Relationship between amount of lung resected and outcome after lung volume reduction surgery.

BACKGROUND: Lung volume reduction surgery (LVRS) is being actively investigated for palliative treatment of severe emphysema. Considerable focus is directed toward patient selection and outcomes of LVRS. However, there is little information available regarding surgical methods to guide optimal extent of resection. We hypothesized that acute improvement and long-term survival after bilateral staple LVRS would be related to the extent of tissue resected. METHODS: The relationship between acute improvement in forced expiratory volume in 1 second and forced vital capacity was examined as a function of the total grams of lung tissue resected in 237 patients who underwent bilateral staple LVRS by a single group of surgeons. Overall survival was assessed based on extent of resection by quartiles of tissue weight resected using Kaplan-Meier survival methods. RESULTS: Improvement in forced expiratory volume in 1 second and forced vital capacity correlated with extent of tissue resected (p < 0.01), although there was considerable variability to individual response (r = 0.3). In contrast, there was no apparent relationship between the amount of tissue resected and overall postoperative survival (p = 0.7). CONCLUSIONS: There is a correlation between the amount of tissue resected and improvement in forced expiratory volume in 1 second and forced vital capacity after bilateral staple LVRS, with generally greater postoperative improvement after larger volume resections. However, there does not appear to be greater long-term survival with larger volume resections despite greater improvement in spirometry. This study suggests that factors other than improvement in spirometric variables may govern optimal LVRS resection volumes and long-term outcome. Future studies will clearly be needed in this important area of LVRS emphysema research.

Survival after unilateral versus bilateral lung volume reduction surgery for emphysema.

OBJECTIVE: Bilateral staple lung volume reduction surgery (LVRS) immediately improves pulmonary function and dyspnea symptoms in patients with advanced heterogeneous emphysema to a greater degree than do unilateral procedures. However, the long-term outcome after these surgical procedures needs to be critically evaluated. We compare 2-year survival of patients who underwent unilateral versus bilateral video-assisted LVRS in a large cohort treated by a single surgical group. METHODS: The cases of all 260 patients who underwent video-assisted thoracoscopic stapled LVRS from April 1994 to March 1996 were analyzed to compare results after unilateral versus bilateral procedures. Overall survival was calculated by Kaplan-Meier methods; Cox proportional hazard methods were used to adjust for patient heterogeneity and baseline differences between groups. RESULTS: Overall survival at 2 years was 86.4% (95% CI 80. 9%-91.8%) after bilateral LVRS versus 72.6% (95% CI 64.2%-81.2%) after unilateral LVRS (P =.001 for overall survival comparison). Improved survival after bilateral LVRS was seen among high- and low-risk subgroups as well. Average follow-up time was 28.5 months (range, 6 days to 46.6 months) for the bilateral LVRS group and 29.3 months (range, 6 days to 45.0 months) for the unilateral LVRS patients. CONCLUSIONS: Comparison of unilateral versus bilateral thoracoscopic LVRS procedures for the treatment of emphysema reveals that bilateral LVRS by video-assisted thoracoscopy resulted in better overall survival at 2-year follow-up than did unilateral LVRS. This survival study, together with other studies demonstrating improved lung function after bilateral LVRS, suggests that bilateral surgery appears to be the procedure of choice for patients undergoing LVRS for most eligible patients with severe heterogeneous emphysema.

Diffusing capacity limitations of the extent of lung volume reduction surgery in an animal model of emphysema.

OBJECTIVE: The purpose of this study was to investigate in an elastase-induced emphysema rabbit model the effects of increasing resection volumes during lung volume reduction surgery on pulmonary compliance, forced expiratory air flow, and diffusing capacity to assess factors limiting optimal resection. METHODS: Emphysema was induced in 68 New Zealand White rabbits with 15,000 units of aerosolized elastase. Static respiratory system compliance, forced expiratory flow, and single-breath diffusing capacity were measured before the induction of emphysema, after the induction of emphysema, and 1 week after a bilateral upper and middle lobe lung volume reduction operation. RESULTS: Static respiratory system compliance with 60 mL insufflation above functional residual capacity increased with emphysema induction and then decreased progressively with resection of larger volumes of lung tissue (P =.001 by analysis of variance). Expiratory flow improved after lung resection in the rabbits with large resection volumes. In contrast, diffusing capacity tended to deteriorate with larger resection volumes (P =. 18). CONCLUSION: Improvements in respiratory system compliance and forced expiratory flow after lung volume reduction operations may account for the improvements seen clinically. Declines in diffusing capacity with extensive lung reduction may limit the clinical benefits associated with greater tissue resection volumes. Future investigations with animal models may reveal other physiologic parameters that may further guide optimal lung volume reduction procedures.

Survival following bilateral staple lung volume reduction surgery for emphysema.

STUDY OBJECTIVES: Despite numerous reports of short-term response to lung volume reduction surgery (LVRS) for treatment of emphysema, to our knowledge, longer-term survival has not been reported. We describe survival following LVRS in a large cohort of 256 patients treated with bilateral staple LVRS (n = 236 video-assisted thoracic surgery [VATS] approaches, n = 20 median sternotomy) by a single group of physicians over a 3 1/2-year period from April 1994 to November 1997. DESIGN: Prospective survival study. Overall survival, survival stratified by preoperative presentation, and acute postoperative response were investigated using Kaplan-Meier methods. The simultaneous effects of preoperative predictors and postoperative response variables on survival were examined using a Cox proportional hazards model. SETTING: Community hospital and university medical center. PATIENTS: We studied 256 consecutive patients with severe emphysema treated with LVRS. INTERVENTIONS: Bilateral staple LVRS by VATS. MEASUREMENTS AND RESULTS: Overall survival information was known with certainty for 246 of 256 patients as of February 1, 1998. Median follow-up time was 623 days (range, 0 to 1,545 days). Mean FEV1 was 0.635L+/-0.015 L preoperatively and rose to 1.068L+/-0.029 L postoperatively. By standard analysis methods (missing patients censored at the time of last contact), 1-year survival was 85+/-2.3% compared with 83+/-2.4% 1-year survival with "worst case" analytic methods (assuming all missing patients died). Two-year survival averaged 81+/-2.7% by standard analysis vs 76+/-2.9% by worst case evaluation. Survival was significantly better for patients who were younger (< or = 70 years old, p = 0.02) and with higher baseline FEV1 (> 0.5, p < 0.03) and PO2 (> 54, p < 0.001). Patients who had greatest short-term improvement in FEV1 following surgery (> 0.56 L increase) also had significantly better longer-term survival following LVRS. CONCLUSIONS: To our knowledge, this is the first longer-term survival analysis of a large series of patients who underwent bilateral staple LVRS for emphysema. Substantial long-term mortality is seen, particularly within identifiable high-risk subgroups. Careful comparison to comparably matched control patients will be needed to definitively assess the benefits and risks of LVRS. This study suggests that prospective, controlled trials may need to stratify patient randomization based on preoperative risk factors to obtain meaningful results.

Video-assisted thoracic surgery (VATS) lobectomy for bronchogenic carcinoma.

Video-assisted thoracic surgery (VATS) lobectomy remains controversial because surgeons have been concerned about the safety of the procedure and the adequacy of the cancer operation when it is performed for lung cancer. This review of a 4.5-year experience with 212 VATS lobectomies for primary lung cancer was undertaken to address these issues. All operations involved a standard anatomic dissection and lymph node sampling or dissection. The mean length of stay was 4.6 days. There were no serious problems of intraoperative bleeding. There was one death owing to mesenteric venous infarct. The 4.5-year survival for stage I lung cancer was 76%. The data suggest that a complete cancer operation for primary lung cancer can be safely performed with VATS, with survival that is comparable with operations performed with a thoracotomy.

Insight on emphysema--the first 300 cases of surgical treatment.

Our experience with lung volume reduction surgery for emphysema now encompasses more than 300 cases, including several prospective trials. We have a 3.5% operative mortality rate and, with aggressive use of Heimlich valves over the past 6 months, an average hospital length of stay of 8 days. Proper patient selection is essential and can be based primarily on results of pulmonary function tests (PFTs), ventilation/perfusion (V/Q) scans, and computed tomography (CT) scans. We have found that bilateral is more effective than unilateral staple lung volume reduction surgery, which is in turn better than unilateral laser surgery. In patients with bilateral upper lobe disease, average FEV1 (forced expiratory volume in a 1-second interval) improvement is 82%; overall, it is 61% (range -33 to 217%). We conclude that lung volume reduction surgery can be performed safely with acceptable mortality and excellent clinical results in properly selected, motivated patients.

Rate of FEV1 change following lung volume reduction surgery.

INTRODUCTION: Lung volume reduction surgery (LVRS) improves pulmonary function and dyspnea symptoms acutely in selected patients with heterogeneous emphysema. Limited data are available regarding long-term function following LVRS. We analyzed short-term (<6 months) and long-term rate of change of pulmonary function in 376 patients who underwent unilateral or bilateral LVRS using thoracoscopic or median sternotomy, staple, laser, or combined techniques. We hypothesized that the long-term rate of deterioration in lung function would be dependent on the surgical procedure used and would be greatest in those with the largest short-term postoperative improvement. METHODS: Pulmonary function was assessed preoperatively and at repeated intervals following LVRS. The change in pulmonary function over time was assessed for each patient by determining the individual change in FEV1 using linear regression analysis short and long term. Overall rate of change in pulmonary function was calculated for the composite group of patients and subgrouped by operative procedure. RESULTS: Lung function appears to improve in the first few months following LVRS in most patients, maximizing at approximately 3 to 6 months and declining thereafter. The short-term incremental improvement following staple procedures is superior to improvements following laser procedures or unilateral surgery: FEV1 increase (mean+/-SD) of 0.39+/-0.03 L for bilateral staple, 0.25+/-0.03 L for unilateral staple, 0.10+/-0.03 L for unilateral laser, and 0.22+/-0.1 L for mixed unilateral staple/laser procedures. However, the long-term rate of decline in FEV1 was greatest for bilateral staple LVRS procedures as well: 0.255+/-0.057 L/yr for bilateral staple, 0.107+/-0.068 L/yr for unilateral staple, 0.074+/-0.034 L/yr for unilateral laser, and 0.209+/-0.12 L/yr for mixed staple laser procedures. There was a general correlation between the magnitude of short-term incremental improvement and the rate of deterioration in FEV1 (r=0.292, p=0.003). CONCLUSIONS: While bilateral staple LVRS procedures lead to greater short-term improvement in FEV1, the more rapid rate of FEV1 decline in these patients and the general association between greater short-term incremental improvement and higher rates of deterioration raise questions regarding optimal long-term procedures. Further studies will be needed to answer these important questions.

Changes in pulmonary physiology after lung volume reduction surgery in a rabbit model of emphysema.

OBJECTIVE: The purpose of this study is to investigate the effects of lung volume reduction surgery on pulmonary compliance, airway flow, and helium lung volumes in an elastase-induced emphysema animal model. METHODS: A 15,000-unit bolus of elastase was aerosolized through an endotracheal tube in 14 New Zealand White rabbits to induce emphysema. Stapled lung volume reduction of bilateral upper and middle lobes was performed through a midline sternotomy at 4 weeks after induction of emphysema. Lung functions were measured at baseline before induction of emphysema, preoperatively at 4 weeks, and 1 week postoperatively. RESULTS: Compliance increased after induction of emphysema and decreased in response to lung volume reduction surgery. Functional residual capacity decreased after lung volume reduction surgery in proportion to the amount of excised lung tissue. Expired flows suggested improvement in response to lung volume reduction surgery. Histologic examination confirmed presence of diffuse heterogeneous emphysema in each animal at necropsy. CONCLUSIONS: The decreased compliance and increased airway flow after volume reduction surgery in this model parallels findings in human studies and suggests that similar mechanisms of increased elastic recoil and airway support contribute to improvement.

Bovine pericardium versus bovine collagen to buttress staples for lung reduction operations.

BACKGROUND: Air leaks after stapled lung volume reduction operations for emphysema remain the most common postoperative complication. Cooper developed the use of bovine pericardium buttress for the staple lines in an attempt to decrease the occurrence of prolonged postoperative air leaks. However, the materials cost for a bilateral procedure may add $3,000 to $4,000 to the cost of the operation. We undertook this study to evaluate the efficacy of a less expensive buttress. METHODS: Fifty-seven patients underwent a bilateral thoracoscopic stapled operation with bovine pericardium (Peri-Strips) on one side and bovine collagen (INSTAT) on the contralateral side to buttress the staples. RESULTS: The average time to chest tube removal was 8.6 +/- 7.2 days for Peri-Strips and 10.7 +/- 8.7 days for INSTAT (p = 0.16). No significant differences were seen when right-sided and left-sided application were considered separately (p = 0.12). CONCLUSIONS: Peri-Strips or INSTAT for buttressing staple lines in thoracoscopic stapled bilateral lung volume reduction operations were equally effective. Materials cost savings of up to 80% per case can be realized by using the less expensive but equally effective INSTAT for buttressing staple lines.

Is lobectomy by video-assisted thoracic surgery an adequate cancer operation?

BACKGROUND: Although the public perceives video-assisted thoracic surgery (VATS) as advantageous because it is less invasive than a thoracotomy, the medical community has questioned the safety of VATS lobectomy and its adequacy as a cancer operation. Reported series have not been able to address these issues because follow-up has been only short-term. METHODS: A multiinstitutional, retrospective review was performed in 298 consecutive patients who underwent VATS for a standard anatomic lobectomy with lymph node dissection for lung cancer. Pathologic staging was I in 233 (78%), II in 27 (9%), and IIIA in 38 (13%) patients. Kaplan Meier survival analysis was performed. RESULTS: The conversion rate from VATS lobectomy to thoracotomy was 6%, but none were for massive intraoperative bleeding. The only death (0.3%) was because of mesenteric venous thrombosis. Forty minor complications occurred in 38 patients (12.8%) undergoing VATS. The mean and median lengths of stay were 5+/-3.39 and 4 days, respectively. Recurrence in an incision occurred in 1 patient (0.3%). The Kaplan Meier 4-year survival for stage I was 70%+/-5%. CONCLUSION: The VATS lobectomy for bronchogenic carcinoma appears to be a safe operation, with the same survival as expected for a lobectomy done by thoracotomy.

Video-assisted thoracic surgery for lung volume reduction surgery.

Lung volume reduction surgery by video thoracoscopy can result in significant improvement in quality of life and pulmonary function for selected patients suffering from severe emphysema. Clinical trials comparing the use of lasers versus staples, unilateral versus bilateral procedures, and video surgery versus mediansternotomy are summarized. Patient selection and patient care issues are addressed. Information gathered from the selection, evaluation, and study of almost 500 patients treated surgically for emphysema at a single institution is summarized.

Dyspnea response following bilateral thoracoscopic staple lung volume reduction surgery.

PURPOSE: Lung volume reduction surgery (LVRS) has shown promise for treating patients with severe emphysema in recent clinical trials. However, response following surgery is difficult to assess due to frequent discrepancies between subjective and objective outcomes. We evaluated the relationship between improvement in dyspnea and pulmonary function response in 145 consecutive patients with inhomogeneous emphysema enrolled in a bilateral thoracoscopic lung volume reduction protocol in order to assess predictors of improved dyspnea outcome and correlation of subjective and objective improvement measures. MATERIALS AND METHODS: Baseline complete pulmonary function testing, spirometry, gas exchange, plethysmography, gas dilution lung volumes, along with resting dyspnea index determinations were performed preoperatively, and repeated short term (mean, 33 days; n=129) and long term (>6 months; mean, 276 days; n=84) following surgery. RESULTS: Improvement in FEV1 percent predicted was significantly associated with improvement in dyspnea scores, though considerable variability exists (r=0.04, p<0.01, short term; r=0.4, p=0.1, long term). In this preselected patient group, those with the extreme degrees of hyperinflation may have less improvement in dyspnea following LVRS than those with milder preoperative hyperinflation. Greater improvement in dyspnea short term and long term was seen in patients with lower presenting residual volume/total lung capacity ratios (r=0.4, p=0.02, short term; r=0.4, p<0.05, long term). CONCLUSIONS: Bilateral thoracoscopic staple LVRS results in significant objective and subjective improvement in patients with severe emphysema and hyperinflation. There was considerable variability between improvement in dyspnea and improvement in spirometry, and preoperative predictors of response may differ between these outcome variables. Further studies are needed to define the long-term implications of these findings.

Comparison of Ho:YAG versus Nd:YAG thoracoscopic laser treatment of pulmonary bullae in a rabbit model.

OBJECTIVE: To determine the relative efficacy and morbidity of Ho:YAG versus Nd:YAG laser treatment of bullous lung disease in an animal model. SUMMARY BACKGROUND DATA: Laser coagulation procedures for treatment of emphysematous pulmonary bullae and heterogeneous emphysema continue to evolve. The role of lasers in lung volume reduction surgery remains controversial due to issues of relative efficacy and morbidity. The Nd:YAG laser is most commonly used for these procedures. We hypothesized that the shallower penetration of the Ho:YAG laser may be better suited for laser bullae coagulation and emphysema lung volume reduction with increased efficacy and reduced lung injury. METHODS: Thirty New Zealand White rabbits (15 normal rabbits; 15 with bullous lung disease) were evaluated with Ho:YAG compared to Nd:YAG laser exposures. Bullae were coagulated by either Ho:YAG or Nd:YAG treatment. In all animals (bullous-induced and normals), unaffected lung tissue in the upper lobes and contralateral lungs were treated with 5 spot exposures of Nd:YAG and Ho:YAG, each to assess depth of lung injury. Animals were sacrificed at Days 0, 7, and 21 and their lungs were examined histologically. RESULTS: Ho:YAG and Nd:YAG exposures caused equivalent lung injury to normal lung tissue. In the acute phase, parenchymal necrosis depth was similar for both Ho:YAG and Nd:YAG (850 +/- 273 microns vs. 900 +/- 270 microns respectively, p = 0.7). By Day 7, lung necrosis depth was 925 +/- 133 microns Ho:YAG vs. 1225 +/- 235 microns Nd:YAG (p = 0.33), and lung fibrosis depth was 300 +/- 134 microns Ho:YAG vs. 558 +/- 127 microns Nd:YAG (p = 0.11). By Day 21, pulmonary parenchymal necrosis was not seen. Pleural fibrosis depth was maximal at Day 21, reaching 250 +/- 102 microns for Ho:YAG vs. 300 +/- 156 microns Nd:YAG (P = 0.88). Pleural necrosis depth was 67 +/- 42 microns Ho:YAG vs 48 +/- 34 microns Nd:YAG (p = 0.42) on Day 7 and resolved by Day 21. During surgical coagulation procedures, the Ho:YAG laser was dramatically more efficient in coagulating bullae. The Ho:YAG laser required less exposure at equivalent power and resulted in immediate desiccation of bullae, in sharp contrast to the Nd:YAG laser. CONCLUSIONS: Because the Ho:YAG was more effective and did not result in more acute lung injury than the standard Nd:YAG laser in this study, Ho:YAG lasers may have improved potential for laser treatment of bullae or lung volume reduction surgery (LVRS) compared to Nd:YAG lasers.

Patient selection criteria for lung volume reduction surgery.

OBJECTIVE: Our intent was to refine the patient selection criteria for lung volume reduction surgery because various centers have different criteria and not all patients benefit from the procedure. METHODS: Patient information, x-ray results, arterial blood gases, and plethysmographic pulmonary function tests in 154 consecutive patients who underwent bilateral thoracoscopic staple lung volume reduction surgery were compared with clinical outcome (change in forced expiratory volume in 1 second and dyspnea scale) with t tests and analysis of variance. RESULTS: Three hundred thirty-three of 487 (69%) patients evaluated for lung volume reduction surgery were rejected for lack of heterogeneous emphysema (n = 212), medical contraindications (n = 88), hypercapnia (n = 20), uncontrolled anxiety or depression (n = 10), or pulmonary hypertension (n = 1). Two patients died during the evaluation process. When tested by analysis of variance, there was no difference in clinical outcome associated with preoperative forced expiratory volume in 1 second, residual volume, total lung capacity, single-breath diffusing, and arterial oxygen or carbon dioxide tension. All patients selected for the operation had a heterogeneous pattern of emphysema. The upper lobe heterogeneous pattern of emphysema on chest computed tomography and lung perfusion scan was strongly associated with improved outcome with a mean (95% confidence interval) improvement in forced expiratory volume in 1 second of 73.2% (63.3 to 83.1) for the upper lobe compared with a mean (95% confidence interval) improvement of 37.9% (22.9 to 53.0) for the lower lobe or diffuse pattern of emphysema. CONCLUSION: The most important selection criteria for lung volume reduction surgery is the presence of a bilateral upper lobe heterogeneous pattern of emphysema on chest computed tomography and lung perfusion scan. After patients have been selected on the basis of a heterogeneous pattern of emphysema, clinical factors and physiology are not associated with clinical outcome well enough to further refine patient selection criteria. These results do not support the arbitrary patient selection criteria for lung volume reduction surgery reported in the literature.

Should lung volume reduction for emphysema be unilateral or bilateral?

Both unilateral and bilateral lung volume reduction procedures are being advocated for treatment of severe, generalized emphysema. We analyzed the results of 166 consecutive patients who underwent unilateral (n = 87) or bilateral (n = 79) thoracoscopic stapled lung volume reductions to help define the role for these procedures. There was no statistically significant difference in the operative mortality (3.5% vs 2.5%), mean length of stay (11.4 +/- 1 vs 10.9 +/- 1 days), or morbidity for the unilateral and bilateral groups, respectively (p not significant for all variables). Oxygen dependence was eliminated in 18 (36%) of 50 patients who had unilateral procedures and 30 (68%) of 44 of those who had bilateral procedures (p < 0.01). Prednisone was eliminated for 38 (54%) of 51 unilateral-procedure patients, compared with 30 (85%) of 35 bilateral-procedure patients (p = 0.02). Overall, bilateral procedures produced a mean improvement in the forced expiratory volume in 1 second (FEV1) of 57%, compared with 31% for unilateral reduction procedures (p < 0.01). Our bilateral staple procedure produced a 72.8% mean increase in the FEV1 for patients who had upper lobe emphysema. Especially compromised patients (age > or = 75, with preoperative room air Po2 < or = 50 mm Hg or FEV1 < or = 500 ml) had the same morbidity and operative mortality with unilateral or bilateral procedures, but they had a higher 1-year mortality (17% vs 5%), primarily because of respiratory failure after the unilateral operation (p < .001). Although unilateral staple lung volume reduction may produce an excellent result in a given patient, the bilateral procedure appears to be the procedure of choice, because it provides better overall results at no increased morbidity or mortality compared with the unilateral procedure. The results of bilateral staple lung volume reduction by thoracoscopy appear to be comparable to those of median sternotomy.

Combined operations for lung volume reduction surgery and lung cancer.

Fifty-three lung masses were found in 51 (16%) of 325 patients who underwent lung volume reduction surgery. This included 11 non-small cell lung cancers and 42 benign lung masses. Eleven patients (mean age, 69.4 years) underwent a combined lung volume reduction surgery and resection of clinical stage I lung cancers (lymph node dissection with either lobectomy [3] or wedge resection [8]). There were no deaths or major complications. The average length of stay was 8.7 days. The mean FEV1 was 654 mL (21.7% predicted) preoperatively and 1,079 mL (49% predicted) postoperatively. Patients who are screened for lung volume reduction surgery should be carefully evaluated for possible lung masses. Lung volume reduction surgery allows lung cancer surgery in patients who otherwise would be considered to have physiologically inoperable disease.

Use of the Heimlich valve to shorten hospital stay after lung reduction surgery for emphysema.

BACKGROUND: Prolonged air leak is the major complication after lung reduction surgery for emphysema and the major determinant of hospital length of stay. METHODS: Twenty-five of 107 patients (24%) (mean age, 66 years) with an average forced expiratory volume in 1 second of 0.55 L experienced a prolonged air leak (>5 days) after lung reduction surgery. These persistent air leaks were treated by replacing the chest drainage system with Heimlich valves to facilitate earlier hospital discharge even though 64% of the patients had apical air spaces that measured 1 to 7 cm. RESULTS: These patients had a mean postoperative stay of 9.1 days. Chest tubes were then removed an average of 7.7 days later. All apical air spaces resolved, and there were no deaths, empyemas, or pneumonias. CONCLUSIONS: In conclusion, the use of the Heimlich valve after operation for emphysema was associated with minimal morbidity and shortened the mean hospital stay for patients with prolonged air leaks by 46%. This study demonstrates an important concept in the postoperative management of these patients--do not use suction on severely emphysematous lung.

Cardiac xenografting in the pig-to-rhesus monkey model: manipulation of antiendothelial antibody prolongs survival.

Transplantation of immediately vascularized grafts across species barriers in which preformed cytotoxic antibodies exist, otherwise known as discordant combinations, has uniformly resulted in hyperacute rejection. We studied how well plasma exchange and perfusion through organs removes preformed immunoglobulin M cytotoxic antibodies and prolongs survival of a porcine heart heterotopically transplanted into a rhesus monkey. With the use of plasma exchange or absorption of antibodies by porcine kidney perfusion with or without immunosuppression, graft survival was prolonged, although antibody-mediated rejection ultimately occurred. In one case in which plasma exchange, kidney perfusion, and immunosuppression were combined, a functioning pig heart survived in a rhesus monkey for 8 days without evidence of rejection. The animal was killed on day 8 according to protocol because of a wound dehiscence. With this animal we were able to demonstrate that circulating antibodies against graft endothelium had bound to the graft endothelium without inducing rejection, a process referred to as accommodation. In this case, despite the presence of antiendothelial antibodies, complement did not appear to be activated, and fibrin thrombi did not form. Although we have achieved this rejection-free survival only in one animal, this case suggests that it may be possible to maintain xenotransplants in discordant species without rejection if preformed antibodies are appropriately lowered or altered during the initial period of graft implantation.

Mechanism of complement activation in the hyperacute rejection of porcine organs transplanted into primate recipients.

The authors investigated the importance of natural antibody and complement in the pathogenesis of hyperacute xenograft rejection using in vivo and in vitro pig to primate models. Studies were carried out in rhesus monkeys transplanted with a pig heart or kidney in which hyperacute rejection was observed within a few hours. The rejected organs showed deposits of IgM, C3, C4, C5, and C9 neoantigen along small blood vessels, but few deposits of factors B and P. Removal of anti-endothelial cell "natural" antibodies by plasmapheresis, immunoabsorption, and immunosuppression techniques resulted in marked prolongation of the survival of a subsequently transplanted heart, even when complement levels were within the normal range. Thus, complement, in the absence of natural antibodies, did not initiate hyperacute rejection in this species combination. The requirements for complement activation in human serum to cause cytotoxicity of porcine endothelial cells were then evaluated. Cytotoxicity was abrogated by depleting human serum of IgM, C2, or C5, but not of factor B. Restoration of the effect of serum on endothelial cells was achieved by reconstitution of the respective depleted sera with purified IgM or with the corresponding complement proteins, indicating that IgM and the classical, but not the alternative, pathway of complement, were involved. Identical conclusions were drawn from experiments to ascertain the requirements for complement activation in human serum to mediate binding of iC3b to porcine endothelial cells. The authors conclude that in a pig to primate xenograft complement does not directly initiate injury to the graft but rather requires activation by bound xenoreactive natural antibodies; IgM antibodies directed against endothelial cells activate the classical complement pathway, which then contributes to endothelial cell activation and subsequent events characteristic of hyperacute rejection.