Contrasting natures of lung growth after transplantation and lobectomy.

OBJECTIVE: We hypothesized that posttransplantation lung growth in an immature recipient and postlobectomy compensatory lung growth are two distinct processes. METHODS: Mature swine underwent left upper lobectomy, and growth of the left lower lobe was studied after 2 weeks and after 3 months. Left lower lobes from another set of mature pigs were transplanted into immature animals, and growth of the transplanted lobe was then studied after 2 weeks and after 3 months. Left lower lobes from mature animals that did not undergo operation were used as normal control lobes. The lobes were weighed on removal and fixed intrabronchially. Sections stained with hematoxylin and eosin were used to determine alveolar surface density and percentage volume of respiratory region. Immunostaining for 5-bromo-2'-deoxyuridine was used to determine alveolar cell proliferation index, and epidermal growth factor receptor expression was detected by Western blot. RESULTS: Postlobectomy lung growth (increase in lobe weight) reached statistical significance at 2 weeks, with a concomitant rise in cell proliferation index. The transplanted lobe, in contrast, exhibited a gradual growth response, with a statistically significant increase in cell proliferation index at 3 months. Volume of respiratory region was noted to increase only in the transplanted lobe at 3 months. Epidermal growth factor receptor expression was upwardly regulated relative to that in normal control lobes in the 2-week postlobectomy and 3-month posttransplantation lobes. CONCLUSIONS: Postlobectomy lung growth appears to be regulated by a different mechanism than is posttransplantation lung growth and is a more rapid and restorative process. The growth peaks in both processes correlate with upward regulation of cell proliferation index and epidermal growth factor receptor expression.

Adenosine A2A receptor activation decreases reperfusion injury associated with high-flow reperfusion.

INTRODUCTION: High pulmonary artery flow rates can result in severe reperfusion injury after lung transplantation. Our hypothesis was that selective activation of the adenosine A(2A) receptor with a highly specific analog (ATL-146e) would inhibit leukocyte activation and decrease reperfusion injury after high-flow reperfusion. METHODS: Using our isolated, ventilated, blood-perfused rabbit lung model, all groups (n = 8 per group) underwent lung harvest, 4 hours of cold storage, and blood reperfusion for 30 minutes. Measurements of pulmonary artery pressure (in millimeters of mercury), arterial oxygenation (in millimeters of mercury), myeloperoxidase, peak inspiratory pressure, and wet/dry weight ratio were obtained. Groups 1 (high flow) and 2 (high flow ATL-146e) underwent reperfusion at 120 mL/min for 30 minutes. Groups 3 (controlled high flow) and 4 (controlled high flow ATL-146e) underwent controlled reperfusion with an initial reperfusion of 60 mL/min for the first 5 minutes, followed by a rate of 120 mL/min for 25 minutes. During reperfusion, groups 2 and 4 received ATL-146e at 4 microg. kg(-1). min(-1). RESULTS: ATL-146e significantly improved lung physiologic measurements under both high-flow (group 1 vs group 2) and controlled high-flow (group 3 vs group 4) conditions after 30 minutes. CONCLUSIONS: The adenosine A(2A) receptor analogue ATL-146e significantly decreases the severity of reperfusion injury in the setting of both high-flow and controlled high-flow reperfusion.

Controlled perfusion decreases reperfusion injury after high-flow reperfusion.

INTRODUCTION: Some investigators have suggested that high pulmonary artery flow rates increase the risk of severe reperfusion injury after lung transplantation. We hypothesized that controlling the initial flow rate and pulmonary artery pressure would decrease the severity of lung dysfunction in the setting of high-flow reperfusion. METHODS: Using our isolated, ventilated, blood-perfused rabbit lung model, all groups underwent lung harvest, 4-hour storage (4 degrees C), and blood reperfusion. We measured pulmonary artery pressure, peak inspiratory pressure, arterial oxygenation, and wet-to-dry weight ratio. Group 1 (control, n = 8) underwent reperfusion at 60 ml/min for 30 minutes. Group 2 (high flow, n = 8) underwent reperfusion at 120 ml/min for 30 minutes. Group 3 (controlled flow, n = 8) underwent initial reperfusion at 60 ml/min for 5 minutes, followed by reperfusion at 120 ml/min for 25 minutes. RESULTS: Group 1 had significantly improved pulmonary artery pressure, peak inspiratory pressure, arterial oxygenation, and wet-to-dry weight ratio measurements compared with groups 2 and 3 after 30 minutes of reperfusion. However, Group 3 had improved pulmonary artery pressure, peak inspiratory pressure, arterial oxygenation, and wet-to-dry weight ratio measurements compared with Group 2. CONCLUSIONS: High-flow reperfusion results in severe reperfusion injury after lung transplantation. Controlled reperfusion using a low initial flow rate decreases the severity of reperfusion injury associated with high-flow rates.

Coronary risk stratification in patients with end-stage lung disease.

BACKGROUND: Significant coronary artery disease (CAD) has been a contraindication for listing patients for lung transplantation. We hypothesize that coronary risk stratification can help identify a sub-set of patients who need additional diagnostic tools and intervention. METHODS: We performed a retrospective review of 72 consecutive patients who underwent lung transplantation at our institution from 1995 to 2000. Further, a review of patients who are currently listed for transplantation yielded 48 patients. We then identified the various risk factors for CAD, the diagnostic tools used, and pre-operative intervention. Risk factors identified included smoking history, diabetes, hypertension, hypercholesterolemia, CAD, congestive heart failure, age >50, and arrhythmias. Based on these risk factors, the patients were then classified into 2 groups: low risk (< or =1 risk factors) and high risk (> or =2 risk factors). We identified the patients in each group who underwent coronary angiography (CA), those with angiographic evidence of CAD, and those who received pre-operative intervention. RESULTS: Of the 72 patients who underwent lung transplantation, 48 were identified as at high risk for CAD. Of these, 5 patients had CAD diagnosed before surgery using CA, and 1 patient received pre-operative intervention. Of the 48 patients currently on the lung transplant list, we identified 28 patients as high risk for CAD, 12 of whom were noted to have CA, and 2 of whom received pre-operative intervention. CONCLUSIONS: Although CAD was once a contraindication for lung transplantation, pre-operative risk stratification allows identification of CAD with CA in a high-risk group. We believe that by using appropriate pre-operative cardiac intervention, patients with severe CAD could successfully undergo lung transplantation.

Ischemia-reperfusion injury after lung transplantation increases risk of late bronchiolitis obliterans syndrome.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is the most common cause of long-term morbidity and mortality after lung transplantation. Our hypothesis was that early ischemia-reperfusion injury after lung transplantation increases the risk of BOS. METHODS: Data on 134 patients who had lung transplantation between January 1, 1990 and January 1, 2000, was used for univariate and multivariate logistic regression analysis. RESULTS: After lung transplantation, 115 patients (115 of 134, 86%) survived more than 3 months. In that group, 41 patients developed BOS, of which 23 had progressive disease. Univariate analysis revealed that ischemia-reperfusion injury (p = 0.017) and two or more acute rejection episodes (p = 0.032) were predictors of BOS onset, whereas ischemia-reperfusion injury (p = 0.011) and cytomegalovirus infection (p = 0.009) predicted progressive BOS. Multivariate logistic regression analysis showed that ischemia-reperfusion injury was an independent predictor for both BOS development and BOS progression. Two or more acute rejection episodes were also an independent predictor of BOS development, whereas cytomegalovirus infection was an independent predictor of progressive BOS. CONCLUSIONS: Ischemia-reperfusion injury increases the risk of BOS after lung transplantation.

Preoperative shock determines outcome for acute type A aortic dissection.

BACKGROUND: Acute type A aortic dissection is a life-threatening catastrophe. Surgical results have not improved. METHODS: The charts of all 70 patients surgically treated for acute type A primary aortic dissection during the period of January 1988 through April 2001 were reviewed. RESULTS: Average age was 59 +/- 2 years. Comorbidities included hypertension (66%), coronary artery disease (17%), and Marfan's syndrome (11%). At presentation, 23% were in shock, 17% had neurologic dysfunction, and 36% had coronary ischemia. The aortic valve was preserved in 55. Distal aortic anastomosis was performed under aortic cross-clamp ("closed") in 32 and "open" under circulatory arrest in 38 patients. Operative mortality was 18.6% (13 of 70 patients). Patients in shock had an operative mortality of 50% compared with stable patients of 9% (p = 0.0002). Mortality was similar regardless of technique. Univariate analysis revealed preoperative shock (p = 0.0002), tamponade (p = 0.003), and neurologic deficit (p = 0.02) to be associated with mortality. Multivariate analysis revealed hemodynamic stability (odds ratio = 0.10, p = 0.04) and outside transfer (odds ratio = 0.12, p = 0.03) to be negative predictors of mortality. Of 57 survivors, follow-up was 93% complete for an average of 46 +/- 6 months. The overall late reoperation rate was 24.6% (14 of 57 patients) at 50.3 +/- 12.3 months. Twelve patients (21%) underwent future aortic aneurysmal repair. No difference in reoperation rate was seen comparing "closed" (26%) with "open" (18%; p = 0.46). Of 42 preserved native valves, only 3 (7.1%) needed future valve replacement. CONCLUSIONS: In our experience, operative mortality was determined by preoperative hemodynamic instability. Technique did not impact survival or late reoperation. Early diagnosis and repair is critical to improving survival.

Elimination of fat microemboli during cardiopulmonary bypass.

BACKGROUND: Fat emboli have been implicated in cerebral dysfunction after cardiopulmonary bypass (CPB). We sought to identify the source of fat emboli during CPB and devise a technique for their elimination. METHODS: Patients undergoing CPB were prospectively randomized to either cardiotomy suction (n = 7) or cell-saving suction device (n = 6). Blood was collected at various intervals during CPB, and the fat emboli were identified using oil red O stain. These emboli were grouped based on their diameter into 10- to 50-microm and more than 50-microm particles. The number of fat emboli per slide examined was graded according to the following scale: 1 (1 to 10), 2 (11 to 20), 3 (21 to 30), and 4 (> 30 emboli). In the second phase of the experiment, a 21-microm filter was attached in series, distal to the cardiotomy reservoir (n = 6), and fat emboli were quantified. RESULTS: Blood from the pericardial well was saturated with fat emboli of both sizes. Patients randomized to the cardiotomy suction had a significantly higher number of fat emboli at the end of CPB when compared with those randomized to the cell-saving suction device and dual-filter group. Processed blood from both the cardiotomy reservoir and cell-saving device was noted to have an abundance of fat emboli when compared with blood processed through the dual filters. CONCLUSIONS: Processed blood from both the cardiotomy reservoir and cell-saving device appear to have an abundance of fat emboli that are completely eliminated by using a 21-microm arterial filter in series with the cardiotomy reservoir. This intervention could potentially reduce neurocognitive dysfunction associated with CPB.

Adenosine A2A agonist reduces paralysis after spinal cord ischemia: correlation with A2A receptor expression on motor neurons.

BACKGROUND: The adenosine A2A agonist ATL-146e ameliorates reperfusion inflammation, reducing subsequent paralysis and neuronal apoptosis after spinal cord ischemia. We hypothesized that neuroprotection with ATL-146e involves inducible neuronal adenosine A2A receptors (A2A-R) that are upregulated after ischemia. METHODS: Eighteen rabbits underwent laparotomy, and 14 sustained spinal cord ischemia from cross-clamping the infrarenal aorta for 45 minutes. One group (ischemia-reperfusion [I/R] + ATL) received ATL-146e intravenously for 3 hours during spinal cord reperfusion. A second group (I/R) received equivolume intravenous saline solution for 3 hours and served as an ischemic control, and a third group (Sham) underwent sham laparotomy. At 48 hours, all subjects were assessed for motor impairment using the Tarlov scoring system (0 to 5). Lumbar spinal cord sections were immunolabeled for A2A-R and graded in a blinded fashion using light microscopy. RESULTS: There was a significant improvement in Tarlov scores in I/R + ATL animals compared with the I/R group. Sham-operated animals demonstrated no A2A-R immunoreactivity. There was a dramatic increase in A2A-R immunoreactivity in neurons of lumbar spinal cord sections from I/R compared with I/R + ATL and sham-operated animals. CONCLUSIONS: Reduction in paralysis in animals receiving ATL-146e correlates with the new finding of A2A-R expression on lumbar spinal cord motor neurons after ischemia. Adenosine A2A agonists may exert neuroprotective effects by binding to inducible neuronal A2A-R that are upregulated during spinal cord reperfusion, and reduced in response to administration of an A2A-R-specific agonist.

An unusual case of Bouveret's syndrome.

A 69-year-old man presented to the emergency department with a 12-hour history of severe abdominal pain. His medical history was significant for a small-bowel obstruction that resolved with conservative therapy 4 months prior to admission. In the distant past, a Billroth II gastric resection was performed for ulcer disease. He was hypothermic, and laboratory studies showed elevated serum liver and pancreatic enzymes. A CT scan of the abdomen demonstrated fat stranding and a small amount of free air in the area of the pancreas. Gram-negative rods subsequently grew from blood cultures. A presumptive diagnosis of necrotising pancreatitis was made, and supportive care was instituted. Follow-up CT scan performed several days later demonstrated a large filling defect in the stomach. Endoscopy showed this defect to be a giant gallstone, and the diagnosis of Bouveret's syndrome was made. The patient underwent laparotomy. A duodenal perforation in the posterior aspect of the fourth portion was identified. The perforation had been caused by chronic impaction of the giant stone. The stone was removed through the perforation, and the perforation was closed in multiple layers. Drainage of the retroperitoneum was effected through large catheters placed through the flank. The presentation, diagnostic evaluation, treatment, and complications of this condition are discussed.

Ileofemoral malperfusion complicating type a dissection: revascularization prevents renal failure.

We report four cases of lower extremity malperfusion complicating acute type A dissection. Two patients were treated with acute type A dissection repair, followed by axillobifemoral bypass grafting when malperfusion persisted after aortic replacement and required dialysis. Two patients were managed with lower extremity revascularization procedures before acute type A dissection repair and had preserved renal function. Lower extremity revascularization before cardiopulmonary bypass minimizes ischemia and allows for controlled limb reperfusion under hypothermic conditions compared with delayed normothermic reperfusion when performed after acute type A dissection repair. This strategy may increase limb function salvage and decrease the incidence of dialysis after acute type A dissection repair in patients presenting with lower extremity malperfusion.

Cardioscope-assisted excision of a left ventricular tumor--a case report.

BACKGROUND: A 56-year-old male with a past history of excision of a malignant melanoma from his lip presented with squeezing chest pain. The patient was evaluated and determined to have a tumor of the left ventricle. Excision of such a tumor is indicated to prevent embolization and also to prevent the possibility of outflow tract obstruction. METHODS: The patient underwent transesophageal echocardiography and was placed on cardiopulmonary bypass with cold-blood cardioplegia. The ascending aorta was opened and a video-assisted cardioscope was inserted through the aortic valve and used to visualize the tumor. The tumor was resected under direct vision and the aorta was closed. RESULTS: Frozen section analysis revealed the tumor to be a benign hemangioma. The patient had an uneventful recovery with no evidence of ventricular septal defect or embolization. CONCLUSIONS: Performing the cardioscopy via the aortotomy helped us to avoid an atriotomy and/or ventriculotomy and enabled us to discern the precise extent of the tumor and rule out concomitant pathology. The use of cardioscopy as an adjunct for excision of intraventricular abnormalities can assist in determining the precise location and size of tumors and in resecting tumors in areas of the heart that might otherwise be difficult to visualize.

Ventricular reconstruction results in improved left ventricular function and amelioration of mitral insufficiency.

INTRODUCTION: Surgical restoration of the left ventricular wall (Dor procedure) has been advocated as a therapy for left ventricular dysfunction due to ischemic cardiomyopathy. This procedure involves placement of an endoventricular patch through a ventriculotomy. METHODS: We reviewed our series of patients that underwent the Dor procedure within the past 4 years and examined their pre and postoperative ventricular function and mitral valve function. Pre and postoperative ejection fraction and degree of mitral regurgitation were analyzed using the paired Student t-test. We hypothesized that this procedure would result in improved ventricular function and that it would also help improve mitral valve function. RESULTS: Thirty-four patients underwent this procedure, with one death. Of these, 30 patients underwent concomitant coronary artery bypass grafting and 8 patients had mitral intervention (seven had an Alfieri repair of the mitral valve, and one had mitral valve annuloplasty). The average preoperative ejection fraction among these patients was 26.8% (range 10-45%). The postoperative ejection fraction was significantly higher at 35.4% (range 25-52%) (P <.001). We noted an improvement in ejection fraction in 27 patients (82%). We also noted that 21 of 33 patients (64%) had improvement in the degree of mitral regurgitation based on echocardiography data (P <.001). CONCLUSIONS: We conclude that the Dor procedure results in improvement in the left ventricular function. Furthermore, we also note that this procedure ameliorates mitral regurgitation in a majority of these patients even in the absence of associated mitral valve procedures, probably due to reduction in the size of the ventricle and improved orientation of the papillary muscles.

Pyrrolidine dithiocarbamate reduces lung reperfusion injury.

BACKGROUND: The inflammatory cascade has emerged as the primary mediator of reperfusion injury. Nuclear factor kappaB (NF-kappaB) is a rapid response transcription factor that activates genes responsible for the mediators of inflammation. Heat shock protein 70 (HSP70) has been shown to protect against lung injury. We hypothesized that the antioxidant pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kappaB and upregulator of HSP70, would decrease lung injury after ischemia and reperfusion. METHODS: Using our isolated, ventilated, blood-perfused rabbit lung model, all groups underwent lung harvest followed by 10-h storage (4 degrees C) and blood reperfusion for 30 min. Group I lungs (n = 5) served as controls. In group II lungs (n = 5), both lung and blood donors received PDTC (100 mg/kg) intravenously 30 min before harvest. NF-kappaB activity was evaluated with electrophoretic mobility shift assay, and Western blot was performed for HSP70. RESULTS: Group II demonstrated superior pulmonary function. Although HSP70 expression was somewhat elevated in group II lungs, NF-kappaB binding activity was not different between the groups. CONCLUSIONS: PDTC improves pulmonary function after ischemia and reperfusion in an isolated rabbit lung model. The improved function correlates with elevated HSP70 expression during initial reperfusion, independent of NF-kappaB activity.

Adenosine A2A analogue ATL-146e reduces systemic tumor necrosing factor-alpha and spinal cord capillary platelet-endothelial cell adhesion molecule-1 expression after spinal cord ischemia.

OBJECTIVE: Inflammation is likely a major contributor to spinal cord reperfusion injury after aortic reconstruction. Systemic 4-(3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl)-cyclohexanecarboxylic acid methyl ester (ATL-146e), a selective adenosine A(2A) agonist, has been shown to reduce paralysis after spinal cord ischemia. We hypothesized that ATL-146e reduces cytokine production during spinal cord reperfusion, curtailing inflammation and decreasing spinal cord capillary platelet-endothelial cell adhesion molecule-1 (PECAM-1) expression. STUDY DESIGN: New Zealand White rabbits sustained spinal cord ischemia with 45-minute cross-clamping of the infrarenal aorta. One group of animals received intravenous ATL-146e at 0.06 microg/kg/min for 3 hours during reperfusion, beginning after 30 minutes of ischemia. A second group received saline solution vehicle alone for 3 hours, serving as an ischemic control. A third group served as sham-operated animals, undergoing laparotomy with anesthesia. Serum was assayed with enzyme-linked immunosorbent assay for tumor necrosing factor-alpha (TNF-alpha). Animals were allowed to recover for 48 hours and were evaluated for hind-limb motor function with the Tarlov (0 to 5) scoring system. At necropsy, animals from each group yielded spinal cords for immunohistochemical staining for PECAM-1. Data are expressed as mean +/- standard error of the mean, with statistical analysis with Student t test and Kruskal-Wallis nonparametric test. RESULTS: Markedly improved Tarlov scores were seen in rabbits with ATL-146e (P <.001) during spinal cord reperfusion as compared with ischemic control animals. A significant reduction was found in TNF-alpha in the sera of rabbits with ATL-146e infusion (P <.01) as compared with ischemic control animals. Significantly reduced endothelial PECAM-1 staining intensity (P <.05) was seen in microscopic spinal cord sections from rabbits with ATL-146e. CONCLUSION: ATL-146e, an adenosine A(2A) agonist, reduces spinal cord reperfusion injury. The mechanism of the protection may involve a reduction in circulating TNF-alpha during a critical 3-hour reperfusion interval and reduction in spinal cord endothelial PECAM-1 upregulation.