf) before perfusion and donor harvesting (n=6), group II after ischemia and before reperfusion (n=6). Untreated lungs served as controls (group III). Serial measurements of graft pulmonary vascular resistance (PVR), alveolar arterial oxygen difference (AADO2), compliance and resistance were obtained. Final graft assessment included weight gain and histological analysis. Data is listed as mean ± standard error (*p<0.05 by ANOVA).
The mean survival after reperfusion in group I was 120 min. versus 113 ± 3 in group II and 117 ± 3 in group III. The weight increase was 12 ± 4% in group I, 105 ± 15% in group II and 87 ± 17% in group III.
There was no significant difference in the histological analysis regarding interstitial and intra-alveolar edema or pulmonary hemorrhage.
Graft pretreatment before perfusion resulted in significantly improved oxygenation and compliance as well as decreased vascular resistance when compared to controls or treatment before reperfusion. It is therefore concluded that donor surfactant pretreatment is advantageous for preservation of overall graft function after 16 hours of ischemia.
*By invitation F17. BOTH BLOOD AND CRYSTALLOID BASED EXTRACELLULAR SOLUTIONS ARE SUPERIOR TO INTRACELLULAR SOLUTIONS IN LUNG PRESERVATION. Oliver A.R. Binns, M.D.*, Nuno F. DeLima, M.D.*, Scott A. Buchanan, M.D.*, Jeff T. Cope, M.D.*, Robert C. King, M.D.*, Chris A. Marek, B.S.*, Curtis G. Tribble, M.D. and Irving L. Kron, M.D. Charlottesville, Virginia
Lung transplantation remains limited by donor ischemic time, inadequate graft preservation, and reperfusion injury. We evaluated the effects of an extracellular preservation solution, with or without the addition of blood, as compared to the standard intracellular solution Euro-Collins. Using an isolated, whole blood perfused/ventilated rabbit lung model, we studied three groups of animals. Lungs were flushed with either Euro-Collins (EC), low-potassium-dextran (LPD), or a 20% blood/low-potassium-dextran solution (BLPD). All lungs were harvested en bloc, stored inflated at 4°C for 18 hrs, and then reperfused at 60 ml/min with whole blood. Continuous measurements of pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), left atrial pressure, dynamic airway compliance (CPL), and weight gain were obtained. Fresh, non-recirculated venous blood was used to determine the single pass pulmonary venous-arterial O2gradient (V-A O2). All data are reported as means ± SEM after 30 minutes of reperfusion and analyzed by ANOVA.
We conclude that extracellular solutions provide superior preservation of pulmonary function as demonstrated by increased oxygenation, decreased pulmonary artery pressure, decreased pulmonary vascular resistance, improved airway compliance, and decreased edema formation as measured by wet-to-dry ratios. However, the addition of blood does not confer any demonstrable advantage over LPD alone in this model of 18 hour cold ischemia. A potential mechanism of injury by intracellular solutions may involve endothelial damage of the pulmonary vasculature.
*By invitation F18. NICORANDIL, K+ CHANNEL OPENER, AMELIORATES LUNG REPERFUSION INJURY. Motohiro Yamashita, M.D.*, Ralph A. Schmid, M.D.*, Shozo Fujino, M.D.*, Koei Ando, M.D.*, Joel D. Cooper, M.D. and G. Alexander Patterson, M.D. St. Louis, Missouri
Adenosine triphosphate-sensitive K+ (KATP) channels are a class of ionic channels recently found important in ischemic injury. Nicorandil (Nic) acts as a KATPchannel opener. Nic also acts as a nitric oxide donor and through that mechanism may reduce lung allograft reperfusion injury. In this study, we examined the effect of Nic on post-transplant function of preserved lung allografts. Donor lungs were flushed with modified Euro-Collins solution and stored for 21 hours at 1°C. Immediately following transplantation, the contralateral right main pulmonary artery and bronchus were ligated to assess isolated allograft function. Hemodynamics and arterial blood gas analysis (FiO2 1.0) were assessed for 6 hours prior to sacrifice. Allograft myeloperoxidase (MPO) activity was assessed as an index of leukocyte sequestration. Group I (n=5) animals received no Nic. In group II (n=5), Nic (24 mg/L) was added to the flush solution, recipient animals received Nic (0.5 mg/kg, IV) just prior to reperfusion and a continous infusion of Nic (0.74 ± 0.03 mg/kg/hr) during the assessment period. In group III (n=4), Nic was administered as in group II. In addition, group III animals received glibenclamide, a potent KATP channel antagonist (3 mg/kg) 15 minutes before Nic administration. Superior gas exchange (Fig. 1), hemodynamics and MPO data (Table 1) were noted in group II. The improvement of gas exchange and hemodynamics was suppressed by glibenclamide. These findings suggest Nic administration in the flush solution and during the reperfusion period ameliorates allograft function, improves cardiac output, and reduces pulmonary vascular resistance (PVR) and MPO activity in the transplanted lung. Lung allograft reperfusion injury is reduced by Nic likely as a result of its effect on KATP channels.
*By invitation 7:00 a.m. FORUM SESSION III - CARDIAC SURGERY Room 6A/B, San Diego Convention Center
Moderators: D. Craig Miller, M.D. Randall B. Griepp, M.D.
F19. MECHANISMS UNDERLYING DEGENERATION OF CRYOPRESERVED HOMOGRAFTS. José P. Neves, M.D.*, Sérgio Gulbenkian, MSc., Ph.D.*, Ana P. Martins, M.D.*, Antònio M. Ferreira, Pharm.D., Ph.D.,* Ramiro Mascarenhas, Vet.D., Ph.D.*, Ricardo N. Santos, MSc.* and João Q. Melo, M.D, Ph.D.* Lisbon and Santarem, Portugal Sponsored by: Manuel E.M. Macedo, Lisbon, Portugal
Recent studies comparing heart valve (HV) homografts and valves of transplanted hearts showed that while the latter contained fibroblasts of both donor and recipient origin, the former were mostly acellular. These differences could be either due to the occurrence of an immune response in HV recipients that was prevented or abrogated by the immunosuppressive therapy administered to transplanted patients but not to the HV recipients, or to the cryopreservation process to which the HV homografts were subjected. To distinguish between these two alternatives, an experimental model was designed in which the behavior of cryopreserved autografts (CA) and homo-grafts (CH), implanted in the same animal, were compared. Fresh autografts (FA) were used to analyze the role of denervation and devascularization.
Cryopreserved aortic conduit homografts were implanted in the descending thoracic aorta of 15 sheep (6 males), aged 2 to 18 months. The excised aortic segment was then subjected to the same cryopreservation process used for the treatment of the homograft. One to eight weeks later, the CA was implanted, 1 to 2 cm below the CH. The intermediate segment of the native aorta was, at this point, dissected to be used as an FA control. Animals were sacrificed at different intervals (2 weeks, 1, 3, 6, 12, and 24 months) and the implanted segments harvested together with a portion of native aorta. Histological and immunohistochemical analysis as well as cell viability assessment were then performed on each of the explanted segments. Similar studies were also conducted on fragments of CA and CH collected before implantation.
With the exception of a partial loss of the endothelial
cells, cryopreserved specimens had preserved cell viability and histology prior
to implantation. Explanted CH, however, showed profound histological changes
that affected all strata, as well as a decline in cell viability. Thus, after
an initial period of non-specific inflammatory reaction which in most cases
subsided after one
In conclusion, it appears that the immunological reaction rather than the cryopreservation process is responsible for the degeneration that occurs in CH. Of particular interest were the findings that re-innervation, re-endothelization and regeneration of vasa vasorum occurred both on CA and FA. These conclusions are also important to the knowledge of the long-term behavior of aortic root replacement with CH or FA (Ross operation) in patients.
*By invitation F20. BOTH PAPILLARY TIPS KEEP CONSTANT DISTANCE FROM THE MITRAL ANNULAR PLANE UNDER VARIOUS CONDITIONS. Masashi Komeda, M.D., Ph.D.*, Julie R. Glasson, M.D.*, Ann F. Bolger, M.D.*, George T. Daughters, M.S.*, Neil B. Ingels, Ph.D.* and D. Craig Miller, M.D. Stanford and Palo Alto, California
Mitral valve homografts are drawing more attention because they may preserve normal mechanics of the mitral subvalvular apparatus and improve postoperative LV performance, similar to reparative valve surgery. The dynamic nature of the LV, however, complicates precise preoperative and intraoperative assessment of LV geometry essential for homograft placement or complex valve repairs. To study various effects on 3-D mitral geometry, we investigated eight closed-chest dogs using implanted radiopaque markers under 4 conditions: 1) Baseline: automatic blockade (esmolol at 50-100 ug/kg/min), 2) Caval Occlusion: reduced preload (EDV fell from 143 ± 16 to 104 ± 13 ml [p<0.001], 3) Tachycardia: atrial pacing (heart rate increased 108 ± 11 to 131 ± 5 min-1 [p<0.001], and 4) Nitroprusside: decreased afterload (2-5 μg/kg/min) (maximum LV pressure decreased from 132 ± 23 to 108 ± 29 mmHg [p<0.001]. Using cylindrical coordinates with the origin at the midpoint of the line connecting the anterior and posterior commissures and the LV long axis (z-axis) defined by the origin and the LV apex, DTIP-MA(the distance along the z-axis between the papillary muscle [PM] tip and mitral annular plane) was measured at end-diastole and end-systole (mm, mean ± 1SD; n=8 for posterior PM, and n=7 for anterior PM):
There were no significant differences in any dimensions by ANOVA. The distance between each PM tip and mitral annular plane was constant regardless of time during the cardiac cycle, or changes in preload, afterload, and heart rate. The mechanisms of maintaining this fixed tip-annulus distance are not known; however, these findings raise the possibility that the PM tip-annular distance might be a useful parameter to determine mitral homograft chordal length or help create more precise intraoperative strategies for complex valve repairs. Further investigations in dilated LV models with MR and the clinical setting are obviously necessary to define mechanisms and confirm these observations.
*By invitation F21. PORT-ACCESS MITRAL VALVE REPLACEMENT IN DOGS. Mario F. Pompili, M.D.*, John H. Stevens, M.D.*, Thomas A. Burdon, M.D.*, William S. Peters, M.B., Ch.B.*, Lawrence C. Siegel, M.D.*, Greg H. Ribakove, M.D.* and Bruce A. Reitz, M.D. Palo Alto and Stanford, California; New York, New York
Introduction: Minimally invasive techniques have been elusive in cardiac surgery. We describe a method of MVR using an endovascular CPB system and one 35 mm by 17 mm oval port and two 10 mm lateral thoracic ports in dogs.
Methods: Fifteen dogs, 28 ± 3 kg (mean ± SD), were studied using the port-access MVR system (Heartport, Redwood City). Eleven dogs underwent acute studies and were euthanized immediately following the procedure. Four dogs were recovered and euthanized 4 weeks after surgery. CPB was conducted via femoral cannulae using an endovascular balloon catheter for aortic occlusion, root venting and delivery of antegrade cardioplegia. Catheters were inserted in the jugular veins for pulmonary artery venting and retrograde cardioplegia delivery. Through the oval port, a prosthesis (St. Jude or Carbomedics) was inserted via the left atrial appendage and secured to the annulus with 8 to 12 sutures. De-airing was performed.
Results: All animals were weaned from CPB in sinus rhythm. There was no MR by left ventriculography or PAOP v-wave in all but 2 dogs. In these 2 dogs, there was interference with prosthetic valve closure by residual native anterior leaflet tissue. Pathologic examination otherwise showed normal healing without peri-valvular discontinuity. Microscopic and SEM studies showed no damage to the valve surfaces. Cardiac output and PAOP were unchanged (2.8 ± 0.7 1/min and 7 ± 3 mmHg preop vs. 2.6±0.6 and 9 ± 4 postop). CPB duration was 113 ± 23 minutes and aortic clamp duration was 71 ± 15 minutes. Transthoracic echo of the 4 chronic dogs showed normal ventricular function and prosthetic valve function four weeks postoperatively.
Discussion: Mitral valve replacement with a minimally invasive method has been demonstrated in dogs. A clinical trial is appropriate.
*By invitation F22. THE INDUCTION OF TOLERANCE TO AN EXPERIMENTAL CARDIAC ALLOGRAFT REQUIRES INTRATHYMIC INOCULATION OF CLASS IIMHC DISPARATE ANTIGENS. Zhenya Shen, M.D.*, Muhammad Mohiuddin, M.D.*, Hitoshi Yokoyama, M.D., Ph.D.*, G. Russell Reiss, M.D.* and Verdi J. DiSesa, M.D. Philadelphia, Pennsylvania
Indefinite donor-specific tolerance to a cardiac allograft disparate in both Class I and Class II major histocompatibility (MHC) antigens has been achieved in our laboratory and others by the pre-transplant intrathymic (IT) injection of donor spleen cells and a single intraperitoneal (IP) injection of anti-lymphocyte serum (ALS). This study was designed to determine whether this phenomenon was reproducible with either Class I MHC only or Class II MHC only disparate grafts. Three strains of inbred rats were studied in these experiments. Donors of cells and hearts in all experiments were RP rats which are rat MHC RT1 (AuBlDl). Class I MHC disparate grafts were performed by placing an RP heart into a Lewis recipient (RT1 A1B1D1C1) and Class II disparate grafts were performed with RP donors and Wistar Furth (WF) recipients (RT1 AuBuDuCu). Lewis (n=10) and WF (n=10) recipients underwent intra-peritoneal injection of 1 ml ALS and intrathymic injection of 5x107 RP spleen cells. Three weeks later heterotopic cardiac transplantation was done using a heart from an RP rat. Control rats had no pretreatment or ALS alone. Without any pretreatment, RP hearts survive 7-9 (mean 8) days in Lewis recipients (n=5) and 9-14 (mean 12) days in WF recipients (n=5). ALS alone produces slight prolongation of graft survival (12 days in Lewis recipients [n=5] and 14 days in WF recipients [n=5]). Lewis rats pretreated with Class I disparate RP splenocytes and ALS had graft survivals of 8 - 27 (mean 14) days not significantly different from the effect of ALS alone. Class II disparate RP grafts placed in pretreated WF rats had significant prolongation of graft survival with 4 out of 5 grafts surviving more than 60 days (p<0.01 vs ALS alone). These results suggest that a disparity at the Class II locus of the MHC is critical for the induction of cardiac allograft tolerance after by intrathymic inoculation of allogeneic cells. This implies that the specific requirements for antigen presentation in the thymus are quite stringent even in this rodent model.
*By invitation F23. INCREASED GRAFT AND SYSTEMIC VASCULAR PERMEABILITY DURING EARLY CARDIAC ALLOGRAFT REJECTION IS MEDIATED BY GRAFT AND SYSTEMIC EXPRESSION OF INDUCIBLE NITRIC OXIDE SYNTHASE. Neil K. Worrall, M.D.*, Kathy Chang, Ph.D.*, Patrick M. Sullivan, B.A.*, Thomas P. Misko, Ph.D.*, Jia-Ji Hui, M.D.*, Joseph R. Williamson, M.D.* and T. Bruce Ferguson, Jr., M.D. St. Louis, Missouri
We recently demonstrated that inducible nitric oxide synthase (iNOS) expression results in increased nitric oxide (NO) production during cardiac allograft rejection. In contrast to the physiologically protective role of NO in decreasing leukocyte adherence to endothelium, NO has also been implicated in mediating increased vascular permeability caused by various pathophysiological mediators, including LPS, TNF, and histamine. The present study examined whether NO contributes to increased vascular permeability to macromolecules during the early stages of graft rejection. Given the clinical systemic sequelae of rejection, we also examined whether early allograft rejection was associated with increased systemic vascular permeability. A double tracer permeation and microsphere method was used to examine vascular permeation (VP) during early graft rejection (POD 4) in a rat heterotopic cardiac transplant model: at time 0, 125I-albumin was injected iv to measure VP; 8 min. later 131I-albumin was injected iv (intravascular space marker); and 1 min. later 46Sc-labeled microspheres were injected iv (blood flow). One min. later the tissues were excised for γ-spectrometry, weighed, and 1) 125I-albumin VP (intravascular tracer corrected), 2) blood flow, and 3) water content (wet/dry weight ratio) determined for each tissue. Allografts (Lewis to ACI) had increased VP and wet/dry weights in the grafted heart, lung, and brain compared to isografts (ACI to ACI) and controls (SEE TABLE). Increased allograft VP was associated with increased NO production (serum nitrite/nitrate levels) and with iNOS mRNA expression (determined by ribonuclease protection assay) in the grafted heart and the lung (not examined in brain; not detectable in the control or isograft tissues). iNOS inhibition with aminoguanidine (AG; 375 mg/kg/d iv) prevented the increased graft and systemic VP and water content, and normalized the serum nitrite/nitrate levels. Blood flow, cardiac output, and BP were not different between groups and were not affected by AG (not shown). AG had no effect on: 1) mild histological rejection score in allografts (1.7 ± 0.4 vs 1.6 ± 0.3; 0-5 scale); and 2) VP in isografts and controls (data not shown). These data demonstrate the novel observations that: 1) early allograft rejection increases vascular permeability and tissue water content in the systemic vasculature; 2) increased allograft heart and systemic vascular permeability is associated with increased NO production and iNOS mRNA expression in the allograft heart and lung; and 3) inhibition of NO production by iNOS prevents allograft heart and systemic vascular barrier dysfunction during early rejection.
*By invitation F24. BASAL NITRIC OXIDE EXPRESSES ENDOGENOUS CARDIOPROTECTION DURING REPERFUSION BY INHIBITION OF NEUTROPHIL-MEDIATED DAMAGE AFTER SURGICAL REVASCULARIZATION. Hiroki Sato, M.D.*, Zhi-Qing Zhao, M.D, Ph.D.*, James E. Jordan, B.S.*, James C. Todd, B.S.*, Ping Li, Ph.D.*, John W. Mammon, Jr., M.D. and Jakob Vinten-Johansen, Ph.D.* Winston-Salem, North Carolina
Ischemia-reperfusion damages endothelium and impairs basal production of nitric oxide (NO). Basally released NO is cardioprotective by inhibiting neutrophil activities. Loss of endogenous NO with endothelial injury may occur during two phases: cardioplegic ischemia or reperfusion (aortic declamping). This study tested the hypothesis that inhibition of endogenously released NO in hearts subjected to regional ischemia, cardioplegic arrest and reperfusion: 1) restricts endogenous cardioprotection and permits neutrophil (PMN)-mediated damage, and 2) expresses damage primarily during the reperfusion phase. L-nitro-arginine (L-NA) was used to block basal NO production. In 22 anesthetized dogs, the LAD was ligated for 90 min followed by 1 hr arrest with cold multidose (q. 20 min) blood cardioplegia (BCP). Dogs were divided into 3 groups: SBCP, n=8: standard blood cardioplegia (BCP); LNA-BR, n=7: L-NA was administered during both phases of potential injury, as additive to BCP (1 mM) and infusion during reperfusion (34 mg/kg); LNA-R, n=7: L-NA was administered only at reperfusion. The LAD ligature was released during the second infusion of cardioplegia. Infarct size (TTC stain) was increased in LNA-R compared to SBCP (49 ± 6%* vs 34 ± 2%), but was not further extended in LNA-BR (56 ± 3%), suggesting primarily a reperfusion process. PMN-specific myeloperoxidase in the area at risk was elevated comparably in LNA-BR and LNA-R (2.9 ±0.5*, 3.9 ±1.0* U/g tissue) vs SBCP (1.7 ± 0.3), suggesting PMN accumulation during reperfusion. PMN adherence in experimental ischemic-reperfused LAD segments was comparably greater in LNA-BR (195 ±21* PMN/mm2 LAD) and LNA-R (224 ± 20*) relative to SBCP (108 ± 19). There was no significant adherence to nonischemic circumflex arteries. We conclude that blockade of endogenous NO augments postischemic injury mediated by PMN, and this damage is expressed primarily during the reperfusion phase. These data imply that: 1) basal NO participates in endogenous cardioprotection during the reperfusion phase of surgical revascularization; 2) loss of NO production secondary to endothelial injury may be detrimental; and 3) augmentation of basal NO by L-arginine precursor may increase protection. *p<0.05 vs. SBCP.
*By invitation F25. MATURATION ALTERS THE PULMONARY ARTERIAL RESPONSE TO HYPOXIA AND INHALED NITRIC OXIDE IN THE PRESENCE OF ENDOTHELIAL DYSFUNCTION. Jeff L. Myers, M.D.*, Joseph J. Wizorek, B.S.*, Adam K. Myers, Ph.D.*, Michael O'Donoghue, M.S.*, Peter C. Kouretas, M.D.*, Heidi J. Dalton, M.D.*, Yi-Ning Wang, M.D.* and Richard A. Hopkins, M.D. Washington, DC
These studies test the hypothesis that maturational changes in the newborn period alter the response to hypoxia and subsequent NO inhalation in a model of endothelial dysfunction. Eight 48-hour-old piglets and eight 14-day-old piglets underwent high fidelity instrumentation to record pulmonary artery pressure (PA), flow (PAF), and main pulmonary artery radius (Ro). Following treatment with the NO-synthase inhibitor L-NA (20 mg/kg, IV bolus), hemodynamic measurements were performed at baseline, during 10 minutes of hypoxia (FiO2=0.1) and during 10 minutes of NO inhalation (100 ppm). Fourier analysis of the waveforms produced values for input mean impedance (Zm) and characteristic impedance (Zo), reflecting opposition to flow in the distal arteriolar bed and larger proximal pulmonary arteries respectively. Vessel wall elasticity (Ey) was calculated from Zo and Ro.
Both groups underwent severe distal arteriolar vasoconstriction with hypoxia evidenced by the large increases in PAP and Zm. NO relieved this effect. The younger animals underwent no alteration of Zo, Ey, or Ro, indicating the larger proximal vessels were unaffected by either hypoxia or nitric oxide. In contrast, the radius actually increased in 14-day-old animals under the higher transmural pressure (increased PAP), but the vessel wall became stiffer by a factor of almost 10 (increased Ey). The net effect was an increase in Zo that represents a significant increase in the opposition to flow from the right ventricle in animals with a dysfunctional endothelium. In conclusion, NO synthase inhibition, as might be seen in endothelial dysfunction, results in profound vasoconstriction at the distal arteriolar level in both age groups. The lower resting tone in the older piglets (lower baseline Zo and Ey) allows a proximal hypoxic vasoconstrictor effect that is not evident in the younger animals. Also, in the face of endothelial dysfunction, nitric oxide is still effective in relieving hypoxic pulmonary arterial vasoconstriction in both age groups.
*By invitation F26. INTRAOPERATIVE IDENTIFICATION OF SPINAL CORD BLOOD SUPPLY DURING DESCENDING AND THORACOABDOMINAL AORTIC REPAIRS. Lars G. Svensson, M.D., Ph.D.* Burlington, Massachusetts Sponsored by: David M. Shahian, M.D., Burlington, Massachusetts
Previous animal and human studies have shown that the intercostal and lumbar segmental arteries are critical for maintaining adequate spinal cord (SC) perfusion and that failure to reattach segmental arteries may result in postoperative paraparesis or paraplegia. Porcine experimental studies have shown that the vessels supplying the SC can be accurately identified by using hydrogen and a platinum electrode alongside the SC.
METHODS: After obtaining institutional review board approval, informed consent was obtained from 14 patients. Under local anesthetic, a specially constructed catheter with a platinum electrode was placed intrathecally by lumbar puncture alongside the SC and control radiographs obtained to check the positioning of the catheter. Intraoperatively, after crossclamping the aorta, hydrogen in a saline solution was injected into the occluded segment of the aorta and if it was shown that the segment supplied the SC with blood, then in addition, those identified intercostal arteries were injected with hydrogen as necessary. Five patients had descending aortic repairs, three had Type I thoracoabdominal aneurysm repairs, and six had Type II repairs. Postopera-tively, patients underwent highly selective angiography of the reattached intercostal arteries to identify the radicular arteries supplying the SC.
RESULTS: The average aortic crossclamp time was 46.6 minutes (range 20-85 minutes) with an average time for testing of 4.46 minutes (range 0-15 minutes). Postoperative angiography revealed that the radicular arteries supplying the SC had been accurately identified. Five SC perfusion patterns were noted: 1) direct; 2) collateral; 3) no direct supply from segment tested; 4) from atrio-femoral bypass; and 5) occluded reattached intercostals. One patient had permanent paraparesis (1/14, 7%) following intraoperative cardiopulmonary resuscitation for 15 minutes and two patients had transient paraparesis. One patient died postoperatively.
CONCLUSION: The intraoperative use of hydrogen and an intrathecal platinum electrode identifying vessels supplying the spinal cord is safe and accurate, and the additional aortic crossclamp time required is minimal.
*By invitation F27. THE SUPERIORITY OF HYPOCALCEMIC VS NORMOCALCEMIC BLOOD CARDOPLEGIA IN NEONATAL MYOCARDIAL PROTECTION. Kirk Bolling, M.D., MPH*, Michael Kronen, M.D.*, Bradley S. Allen, M.D.*, Shaikh Rahman, M.S.*, Tingrong Wang, M.D.*, Renee S. Hartz, M.D. and Harold Feinberg, Ph.D.* Chicago, Illinois
In newborns, the ideal cardioplegic calcium (Ca2+) concentration continues to be debated. However, most studies examining cardioplegia calcium concentrations were done using a non-clinical model (isolated heart preparation), which (1) may not be clinically applicable and (2) did not examine the effect of calcium concentration in a clinically relevant "stressed" (hypoxic) heart. We therefore attempted to determine the ideal calcium concentration using an in vivo (clinical) model in non hypoxic (uninjured) and "stressed" (hypoxic) hearts.
Twenty neonatal piglets, 5-18 days old, were placed on cardiopulmonary bypass, and their aorta cross clamped for 70 min with either hypocalcemia or normocalcemic multidose blood cardioplegic infusions. Group 1: (n=5, low Ca2+, 0.2-0.3 mM), and Group 2: (n=5, normal Ca2+, 1.0-1.3 mM) were nonhypoxic (uninjured) hearts. Ten other piglets were first ventilated at an FiO2 of 8-10% (O2 saturation 65-70%) for 60 minutes (hypoxia) and then reoxygenated at an FiO2 of 100% utilizing cardiopulmonary bypass. This has been shown to produce a clinically relevant "stress" injury resulting in myocardial depression. They underwent cardioplegic arrest (as above) with either a hypocalcemic (n=5, Group 3) or normocalcemic (n=5, Group 4) blood cardioplegic solution. Myocardial function was assessed using pressure volume loops, and expressed as a percentage of control. Coronary vascular resistance was measured during each cardioplegic infusion. In nonhypoxic hearts (Group 1 and 2), good myocardial protection was achieved at either concentration of cardioplegia calcium as demonstrated by preservation of postbypass systolic function (EES 104% vs 99%), diastolic compliance (152% vs 162%), no increase in myocardial edema (78.9% vs 78.7%), and no change in ATP levels or coronary vascular resistance. Low calcium blood cardioplegia solution repaired the hypoxic/reoxygenation injury in "stressed" hearts (Group 3) resulting in no statistical difference in myocardial function, coronary vascular resistance or ATP levels compared to nonhypoxic hearts (Group 1 and 2). Conversely, when a normocalcemic cardioplegia solution was used in "stressed" (hypoxic) hearts (Group 4), there was marked reduction in postbypass systolic function (EES 49% ± 4%)* loss of diastolic compliance (276% ± 9%)*, increase in myocardial edema (79.7% ± 0.2%)*, rise in coronary vascular resistance*, and no change in ATP levels compared to Groups 1, 2 and 3.
In conclusion, this study demonstrates that: 1) in the clinically relevant, intact, animal model, good myocardial protection is independent of cardioplegia calcium concentration in nonhypoxic (noninjured) hearts; 2) "stressed" (hypoxic) hearts are extremely sensitive to the cardioplegic calcium concentration; and 3) normocalcemic cardioplegia is detrimental to neonatal myocardium subjected to a preoperative hypoxic stress. Optimal myocardial protection in infants undergoing repair of cyanotic congenital defects is therefore provided by a hypocalcemic cardioplegia solution. *p<0.05 mean ± S.E.
*By invitation F28. COST AND EFFICACY OF SURGICAL LIGATION VERSUS TRANSCATHETER COIL OCCLUSION OF PATENT DUCTUS ARTERIOSUS. John A. Hawkins, M.D.*, L. LuAnn Minich, M.D.*, Lloyd Y. Tani, M.D.*, Jane E. Sturtevant, B.S.N.*, Garth S. Orsmond, M.D.* and Edwin C. McGough, M.D. Salt Lake City, Utah
Transcatheter closure of the patent ductus arteriosus (PDA) using coil occlusion (CO) has emerged as primary therapy for the small PDA because of avoidance of surgery and a presumed lower cost. In July 1994, we began a study to compare surgical closure of PDA using new critical pathway methodology with outpatient transcatheter CO of PDA in non-neonatal patients. Selection for transcatheter CO was based on anatomic feasility and patient preference, while surgical closure was performed in remaining patients. Surgical techniques included a small transaxillary, muscle-sparing thoracotomy, triple ligation of the PDA, no chest tube, placement of a small catheter for intermittent intercostal 0.25% bupivicaine, and discharge within 24 hours using critical pathway methods.
From July 1994 until October 1995, 15 patients underwent transcatheter CO of a PDA and 14 patients underwent surgical closure of the PDA. Duration of hospitalization was significantly less for the CO patients (12 ± 8 hours, X ± SD) as compared to the surgical ligation patients (26 ± 6 hours, p<0.05). However, the duration of the procedure was significantly less for surgical ligation (44 ± 6 minutes) as compared to transcatheter CO patients (91 ± 29 min, p<0.05). Total costs, including all hospital and professional fees, were slightly less for surgical ligation ($7,035 ± 403) as compared to CO ($7,298 ± 885, p>0.05). Morbidity in the transcatheter CO included inability to occlude the PDA in 1 patient (1/15, 6.7%) and residual patency in 2 patients (2/15, 13%) on late color flow Doppler echocardiography. Morbidity in the surgical ligation group included nausea and vomiting requiring hospitalization >36 hours in 1 patient (1/14, 7%) and transient left recurrent laryngeal nerve palsy in 1 patient (1/14, 7%). There were no instances of residual PDA patency in the surgical group by echocardiography with color flow Doppler.
Transaxillary thoracotomy without tube thoracostomy and critical pathway methodology allows safe and effective ligation of the PDA with early hospital discharge. This surgical method has slightly lower overall cost, higher efficacy rate, and applicability in all patients as compared to newer transcatheter CO techniques for occlusion of the PDA. These findings are important for future cost-benefit considerations in the context of managed care.
*By invitation 9:30 a.m. SIMULTANEOUS SCIENTIFIC SESSION D - ADULT CARDIAC SURGERYRoom 6A/B, San Diego Convention Center
Moderators: Robert B. Wallace, M.D. Tirone E. David, M.D.
41. CLINICAL SIGNIFICANCE OF PERIOPERATIVE Q WAVE MYOCARDIAL INFARCTION IN THE EMORY ANGIOPLASTY VERSUS SURGERY TRIAL. George T. Hodakowski, M.D.*, Joseph M. Graver, M.D., Ellis L. Jones, M.D., Spencer B. King, M.D.* and Robert A. Guyton, M.D. Atlanta, Georgia Discussant: Bruce W. Lytle, M.D.
The primary end point of the Emory Angioplasty versus Surgery Trial (EAST) was a composite of three events: death, Q-wave infarction (QMI), and a new large defect on three-year postoperative thallium scan. A QMI was identified on predischarge electrocardiograms read by blinded, experienced electrocardiographers. This study examines the clinical significance of QMI in the surgical cohort (194 patients) of EAST. Twenty QMI patients were identified (10.3%) with a large proportion, 13 patients, identified with inferior QMIs. Seven had anterior, lateral, septal, or posterior QMIs (anterior QMIs). In the inferior QMI group, postoperative catheterization (at 1 year or 3 years) in eleven patients revealed normal ejection fraction (EF greater than 55%) in ten (91%), no wall motion abnormalities in ten (91%), and all grafts patent in ten (91%). In the anterior QMI group, postoperative catherization in six patients revealed normal EF in five (83%), no wall motion abnormality in three (50%), and all grafts patent in three (50%). Average peak postoperative CKMB levels (IU) were: no QMI (n=174) 37 ± 43, inferior QMI 43 ±31, anterior QMI 58 ± 38. Mortality in the 20 patients with QMI was 5% (1/20) at three years and was 6.2% (11/174) in patients without QMI. Of 17 QMI patients who had postoperative catheterization, 11 (69%) had a normal ejection fraction, normal wall motion, and all grafts patent with an uneventful three-year postoperative course. The core lab screening of postoperative electrocardiograms, particularly in the case of inferior QMI, appears to identify a number of patients as having a QMI who have minimal and clinically insignificant postoperative electrocardiographic changes. QMI identified in the postoperative period seems to be a weak end point without prognostic importance and therefore not valuable for future randomized trials.
*By invitation 42. CORONARY-CORONARY BYPASS GRAFT: AN ARTERIAL CONDUIT SPARING PROCEDURE. Remi Nottin, M.D.*, Jean Michel Grinda, M.D.*, Sami Anidjar, M.D.*, Thierry Folliguet, M.D.* and Marc Detroux, M.D.* Paris, France Sponsored by: Claude Planche, Paris, FranceDiscussant: Noel L. Mills, M.D.
Only a few cases of coronary-coronary bypass grafting (CCBG) have been previously reported. However, CCBG appears as an interesting additive technique for coronary artery bypass grafting. Proximal and distal anastomosis can be achieved either between two segments of the same coronary artery or between two different coronary arteries.
From December 1989 to December 1994, 120 patients underwent myocardial revascularization using one CCBG (117 patients) or two CCBG (3 patients) in addition to pediculed IMA, Y graft and aorto-coronary bypass for a total of 381 distal anastomoses (3.17 ± 0.79 per patient). Presence of a suitable proximal coronary segment was mandatory. Indications for CCBG were: arterial conduit sparing procedure, inadequate length of the graft, calcified ascending aorta, avoidance of aortic implantation of arterial graft, stenosed or occluded subclavian arteries. Graft conduits used for CCBG were 90 arterial grafts (90/123; 73.2%) including 75 RIMA, 14 LIMA and one radial artery (RA), and 33 saphenous vein (SV) (33/123; 26.8%). CCBG were performed on the right coronary artery (RC) in 113 cases (91.8%), on the circumflex artery (CX) in six (4.8%) and on the left anterior descending coronary artery (LAD) in two (1.6%). In two cases (1.6%), a CCBG was performed between two different coronary arteries, the RC and the LAD.
Two patients (1.6%) died from myocardial infarction during the postoperative period. Early postoperative control angiogram was performed in 63 patients. One month patency rate was 98.5% for 66 CCBG controlled. During the follow-up period of 27 ± 16 months, three patients died and one underwent a reoperation. After two months, 97.5% of tested patients (83/120) had a normal exercise testing. A one year and three year exercise testing was normal in 96.1% and 94.1% of patients, respectively.
In conclusion, CCBG provides good results with a variety of conduits. CCBG could promote an expanded use of arterial grafts, particularly the IMA graft. In addition, CCBG could lead to a sparing of arterial graft material, and allow complex myocardial revascularization with a liberal use of both IMAs.
*By invitation 43. RISK FACTORS FOR STROKE IN PATIENTS UNDERGOING AORTOCORONARY BYPASS SURGERY. Lynda L. Mickleborough, M.D., Paul M. Walker, M.D.*, Yasushi Takagi, M.D.*, Masanori Ohashi, M.D.*, Joan Ivanov, MSc.* and Miguel Tamariz, BSc.* Toronto, Ontario, Canada Discussant: Gary W. Akins, M.D.
To determine predictors of stroke in patients undergoing first time aortocoronary bypass surgery, data were prospectively collected on 1631 consecutive patients. Those with a history of CNS symptoms (119) and/or carotid bruits (185) underwent carotid Doppler evaluation. Patients with symptomatic unilateral disease (>70% stenosis) or significant bilateral disease (77% stenosis) were referred for combined CABG and carotid endarterectomy (21). Postop patients with neurologic symptoms were assessed by a neurologist. Events were classified as reversible (TIA) or (RIND) or irreversible (stroke). Results of sureerv are as follows:
By stepwise logistic regression analysis, three variables were identified as risk factors for stroke. The most important predictor was unilateral carotid occlusion with or without contralateral stenosis (odds ratio = 23.8). In this group, 4/5 strokes occurred on the occluded side. The other two risk factors were presence of ascending aortic disease at time of surgery (OR = 13.1) and previous history of stroke (OR = 4.4).
Conclusion: In patients undergoing CABG, risk factors for perioperative stroke have been identified. Asymptomatic patients with carotid bruits are at low risk. Patients with carotid occlusion are at risk for a stroke on the occluded side.
*By invitation 44. PORT-ACCESS BILATERAL INTERNAL MAMMARY ARTERY GRAFTING FOR LEFT MAIN CORONARY ARTERY DISEASE: CANINE FEASIBILITY STUDY. Thomas A. Burden, M.D.*, William S. Peters, M.B., Ch.B.*, Mario F. Pompili, M.D.*, John H. Stevens, M.D.*, Lawrence C. Siegel, M.D.*, Frederick G. St. Goar, M.D.* and Bruce A. Reitz, M.D. Stanford and Palo Alto, California Discussant: Valavanur A. Subramanian, M.D.
Minimally invasive surgical techniques have been applied to cardiac surgery. We used an endovascular cardiopulmonary bypass system that allows cardioplegia and cardiac venting to extend the applications of minimal access cardiac surgery to bilateral internal mammary artery (IMA) bypass grafting. We report the results of a series of six dogs (22-27 kg). The left IMA was taken down thoracoscopically from three left lateral chest ports, followed by the right IMA from the right side. One left sided port was extended medially 5 cm with or without rib resection, to expose the pericardium. Following heparin administration, both IMAs were divided and exteriorized through the left anterior mediastinotomy. Flow and pedicle length was satisfactory in all cases. Animals were placed on femoral-femoral bypass and the heart arrested with antegrade delivery of cardioplegic solution via the central lumen of a balloon catheter (Endoaortic Clamp; Heartport; Redwood City, CA) inflated in the ascending aorta. All grafts were made through the mediastinotomy under direct vision. In five studies the RIMA was attached to the LAD and the LIMA to the circumflex, and in one study the RIMA was tunneled through the transverse sinus to the circumflex and the LIMA anastomosed to the LAD. All animals were weaned in sinus rhythm without ionotropes. CPB time was 108 ± 27 minutes (mean ± SD) and the mean clamp time was 54 ± 10 minutes. Preoperative and postoperative cardiac outputs were 2.9 ± 0.68 1/min and 2.4 ± 0.30 1/min respectively (p=NS). Preoperative and postoperative pulmonary capillary wedge pressures were 5 ± 1.5 1/min and 5.6 ± 1.6 1/min respectively (p=NS). All 12 grafts were demonstrated to be fully patent by angiography. At postmortem, all target coronary vessels had been correctly grafted, and pedicles were well aligned. We conclude the canine model demonstrates the potential for a less invasive approach to the surgical management of left main coronary artery disease in humans.
10:50 a.m. INTERMISSION
*By invitation 11:10 a.m. SIMULTANEOUS SCIENTIFIC SESSION D - ADULT CARDIAC SURGERYRoom 6A/B, San Diego Convention Center
Moderators: Robert B. Wallace, M.D. Tirone E. David, M.D.
45. HUMAN AORTIC VALVE ALLOGRAFTS ELICIT A DONOR-SPECIFIC IMMUNE RESPONSE. Patrick G. Hogan, BSc., Ph.D., FRACP, FRCPA*, Marjorie Green, Ph.D.*, Lynette Duplock, MSc.*, Susan E. Smith, BSc.*, Ian H. Frazer, M.D., FRCP, FRCPA*, Kenneth L. Gall, BAppSc.* and Marie F. O'Brien, FRCS, FRACS Brisbane, Queensland, Australia Discussant: MarkF. Lupinetti, M.D.
Human aortic valve allografts (AVA), cryopreserved within 2-8 hr of collection and containing viable cells, provided the model for a quantitative analysis of the donor-specific immune response in recipients. It is unclear precisely to what extent and in what form AVA antigens survive cryopreservation. Therefore, 10 recipients of AVA were investigated for anti-donor antibody and T cell-mediated responses against the same donor splenic or peripheral blood mononuclear cells collected at the same time as the AVA. Anti-donor immune responses were measured quantitatively in recipients at 7, 30, 90 and 365 days after AVA implantation using flow cytometric and lymphocytotoxic cross-match assays and mixed lymphocyte cultures (MLCs).
By day 30 after surgery, all 10 recipients developed significant litres of IgG antibodies which were directed against both class I and II major histocompati-bility (MHC) antigens present in the donor tissue. In addition, all recipients developed lower levels of multispecific antibodies which cross-reacted with third party non-donor MHC antigens. Anti-donor antibodies persisted for at least 365 days after surgery. In MLCs, most recipients (6 of 7) had significantly increased levels of donor-specific T cell proliferative responses compared with those to third party lymphocytes at days 30 and 90 after implantation.
These data indicate that MHC antigens in AVA survive our
current early cryopreservation method and elicit a donor-specific antibody and
T cell-mediated response. This alloreactivity is likely to be responsible for
the pathological changes of hypocellularity, valve thickening, fibrosis and
calcification with stenosis observed in failed AVA, particularly in younger
recipients. Therefore, suppression of the anti-donor response in AVA recipients
may reduce degeneration of the AVA and thus enhance its performance. Further
studies of the immune response to AVA are in progress so that the precise
immunological mechanisms responsible for AVA injury can
*By invitation 46. WHAT IS THE BEST PERFUSION TEMPERATURE FOR CORONARY REVASCULARIZATION? Richard M. Engelman, M.D., A. Bernard Fleet, M.D.*, John A. Rousou, M.D., Joseph E. Flack, III, M.D.*, David W. Deaton, M.D.*, Cheryl A. Gregory, R.N.* and Penelope S. Pekow, Ph.D.* Springfield and Amherst, Massachusetts Discussant: Robert A. Guyton, M.D.
An NIH funded prospective randomized trial was begun in 1994 to study the effect of perfusate temperature on recovery after coronary revascularization. Criteria for entry into the study demanded an ejection fraction (EF) >30%, the performance of at least 3 bypass grafts and age ≤ 75 years. This is a review of the first 125 patients to have completed a one-month follow-up. All patients were perfused either cold (C) at 20°C (n=37), tepid (T) at 32°C (n=48) or warm (W) at 37°C (n=39). There were no significant differences between the three groups in any preoperative (81% male, 52% EF) operative (3.7-4.0 grafts/patient, 134-144 min pump time) characteristics and thus, the baseline data were comparable. Antegrade-retrograde blood cardioplegia was used at appropriate temperatures (C=8°C, T=32°C, and W=37°C) for each group. There was no perioperative mortality, and only one of the 124 were reoperated upon for bleeding. Data collected specific to this report concerned bleeding and coagulation parameters, rapidity of recovery, length of postop hospital stay, neurologic function (at 4 days and 1 month postop) and incidence of postop arrhythmias. Mean ± SEM data are presented:
* significant difference between groups by Kruskal Wallis 1 way ANOVA; ** significant difference by Fisher's Exact Text; +difference not significant by Fisher's Exact Text (all 5 CVA patients recovered complete function by 3 mos.); ++significant difference between C and both T&W by pairwise t-tests.
Conclusion: l)Perfusion temperature is a factor in recovery from CBG; 2) Cold is associated with a longer duration of intubation and hospitalization, less blood loss and the least activation of fibrinolysis. It is not protective against CVA; 3) Warm is associated with the shortest duration of extubation and the most fibrinolysis. It is not associated with the highest stroke rate; and 4) Tepid is the best perfusion temperature, the shortest LOS, no strokes, acceptable levels of fibrinolysis, and the lowest level of blood products transfused. The commonly employed technique of allowing the perfusion temperature to drift is most consistent with tepid perfusion.
*By invitation 47. PRECONDITIONING IN CORONARY ARTERY BYPASS SURGERY: A WORD OF CAUTION. Philippe Menasché, M.D., Ph.D., Louis P. Perrault, M.D.*, Alain Bel, M.D.*, Thierry de Chaumaray, M.D.*, Jacqueline Peynet, M.D.*, Adrian Mondry, Ph.D.* and Jean-Marie Moalic, Ph.D.* Paris, France Discussant: Steven F. Bolling, M.D.
Objective: Ischemic preconditioning (PC) is now established as an effective means of reducing infarct size. Use of PC before coronary artery bypass grafting (CAPB) under normothermic ventricular fibrillation has led to the preservation of myocardial levels of high-energy phosphates. However, it is not yet established whether PC can improve the myocardial protection afforded by cardioplegia. The present study was designed to address this issue.
Methods: Twenty patients undergoing CABG with the use of retrograde continuous warm blood cardioplegia were studied. After the institution of cardiopulmonary bypass (CPB), 10 patients were preconditioned with 3 minutes of aortic crossclamping followed by 2 minutes of reperfusion before the onset of cardioplegic arrest. Ten case-matched patients served as controls. Blood samples were simultaneously drawn from the radial artery and the coronary sinus before CPB, at the end of the 5-minute PC protocol or after 5 minutes of CPB in control patients and at the end of cardioplegic arrest. These samples were assayed for CK-MB and lactate. Right atrial biopsy specimens were taken at the same time points and processed by Northern blotting for the expression of the mRNAs of c-fos, a proto-oncogene which induces changes in cardiac gene expression in response to ischemic stimuli, and of heat shock protein (HSP) 70, a stress-induced cardioprotective protein. The blots were hybridized with probes specific for c-fos and HSP 70 mRNAs and for 18S ribosomal RNA. The quantification of c-fos and HSP 70 mRNA was calculated as the ratio between each of these two signals and that yielded by 18S RNA. Results are presented as the percentage of the signal given by rat cardiac RNA used as an internal standard (% I.S.).
Results: There were no differences in pre- or intraoperative variables between the two groups. At the end of arrest (72 ± 6 minutes and 64 ± 5 minutes in control and preconditioned patients, respectively [mean ± SEM]), the release of CK-MB from the myocardium (calculated as the difference between coronary sinus and radial artery values) was markedly greater in preconditioned patients than in the controls (5.7 ± 1.7 ng/mL vs. 1.9 ± 1.1 ng/mL, p=0.05). The trans-myocardial lactate gradient was shifted towards production in the PC group (+0.22 ± 0.13 mmol/L) and towards extraction in the control group (-0.06 ± 0.21 mmol/L). Molecular biology data summarized below did not suggest a protective effect of PC.
There were no PC-related clinical adverse events.
Conclusion: PC does not enhance cardioplegic protection and might even be deleterious. These results do not dismiss the therapeutic exploitation of the mechanisms of endogenous myocardial protection in cardiac surgery. They rather emphasize the need for identifying pharmacologic mediators that could safely and effectively duplicate the cardioprotective effects of ischemic PC.
12:10 p.m. ADJOURN
*By invitation 9:30 a.m. SIMULTANEOUS SCIENTIFIC SESSION E - GENERAL THORACIC SURGERY Room 6C/F, San Diego Convention Center
Moderators: Andre C.H. Duranceau, M.D. Alex G. Little, M.D.
48. LONG-TERM RESULTS AFTER ENBLOC DOUBLE-LUNG TRANSPLANTATION WITH BRONCHIAL ARTERIAL REVASCULARIZATION. Eugene M. Baudet, M.D.*, Claire Dromer, M.D.*, Jean Dubrez, M.D.*, Jacques Jougon, M.D.*, Xavier Roques, M.D.*, Jean-François Velly, M.D.*, Claude Deville, M.D.* and Louis Couraud, M.D. Pessac, France Discussant: Thomas R.J. Todd, M.D.
Background: Since May 1990, bronchial arterial revascularization (BAR) was associated with enbloc double-lung transplantation and tracheal anastomosis in order to improve airway healing. At the same time, it was also suggested that BAR could play a role in preventing the occurrence of obliterative bronchiolitis (OB).
Objective: This study was undertaken to evaluate the long-term results of this technique, and to assess whether BAR could improve tracheal healing and reduce OB incidence.
Material and Methods: Between May, 1990 and January, 1994, 18 patients (pts), 13 males and 15 females, underwent enbloc double-lung transplantation with BAR using a saphenous vein graft interposed between the orifices of bronchial arteries and the recipient's ascending aorta. Follow-up ranged from 22 to 54 months. The results of this combined technique were assessed according to tracheal healing, functional status, OB incidence, and infection and lung rejection episodes.
Results: There was
neither operative death nor re-exploration for BAR-related bleeding. According
to the criteria defined in a previous staging study, tracheal healing was
qualified as grade I in 7 pts, grade IIa in 8, grade IIb in 2, and grade III in
only one pt. Angiographic studies, between postoperative day 15 to 30, have
shown a patent venous graft in 12 of the 15 controlled pts. Eleven pts are
currently alive, with a mean follow-up of 43 months. In all 15 pts surviving
more than one year, 5 have developed a documented bronchiolitis obliterans
syndrome (BOS). Long-term functional results are excellent in the others, with
a mean FEV1 over 80% of predicted value. The 5 pts who have
developed a BOS had an early or late documented vein graft thrombosis. On
Conclusion: Enbloc double-lung transplantation with BAR appears to be a safe, available, and quite effective procedure allowing primary tracheal healing. Moreover, these first results could suggest that long-term BAR patency does have an impact on OB incidence; improved mucosal trophicity and mucociliary clearance could contribute to prevention of obliterative bronchiolitis.
*By invitation 49. BILATERAL VS SINGLE LUNG TRANSPLANTATION FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE. Joseph E. Bavaria, M.D.*, Robert Kotloff, M.D.*, Harold Palevsky, M.D.*, Bruce Rosengard, M.D.*, John R. Roberts, M.D.* and Larry R. Kaiser, M.D. Philadelphia, Pennsylvania Discussant: Thomas J. Kirby, M.D.
Traditionally, despite VQ mismatch, single lung transplantation (SLT) has been the mainstay for end-stage COPD. We tested the hypothesis that bilateral sequential lung transplantation (BLT) has superior short and intermediate term results compared to SLT for COPD.
Methods: One hundred twelve consecutive lung transplants have been performed from 11/91 to 10/95. Sixty-three have been transplanted for COPD. The diagnosis of COPD includes emphysema (82.5%), Alpha-1 antrypsin deficiency (11.1%) and LAM (6.4%). Twenty-three transplants have been bilateral (BLT Group) and 40 have been single (SLT Group). MEAN age was 55 for SLT and 50 for BLT (p=ns). The distribution of the diagnoses was similar between the two groups except for Alpha-1 antrypsin deficiency which tended towards BLT. There were 19 survivors of SLT and 14 survivors of BLT out at least 6 months with complete data for evaluation. FEV1, and 6-minute walk test (6MWT) were evaluated at a mean of 16 months and 12 months postoperative, respectively.
Results: 60-day mortality was 22.5% for SLT vs only 4.3% for BLT (p=0.05). Additionally, Kaplan-Meier analysis reveals 1- and 2-year survival of 71% and 60% for SLT vs 92% and 85% for BLT, respectively. Functional results are summarized in the table. Both 6MWT and FEV1 were improved from baseline by SLT and BLT (p=0.001).
Conclusion: BLT improves FEV1 significantly over SLT (p<0.01). BLT improves 6MWT over SLT but does not reach significance. Both peri-operative mortality and Kaplan-Meier survival (to 2 yrs) is significantly improved using BLT vs SLT for COPD in our series.
*By invitation 50. PULMONARY RETRANSPLANTATION: DOES THE INDICATION FOR SURGERY INFLUENCE POSTOPERATIVE LUNG FUNCTION? Richard J. Novick, M.D., Larry W. Stitt, MSc.*, Hans Joachim Schafers, M.D.*, Bernard Andréassian, M.D.*, Jean Pierre Duchatelle, M.D.*, Walter Klepetko, M.D.*, Robert L. Hardesty, M.D., Adaani E. Frost, M.D.* and G. Alexander Patterson, M.D. London, Ontario, Canada; Homberg, Germany; Clichy, France; Vienna, Austria; Pittsburgh, Pennsylvania; Houston, Texas and St. Louis, Missouri Discussant: Bruce A. Reitz, M.D.
An international series of pulmonary retransplantation was updated in order to determine factors associated with pulmonary function, Bronchiolitis Obliterans Syndrome (BOS) stage and survival in the intermediate-term postoperatively. The study cohort included 160 patients who underwent retransplantation in 35 centers in North America and Europe from 1985 to 1995; follow-up was 100% complete. Survivors were followed for a median of 780 days (versus 630 days in our previous report), with 62 patients alive at 1 year, 39 at 2 years, 27 at 3 years and 13 at four years after retransplantation. Actuarial survival was 45 ±4% (± = SEM), 41 ± 4% and 33 ± 4% at 1, 2 and 3 years, respectively. Nonetheless, in the 89 three-month postoperative survivors, actuarial survival at 2 years was 72 ± 5%. On multivariate analysis, the only predictor of 3-month survival was preoperative ambulatory status (p=0.005, odds ratio 2.97 in favor of ambulatory recipients), whereas individual center experience with at least 5 pulmonary retransplants was the sole predictor of 2-year survival (p=0.04, odds ratio 2.52). Analysis of the forced expiratory volume in 1 second (FEV1) and BOS data revealed that the overall prevalence of stage 3 (severe) BOS was 12% at 1 year, 15% at 2 years and 32% at 3 years after retransplantation, similar to that reported after primary lung transplantation. Sixty-three percent of retransplant recipients were free of BOS (stages 1-3) at 2 years and 56% at 3 years. The FEV1 value at 2 years was associated with subsequent survival at 3 (p=0.002) and 4 years (p=0.01). Furthermore, retransplant recipients in BOS stage 3 at 1 and 2 years had a significantly worse actuarial survival than those in BOS stages 0 to 2 (p<0.01for both years). By 3 years after retransplantation, FEV1 was significantly lower in patients reoperated for obliterative bronchiolitis (OB, 1.10 ± 0.15 L/sec) than in those retransplanted for acute graft failure or an airway complication (1.95 ± 0.29 L/sec, p=0.02); this difference was not apparent in our previous report. Only 31% of patients retransplanted for OB were in BOS stage 0 at 3 years versus 83% of patients retransplanted for other indications (p=0.02). Subset analyses revealed that the interval between transplant procedures in patients with OB did not significantly influence the prevalence of BOS at 2 (p=1.0) and 3 years (p=0.53). We conclude that patients undergoing retransplantation for OB develop more significant pulmonary dysfunction after 3 years of follow-up than those undergoing retransplantation for other indications. Preoperative ambulatory status predicts early survival and individual center experience predicts intermediate-term outcome after retransplantation. Improved management strategies are necessary to prevent the development of progressive draft dysfunction after retransplantation for OB.
*By invitation 51. AEROSOL CYCLOSPORINE LEADS TO IMPROVEMENT IN PULMONARY FUNCTION AND GRAFT HISTOLOGY IN LUNG TRANSPLANT RECIPIENTS WITH PERSISTENT ACUTE REJECTION. Robert J. Keenan, M.D.*, Aldo T. Iacono, M.D.*, James H. Dauber, M.D.*, Samuel A. Yousem, M.D.*, Hartley P. Griffith, M.D. and Akihiko Kawai, M.D.* Pittsburgh, Pennsylvania Discussant: Sara J. Shumway, M.D.
We continued to be plagued by loss of pulmonary allografts from refractory acute or chronic rejection. The present study was undertaken to determine the effectiveness of aerosolized cyclosporine (CsA) for the treatment of persistent acute cellular rejection (ACR). Nine patients (pts) with persistent ACR, documented by transbronchial biopsy, were treated after having failed at least three courses of systemic steroids and/or cytolytic therapy (ATGAM). Patients remained on maintenance immunotherapy consisting of tacrolimus or cyclosporine, azathioprine and prednisone. Only pts with rejection grade >2 were included. Patients were given 300 mg of aerosolized CsA/day (in propylene glycol) 3 times weekly. Serial pulmonary function testing and biopsies were repeated at 6-8 week intervals. Seven of the 9 pts completely resolved their rejection 9-105 days (mean 54 days) after institution of aerosolized CsA therapy. One recipient improved from moderate (grade 3) to minimal (grade 1) ACR while 1 pt remained with persistent mild (grade 2) ACR. Pulmonary function (FEV1), which had declined post-transplant from a best value of 2.02 ± 0.59 L to 1.58 ± 0.58 L (p=0.001) immediately prior to aerosol therapy, improved over 3-4 months to 1.90 ±0.75 L (p=0.006 post-aerosol vs pre-aerosol). As the figure demonstrates, this improvement is in distinct contrast to the decline experienced by a group of 23 historic controls matched for rejection history. No nephrotoxicity or hepatotoxicity was observed.
Aerosolized cyclosporine is an effective rescue therapy for lung transplant patients suffering from persistent acute rejection. A prospective randomized control trial is presently underway.
10:50 a.m. INTERMISSION
*By invitation 11:10 a.m. SIMULTANEOUS SCIENTIFIC SESSION E - GENERAL THORACIC SURGERY Room 6C/F, San Diego Convention Center
Moderators: Andre C.H. Duranceau, M.D. Alex G. Little, M.D.
52. RESULTS OF VATS THYMECTOMY IN PATIENTS WITH MY ASTHENIA GRAVIS. Michael J. Mack, M.D., Rodney J. Landreneau, M.D., Anthony P. Yim, M.D.*, Steven R. Hazelrigg, M.D.* and Granger R. Scruggs* Dallas, Texas, Pittsburgh, Pennsylvania, Hong Kong, Hong Kong, and Springfield, Illinois Discussant: Paul A. Kirschner, M.D.
Although video-assisted thoracic surgery (VATS) has a role in the management of a number of intrathoracic diseases, the efficacy of the procedure for thymectomy in patients with myasthenia gravis has not been examined. Thirty-three consecutive patients in 4 institutions underwent total thymectomy by VATS between March, 1992 and October, 1995. There were 13 males and 20 females with a mean age of 38.61 ± 17.68 years (range 9 to 84 years). The procedures were performed by either a right of left thoracoscopic approach and all anterior mediastinal tissue was removed to ensure a complete thymectomy. There was no perioperative mortality nor long-term morbidity. One patient required conversion to a lateral thoracotomy due to bleeding. All patients were extubated immediately except one patient who required postoperative ventilation. The mean hospital stay was 4.12 ± 6.46 days (range 1 to 37 days), with the median stay 3 days. Mean follow-up is 15.2 ± 5.93 months (range 1 to 41 months). Clinical improvement was seen in 69.6% (23/33) of the patients with 2 or 2 (100%) in Stage I, 14 of 19 (73.6%) in Stage IIA, 4 of 9 (44.4%) in Stage IIB and 3 of 3 (100%) as Stage III. We conclude that VATS thymectomy is as effective in the traditional open surgical approaches for performance of thymectomy in the management of patients with myasthenia gravis. In addition, the better cosmesis of the VATs approach makes thymectomy more acceptable to the patient and neurologist.
*By invitation 53. CHYLOTHORAX AFTER THORACOTOMY. Robert J. Cerfolio, M.D.*, Mark S. Allen, M.D.*, Claude Deschamps, M.D.*, Victor F. Trastek, M.D. and Peter C. Pairolero, M.D. Rochester, Minnesota Discussant: George T. Christakis, M.D.
Between July 1987 and May 1995, there were 11,315 general thoracic surgical procedures performed at our institution, and 47 patients (0.42%) developed a postoperative chylothorax. There were 32 men and 15 women whose median age was 65 years (range 21-88). Initial operation was for esophageal disease in 27, pulmonary disease in 13, mediastinal mass in six, and thoracic aortic aneurysm in one. All patients were initially treated with hyperalimentation, cessation of oral intake, or medium chain triglyceride diet. Nonoperative therapy was successful in 13 patients (27.7%), and oral intake was resumed a median of seven days postoperatively (range 2-15). Reoperation was required in the remaining 34 patients. 88.9% of the patients who had an esophageal procedure required reoperation, whereas only 38.5% of the patients who had a pulmonary resection required reoperation. Preoperative lymphangiogram was performed in 16 patients and identified the site of the leak which was usually at the level of the azygous vein. To control the fistula, the thoracic duct was ligated at the diaphragm in 13 patients, at the level of the fistula in 12, at both levels in 7, and by mechanical pleurodesis and fibrin glue in 2. Initial reoperation was successful in 31 patients (91.2%). Three patients required a second reoperation to control the fistula. Combined operative mortality was 2.1%, and complications occurred in four patients (8.5%). Factors that predicted reoperation were esophageal surgery and an average daily drainage of >1000 cc/day for the first five days postoperatively. We conclude that postoperative chylothorax is an unusual complication which can occasionally be treated nonoperatively; however, when drainage is >1000 cc/day or when it occurs after an esophageal operation, reoperation will usually be necessary. Preoperative lymphoangiogram can help identify the anatomy of the thoracic duct and localize the site of injury. The fistula can usually be controlled by ligation of the duct at the site of the leak or where it enters the thoracic cavity.
*By invitation 54. POSTPNEUMONECTOMY BRONCHOPLEURAL FISTULA FOLLOWING SUTURED BRONCHIAL CLOSURE: INCIDENCE, RISK FACTORS AND MANAGEMENT. Cameron D. Wright, M.D.*, John C. Wain, M.D.*, Douglas J. Mathisen, M.D. and Hermes C. Grille, M.D. Boston, Massachusetts Discussant: Robert J. Ginsberg, M.D.
Postpneumonectomy bronchopleural fistula (BPF) remains a morbid complication following pneumonectomy. Over a 15-year period (1980-1995), 256 consecutive patients underwent pneumonectomy with a standardized suture closure of the bronchus. The bronchus was then covered by autologous tissue. The indications for pneumonectomy were lung cancer (198), other malignancy (20) and benign causes (38). Possible risk factors for BPF in these patients included preoperative radiotherapy (30), preoperative pleuropulmonary infection (37), completion pneumonectomy (35), and postoperative ventilation (31). One hundred three patients underwent right pneumonectomy and 6 (6%) developed BPFs. Left pneumonectomy was performed in 153 patients and 2 (1%) developed BPFs. The only risk factors that were significant for BPF were the need for the postoperative ventilation (p<0.0001) and right pneumonectomy (p=0.04). Two (25%) of the eight patients who developed BPFs died. Five patients developed BPF due to pneumonia requiring ventilation while the cause for 3 patients appeared to be technical. Re-closure was successful in 5 patients (mean postoperative day 12) while 1 patient healed a pinhole fistula by drainage alone. Two patients were treated by drainage alone because of severe adult respiratory distress syndrome and both died. Careful sutured closure of the main bronchus following pneumonectomy yields excellent results. The primary risk factor for BPF is the need for postoperative ventilation. Re-closure can be successful even if performed late.
12:10 p.m. ADJOURN
*By invitation 9:30 a.m. SIMULTANEOUS SCIENTIFIC SESSION F - CONGENITAL HEART DISEASE Room 6D/E, San Diego Convention Center
Moderators: Richard A. Jonas, M.D. Thomas L. Spray, M.D.
55. HYPERTROPHIC OBSTRUCTIVE CARDIOMYOPATHY IN PEDIATRIC PATIENTS: RESULTS OF SURGICAL TREATMENT. David A. Theodoro, M.D.* and Gordon K. Danielson, M.D. Rochester, Minnesota Discussant: Michel N. Ilbawi, M.D.
Between April 1975 and May 1995, 25 pediatric patients on one hospital service underwent left ventricular septal myectomy for hypertrophic obstructive cardiomyopathy (HOCM). Ages ranged from 2 months to 20 years (mean=11 years). Associated cardiac diagnoses included mitral valve insufficiency (n=18), aortic valve insufficiency (n=3), atrial septal defect (n=2), history of ventricular arrhythmias (n=2), and bicuspid aortic valve (n=l). Symptoms included dyspnea (n=18), chest pain (n=12), syncope (n=5), and palpitations (n=2). Five patients were in NYHA class I, 10 were in class II, and 10 were in class III/IV. Preoperative medications included beta blockers (n=17), calcium channel blockers (n=4), disopyramide (n=l), or a combination (n=3), and length of treatment ranged from 2.6 months to 7.2 years (mean=2.2 years). One patient underwent dual-chamber pacemaker implantation without improvement of symptoms or left ventricular outflow tract (LVOT) gradient. Gradients ranged from 50 to 154 mmHg (mean=97.4) as determined by echocardiography (n=17) or cardiac catheterization (n=8). Concomitant cardiac procedures included mitral valve repair (n=3), AICD implantation (n=3), and closure of ASD (n=l). Intraoperative pre-myectomy LVOT gradients ranged from 20 to 117 mmHg (mean=82.3) and post-myectomy gradients ranged from 0 to 41 mmHg (mean=8.6). Post-myectomy mitral insufficiency, determined by double-sampling dye curves, was reduced to 0 to 12% regurgitant fraction (n=20), and no patient required mitral valve replacement. Aortic cross-clamp time ranged from 11 to 53 min (mean=35.3). Postoperative complications included ventricular arrhythmia (n=2), intra-aortic balloon pump support (n=l), and temporary complete heart block (n=l). There was no early mortality and no instances of aortic or mitral valvular damage or surgically created ventricular septal defect. One patient required placement of a pacemaker prior to hospital discharge for complete heart block; however, on follow-up at one year, normal sinus rhythm had returned. Follow-up ranged from 5 months to 15.8 years (mean=5.6 years). There were no late deaths. The mean LVOT gradient by echocardiography was 16 mmHg. Mild mitral valve insufficiency was present in 8 patients, mild aortic insufficiency was present in 3, and all patients were in normal sinus rhythm. Reoperation for recurrent LVOT obstruction was required in two patients at 3.2 years and 12.4 years after initial myectomy, respectively. At 5 years, freedom from reoperation for recurrent LVOT obstruction was 94.4 ±5.4%. We conclude that septal myectomy is a safe and effective means of relieving LVOT obstruction and cardiac symptoms in pediatric patients with hemodynamically important HOCM, and late survivorship compares extremely favorably with that of the natural history of nonoperative management in the pediatric population.
*By invitation 56. FACTORS IN THE EARLY FAILURE OF CRYO-PRESERVED HOMOGRAFT PULMONARY VALVES IN CHILDREN: PRESERVED IMMUNOGENICITY? Roger J. Baskett, M.A.*, David B. Ross, M.D.*, Maurice A. Nanton, M.B.* and David A. Murphy, M.D. Halifax, Nova Scotia, Canada Discussant: Richard A. Hopkins, M.D.
Introduction: Most studies addressing the durability of homograft valves in the right ventricular outflow tract (RVOT) use freedom from death or reoperation as the end point. Very few studies have systematically assessed the homograft valve function over time with echocardiography. The durability of valve function in the RVOT is of increasing importance as more patients are referred for pulmonary valve replacement to protect a failing right ventricle.
Methods: Between 1990 and 1995, 48 homograft valves (15 aortic, 33 pulmonary) cryopreserved on-site were implanted to reconstruct the RVOT in 44 children (mean age: 6 years, range: 3 days to 19 years) with a variety of congenital cardiac lesions. Serial echocardiographic follow-up was performed on all 45 valves in the 41 survivors, with all echocardiograms reviewed in a standardized manner by one blinded pediatric cardiologist. In four cases, the echocardiographic windows were inadequate to reliably comment on valve function and are excluded from this analysis.
Results: Four homograft valves were replaced due to pulmonary insufficiency (3) or stenosis and insufficiency (1) at 2, 7, 14 and 48 months following implantation. Freedom from reoperation is 90% (70% CI, 84-96%) at 4 years. Three valves had >2+ insufficiency at the initial postoperative echocardiogram. Over the follow-up period, a further 15 of the remaining 38 valves (39%) developed progressive pulmonary insufficiency (PR) of at least 2 grades. Three valves developed transvalvular gradients of >50 mmHg, one of which was also insufficient. The freedom from echocardiographic failure (≥2+ PR or ≥50 mmHg gradient) was only 40% at 4 years (70% CI, 29-51%). Young age (p=0.05), low operative weight (p=0.01), small graft size (p=0.03), and homograft retrieval to cryopreservation time <24 hours (p=0.03) were significantly associated with valve insufficiency. The type of valve, donor age, tissue versus heart beating donor, or blood type mismatch were not associated with failure.
Conclusion: Homografts function well as conduits between the pulmonary ventricle and pulmonary arteries if long-term valve competency is not crucial. However, many rapidly become insufficient. This has important implications for the choice of valve if the indication for valve replacement is to protect a ventricle failing due to pulmonary insufficiency. Short homograft retrieval to cryopreservation times have been shown by others to enhance viability and antigenicity. This may explain the association observed in this study between short homograft retrieval to cryopreservation times and valve failure suggesting an immunological basis for this failure.
*By invitation 57. PULMONARY HYPERTENSION AFTER CONGENITAL OPEN HEART SURGERY: AN ANALYSIS OF RISK FACTORS AND MANAGEMENT. Ko Bando, M.D.*, Mark W. Turrentine, M.D.*, Kyung Sun, M.D.*, Thomas G. Sharp, M.D.*, Thomas X. Aufiero, M.D.*, Yasuo Sakine, M.D.* and John W. Brown, M.D. Indianapolis, Indiana Discussant: Pedro del Nido, M.D.
Background and Purpose: Pulmonary hypertensive events (PHE) including persistent pulmonary hypertension and pulmonary hypertensive crisis can cause death after cardiac operations for congenital heart defects (CHD). Monitoring and management of these potentially fatal complications have evolved over the last 15 years. Major changes include monitoring of pulmonary arterial pressure and mixed venous saturation (SvO2 as well as prophylaxis with a-blockers (Chlorpromazine [CP] and/or Prazosin hydro-chloride [PR]) and other vasodilators (nitroglycerin and sodium nitroprusside). The purpose of this study was to identify risk factors for morbidity and mortality of PHE and to determine the impact of postoperative management on outcome.
Method: Two thousand four hundred fifty-four patients with CHD operated on using cardiopulmonary bypass between January 1980 and December 1994 were included in this study. Using univariate and multiple regression analysis, high risk candidates for post-op PHE were identified and risk of morbidity and mortality of PHE was analyzed.
Results: Patients with complete atrioventricular canal (CAVC; n=182), truncus arteriosus (TA; n=47), total anomalous pulmonary venous connection (TAPVC; n=90), transposition of great arteries (TGA; n=67), hypoplastic left heart syndrome (HLHS; n=50) and ventricular septal defect (VSD; n=414) were at high risk for post-op PHE. Fifty-eight percent (36/62) of hospital deaths in the high risk group were associated with PHE. Prevalence and mortality of PHE in each diagnostic group are depicted below.
Analysis of these 850 cases divided into three different time frames revealed important institutional trends.
By multiple logistic regression, pre-op PH (p<0.001), absence of SvO2 monitoring (p<0.001) and absence of CP/PR prophylaxis (p=0.002) were significant risk factors for the development of PHE. Only pre-op PH (p<0.001) was a significant risk factor for early death related to PHE. In each diagnostic group except TAPVC, definitive repair at older age was a significant risk factor for postoperative PHE (p<0.001) and early death related to PHE (p<0.05).
Conclusion: Post-op SvO2 monitoring and CP/PR prophylaxis significantly reduced the prevalence of PHE. Definitive early repair reduces the postoperative morbidity and mortality from PHE.
1991-92 Graham Fellow *By invitation 58. MODIFIED FONTAN PROCEDURE IN 99 CASES WITH ATRIOVENTRICULAR VALVE REGURGITATION. Yasuharu Imai, M.D., Yoshinori Takanashi, M.D.* and Shuuichi Hoshino, M.D.* Tokyo, Japan Discussant: Hillel Laks, M.D.
Modified Fontan procedure generally carries higher risk in cases associated with atrioventricular valve regurgitation (AVVR). Factors influencing death were analyzed. Since January 1985 to August 1995, of 242 patients undergoing modified Fontan procedure, 99 had AVVR ranging in degrees from 1 to 4 (Sellers) by retrograde cineangiography, for which concomitant repair for AVVR was performed. Degree of AVVR was 1.6 ± 0.7 in average, 49 cases had more than grade 2 regurgitation and those with trivial regurgitation by Doppler echocardiography were classified as having no AVVR. Ages at operation ranged from 1 to 27 (9.9 ± 6.1) years. Anomalies consisted of 32 cases with univentricular heart (UVH) of RV type, 14 with UVH of LV type, 7 with classical tricuspid atresia and 46 other anomalies with biventricular heart. There were 24 cases of left isomerism and 25 had right isomerism. Prior to Fontan procedure, 99 palliative procedures mainly consisting of shunt procedure had been performed in 69 cases. Reparative procedures on the valve included circular annuloplasty in 75 cases, conventional annuloplasty in 11, patch-closure of valve in 4, valvoplasty in 4, and none in 4. Hospital mortality was higher in AVVR (12/99, 12%) than in cases without AVVR (4/143, 3%). Three died late during a mean follow-up period of 3.9 ± 2.9 years. Degree of AVVR showed a significant decrease from 1.64 ± 0.74 to 0.4 ± 0.51 (p<0.0001) after operation in survivors. Preoperative factors influencing hospital death and survival were number of parameters exceeding limits of ten commandments 4.92 vs. 3.85 (p<0.0083), cardiothoracic ratio 62 vs. 56% (p<0.0048), ventricular endo-diastolic volume 282 vs. 237% of normal (p<0.0455), pulmonary blood flow 3.5 vs. 5.0 L/minute/m2 (p<0.0183), and Mayo's criteria 3.74 vs. 2.96 (p<0.0275). However, ventricular ejection fraction, pulmonary vascular resistance, degree of AVVR (1.75 vs. 1.62), morphological types of systemic ventricle and ventricular end-diastolic pressure were not related to death. In conclusion, cases with AVVR can be treated with reasonable risk, provided proper repair of the valve is performed.
10:50 a.m. INTERMISSION
*By invitation 11:10 a.m. SIMULTANEOUS SCIENTIFIC SESSION F - CONGENITAL HEART DISEASE Room 6D/E, San Diego Convention Center
Moderators: Richard A. Jonas, M.D. Thomas L. Spray, M.D.
59. PULMONARY ARTERY GROWTH AFTER BIDIRECTIONAL CAVOPULMONARY SHUNT: IS THERE CAUSE FOR CONCERN? V. Mohan Reddy, M.D.*, Edwin Petrossian, M.D.*, Doff B. McElhinney, A.B.*, Phillip Moore, M.D.*, Gary S. Haas, M.D.* and Frank L. Hanley, M.D. San Francisco, California Discussant: Thomas R. Karl, M.D.
Since pulmonary artery (PA) growth may be influenced by blood flow, it is thought that leaving patients with Bidirectional Cavopulmonary Shunt (BCPS) for extended periods of time may result in suboptimal PA growth. Between March 1990 and October 1995, 112 patients underwent BCPS at our institution; 28 of these patients have subsequently undergone a modified Fontan procedure (FP) and comprise the study group for the present report. Median age at BCPS among these 28 patients was 2.3 years (range: 3.2 months to 43 years), and median duration between BCPS and FP was 18 months (range: 1 to 47 months). At the time of BCPS, 8 patients underwent bilateral BCPS, 14 patients had PA augmentation, and 18 patients were left with an extra source of pulmonary blood flow (ExPBF). In these patients, the pre-BCPS and pre-FP angiograms were reviewed and right (R) and left (L) PA diameters were measured at their bifurcation, and indexed right (RPAI), and left (LPAI), and total (TPAI) PA cross-sectional areas were calculated. Since many patients underwent branch PA plasty, right lower lobe (RLL) and left lower lobe (LLL) PA diameters were also measured at their origin and R, L, and total lower lobe (ILL) indices were calculated. Aortic diameters immediately distal to the left subclavian artery and at the diaphragm were measured for control purposes. PAIs and hemodynamic variables were compared from pre-BCPS to pre-FP by paired /-test. Analysis of variance and linear regression were carried out to evaluate variables correlating with change in PAIs between BCPS and FP and with morbidity and mortality following FP. Variables analyzed included pre-BCPS PAIs, duration from BCPS to FP, bilateral BCPS, PA plasty at BCPS, ExPBF, early post-BCPS PA pressure, and pre-FP pulmonary hemodynamics (PA pressure), indexed pulmonary blood flow (Qp), pulmonary to systemic blood flow ratio (Qp:Qs). Aortic diameters increased significantly (p<0.01), and PA pressure (p=0.02), ventricular end-diastolic pressure (p=0.02), pulmonary to systemic blood flow ratio (Qp:Qs; p=0.01), and indexed pulmonary blood flow (Qp; p=0.04) all decreased significantly from pre-BCPS to pre-FP catheterization. There was a significant decrease in TPAI among patients undergoing BCPS with no ExPBF (p=0.02). There were also significant differences in TPAI (p=0.05), RLL PAI (p=0.03), and TLL PAI (p=0.04) changes from BCPS to FP between patients with and without ExPBF, with mean PAIs increasing among patients with ExPBF and, decreasing among patients without ExPBF. There were no significant differences in various indices between patients with single or bilateral BCPS. There were no significant correlations between the PAIs, variables analyzed and post FP outcome (mortality, effusions, PA pressure).
Conclusion: Although it appears that central pulmonary artery growth is affected by BCPS and the presence of ExPBF, none of the variables analyzed, including change in PAIs, correlated with post-FP mortality, effusions, or PA hemodynamics. However, it is possible that if BCPS is chosen as a long-term palliation method, pulmonary artery growth may become an important issue.
*By invitation 60. EXTRACARDIAC FONTAN FOR COMPLEX CARDIAC ANOMALIES: SEVEN-YEAR EXPERIENCE. Antonio Amodeo, M.D.*, Lorenzo Galletti, M.D.*, Salvatore Giannico, M.D.*, Paolo Di Renzi, M.D.* and Carlo Marcelletti, M.D. Rome, Italy Discussant: Leonard L. Bailey, M.D.
Between November 1988 and September 1995, 58 patients with complex cardiac anomalies underwent an extracardiac Fontan (EF). The EF consisted in the combination of a bidirectional cavopulmonary anastomosis and an extra-cardiac conduit between the inferior vena cava (IVC) and the pulmonary artery (PA) except in one pt in whom the IVC was directly anastomosed to the PA. In 37 pts the EF followed a preliminary BCPA, associated with modified Damus-Kaye-Stansel in 16. The conduits used were Dacron (34), aortic homografts (3) and PTFE used electively in the last 20 pts. There were 6 hospital deaths (10.3%). Two pts required conduit take-down due to a failing Fontan for a left PA stenosis and severe atrioventricular valve regurgitation respectively; another two pts required a revision of the cavopulmonary anastomosis due to anastomotic stricture. All pts were discharged on oral anticoagulation for six months. In a mean follow-up of 35 months (3-80 mos), there were no late deaths with 54 pts in NYHA class I or II. Two pts required balloon dilatation and/or stents implantation of PA after EF. Late atrial arrhythmias were detected in 6/58 pts: 4 had mild sinus dysfunction and 2 atrial flutter requiring a PMK implantation in 1. Patency of the Dacron conduits was evaluated in the initial 25 pts by MRI showing a reduction of the conduit internal diameter of 12.7% ± 5.1% in the first month and additional narrowing of 2% over the next 2 years. These data demonstrate that the EF provides excellent early and mid-term results in terms of mortality, morbidity, and incidence of late arrhythmias.
*By invitation 61. COAGULATION FACTOR ABNORMALITIES FOLLOWING THE FONTAN PROCEDURE AND ITS MODIFICATIONS. Marjan Jahangiri, FRCS*, Daryl Shore, FRCS*, Vijay Kakkar, FRCS*, Elliot Shinebourne, FRCP* and Christopher Lincoln, FRCS London, United Kingdom Discussant: John E. Mayer, Jr., M.D.
Recently we reported a high incidence of thromboembolism in patients who underwent the Fontan procedure and its modifications. While haemodynamic factors may well contribute to this, recent evidence suggests that coagulation factor abnormalities may also play a role. We therefore set out to investigate the coagulation status in a group of patients who had undergone the Fontan procedure.
The study population consists of 20 children who had undergone the Fontan procedure and its modifications. They were examined for coagulation factor abnormalities and their serum albumin, total protein and liver enzymes were measured. The median age at the time of surgery was 6.2 years with a male to female ratio of 2.3:1, the median time from the Fontan repair was 4.9 years (18-76 months).
Protein C (p<0.001), protein S (p<0.005) and factor VII (p<0.001) were significantly lower than the normal range. The changes in serum albumin and total protein, factors II, VII, IX and X were not significant.
It is possible that deficiency in protein C, protein S and factor VII partly account for the high incidence of thromboembolism following Fontan type repair. The risk of long-term anticoagulation should be weighed against the best palliative procedure for these patients. We suggest that reduced protein C, protein S and factor VII in this group of patients should be regarded as risk factors and that such patients should be anticoagulated.
12:10 p.m. ADJOURN
*By invitation |
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