Fulminant unilateral pulmonary edema on the wrong side.

A 55-year-old patient had undergone replacement of the proximal descending aorta at the age of 17 for aortic coarctation. The patient required surgical intervention at the age of 55 for development of a false aneurysm at the distal anastomosis. Surgery was complicated by bleeding from the ruptured false aneurysm into the left upper lung lobe, which had to be resected. Recovery from surgery was uneventful. The patient could be extubated and his cardiopulmonary function was stable. On the 3rd postoperative day, acute decompensation occurred and the patient had to be reintubated for severe hypoxia. Chest X-ray showed massive opacification of the right lung indicating fulminant pulmonary edema. Interestingly, no marked changes of the remaining left lung were observed. The patient was treated with antibiotics intravenously for suspected pneumonia. In addition, diuretics and catecholamines were administered for markedly elevated cardiac preload and acute loss of peripheral vascular resistance. Within only 12 hours, the patient recovered dramatically. Follow-up chest X-ray showed no remaining opacification of the right lung. The patient was extubated and cardiopulmonary function has remained stable. The subsequent postoperative course was uneventful and the patient could be discharged from hospital 4 days later.

Leukocyte adhesion in aorta and femoral artery in vivo is mediated by LFA-1.

OBJECTIVE: Cytokine-induced recruitment of leukocytes is an early feature during arterial injury and atherosclerotic plaque formation. The aim of this study was to analyze the role of the beta2-integrin lymphocyte function-associated antigen-1 (LFA-1; CD11a/CD18) in cytokine-triggered firm leukocyte adhesion to arterial endothelium in vivo. MATERIAL AND METHODS: Intravital fluorescence microscopy was used to study leukocyte firm adhesion in the mouse aorta and femoral artery in response to combined local challenge with TNF-alpha and IL-1beta. RESULTS: In wild-type (WT) mice, cytokine stimulation resulted in firm adhesion of 14.6 +/- 2.8 and 11.3 +/- 1.3 leukocytes/mm along the endothelium in the aorta and femoral artery ( P < 0.05 vs. PBS-treated controls, n = 5-6). Notably, the number of firmly adherent leukocytes in aorta and femoral artery of cytokine-stimulated LFA-1-deficient animals was reduced by 54% and 92% indicating an important role of LFA-1 in leukocyte adhesion to arterial endothelium ( P < 0.05 vs. controls, n = 5-6). In addition, pretreatment of WT mice with a monoclonal antibody (mAb) directed against murine LFA-1 attenuated the leukocyte adhesive response by 60% and 86% in aorta and femoral artery, respectively ( P < 0.05 vs. control mAb-treated WT, n = 5-12). CONCLUSION: These novel data demonstrate that cytokine-induced firm leukocyte adhesion in the mouse aorta and femoral artery is LFA-1-dependent in vivo, which may implicate an important role for this beta2-integrin leukocyte extravasation in arterial injury and atherogenesis.

Impact of PAF antagonist BN 52021 (Ginkolide B) on post-ischemic graft function in clinical lung transplantation.

BACKGROUND: Platelet activating factor (PAF) is associated with ischemia/reperfusion injury (I/R) after lung transplantation. Following promising experimental results, this prospective trial investigated the potential effect of PAF antagonist BN 52021 (ginkolide B) on clinical Euro-Collins (EC)-based lung preservation. METHODS: We analyzed 8 double-lung transplant patients in each of 3 groups. In the low-dose group (LDG), donor lungs were perfused with EC containing 2 mg/kg BN 52021, whereas we used 10 mg/kg in the high-dose group (HDG) and placebo in the control group (CG). Before reperfusing the first lung, we administered intravenously 120 mg BN 52021 (LDG), 600 mg BN 52021 (HDG), or placebo (CG). Hemodynamics in terms of pulmonary arterial pressure, pulmonary vascular resistance and serial determinations of the alveolo-arterial oxygen difference (AaDO(2)) were recorded. We measured blood levels of PAF pre-operatively and post-operatively, after 10 minutes and after 3, 8, 24, 48, and 144 hours. RESULTS: Within 32 hours, we noted a tendency toward better AaDO(2) in the LDG and the HDG compared with the CG (p > 0.05). We observed a significant improvement of AaDO(2) after 3 hours (HDG, p = 0.033) and 8 hours (LDG, p = 0.024), with poorest values in the CG. The PAF concentrations were lowest in the HDG, with significant deterioration 10 minutes after reperfusion. In contrast, placebo led to higher PAF levels. We measured significantly lower PAF concentrations (HDG vs CG) at 10 minutes and at 6 days post-operatively. CONCLUSIONS: Use of high-dose PAF antagonist BN 52021 can easily be combined with clinical preservation methods and may help optimize pulmonary function with reduced PAF levels, in the early post-ischemic period.

Serum withdrawal-induced post-transcriptional stabilization of cyclooxygenase-2 mRNA in MDA-MB-231 mammary carcinoma cells requires the activity of the p38 stress-activated protein kinase.

Overexpression of the cyclooxygenase-2 (COX-2) gene is observed in several neoplastic diseases. However, molecular mechanisms involved in the regulation of expression of COX-2 are not well understood. In this report, we describe a unique post-transcriptional regulatory mechanism of COX-2 mRNA stabilization in MDA-MB-231 cells, a highly metastatic cell line derived from a human mammary tumor. High levels of COX-2 mRNA, protein, and enzyme activity were induced by serum withdrawal, which were potently inhibited by the addition of serum or >100-kDa serum factor. Nuclear run-on analysis and actinomycin D chase experiments indicate that regulation is primarily at the level of post-transcriptional mRNA stability. Interestingly, SB203580, an inhibitor of the p38 stress-activated protein kinase (SAPK), and overexpression of the dominant-negative p38alpha construct potently inhibited the serum withdrawal-induced COX-2 mRNA levels. Indeed, the half-life of COX-2 mRNA decreased from 9 to 4.5 h after SB203580 treatment, suggesting that signal transduction by the p38 SAPK pathway is required for COX-2 mRNA stability.

Induction of cyclooxygenase-2 by platelet-derived growth factor (PDGF) and its inhibition by dexamethasone are independent of NF-kappaB/IkappaB transcription factors.

Glucocorticoids are potent inhibitors of cyclooxygenase-2 (prostaglandin G/H synthase-2, COX-2) expression. The focus of this work was to investigate the molecular mechanisms, by which glucocorticoids interfere with platelet-derived growth factor (PDGF)-mediated induction of COX-2 with special emphasis on the role of the transcription factors NF-kappaB/IkappaB alpha. In rat renal mesangial cells, PDGF induced a rapid and transient increase of COX-2 mRNA and protein, which reached maximal levels after 1-2 and 4 h, respectively. The in vivo half-life of COX-2 mRNA, which was estimated to be less than 1 h, was reduced by dexamethasone. Kinetic studies and COX-2 promoter activity assays indicated that dexamethasone also interfered with COX-2 transcription. Inhibition of COX-2 induction by dexamethasone was abrogated by cycloheximide, an inhibitor of translation, indicating dependence on de novo protein synthesis. As a possible mediator of dexamethasone action, the NF-kappaB/IkappaB alpha system of transcription factors was investigated. Dexamethasone doubled IkappaB alpha protein levels within 1 h and reduced complex formation of nuclear NF-kappaB proteins with DNA. Newly synthesized IkappaB alpha may thus bind to NF-kappaB and interfere with gene activation. PDGF-induced signalling, however, barely affected the NF-kappaB/IkappaB alpha system: IkappaB alpha protein remained unaltered for 30 min after treatment of mesangial cells with PDGF and was only reduced by 30% after 1 h. Concomitantly, binding of NF-kappaB proteins to DNA, detected by electrophoretic mobility shift assays, was slightly increased by 30%. Furthermore, stably transfected COX-2 promoter constructs with and without the NF-KB binding site were comparably activated by PDGF (2.5-fold increase of luciferase activity). Taken together, these data indicate that although dexamethasone interferes with the NF-kappaB/IkappaB alpha system of transcription factors, this mechanism is not essential for the inhibition of PDGF-induced COX-2 expression.

Effects of skeletonized versus pedicled internal thoracic artery grafts on free flow capacity during bypass.

The free flow of skeletonized ITA grafts was compared with that of pedicled ITA grafts. One hundred patients with coronary artery diseases underwent elective CABG. In the group I (n = 50), the left ITA was dissected using the skeletonization technique. In the group II (n = 50), the ITA was harvested as a pedicled graft. Free flow of the ITA was recorded before and 15 min after intraluminal application of diluted papaverine. Mean arterial pressure was maintained at 9.31 kPa (70 mmHg). The results showed that before the application of papaverine, free flow of skeletonized and pedicled ITA grafts was identical between the two groups. After treatment with papaverine, the maximum free flow was significantly higher in the skeletonized ITA's in the group I (199.3 +/- 69.6 ml/min) than in the group II (145.7 +/- 70.3 ml/min, P < 0.05). There was on significant difference between the free flow after dilatation of the left and right ITA in the group I (left 199.3 +/- 69.6 ml/min, right 198.9 +/- 61.8 ml/min, respectively). It was concluded that preparation of the ITA with the skeletonization technique resulted in significantly higher free flow capacity than in pedicled grafts and would improve the results of arterial revascularization. The complication rate seems to be lower than with the conventional method.

Cyclooxygenase-1 and -2 isoenzymes.

The cyclooxygenase isoenzymes (COX-1 and -2) catalyze the rate-limiting steps in prostanoid biosynthesis. COX-1 and -2 genes encode two isoenzymes with overlapping yet distinct expression patterns and functions. Physiologically, various extracellular stimuli such as growth factors, cytokines and tumor promoters regulate the expression of COX-1 and -2 genes at both transcriptional and post-transcriptional levels. COX-2 is overexpressed in rheumatoid arthritis, colorectal and breast cancer. Prostanoids produced by the COX pathway signal via plasma membrane-localized, G-protein-coupled receptors as well as via nuclear receptors. Currently, several COX-2-selective inhibitors are developed to control the anti-inflammatory and anti-neoplastic activities of the COX-2 isoenzyme. Inhibition of the COX isoenzyme activity and/or expression may be the basis of future generation of anti-inflammatory and anti-neoplastic drugs.

Chest size matching in single and double lung transplantation.

We applied predicted vital capacity to chest size matching between donor and recipient in lung transplantation to 15 single-lung transplant recipients with pulmonary fibrosis and to 20 double-lung transplant recipients with emphysema or non-emphysema. The predicted vital capacity of the donor was significantly correlated with the predicted vital capacity of the recipient both in double-lung transplantation (r = 0.79, p = 0.001) and single-lung transplantation (r = 0.71, p = 0.003). In double-lung transplantation, the post-transplant vital capacity was correlated with the predicted vital capacity of the recipient (r = 0.74, p = 0.002). Emphysema patients and non-emphysema patients contributed equally to this correlation. In left single lung transplantation, there was a weak correlation between the post-transplant vital capacity and the predicted vital capacity of the donor in the allograft (r = 0.57, p = 0.1095). In right single lung transplantation, the post-transplant vital capacity of the allograft tended to be correlated with the predicted vital capacity of recipient (r = 0.77, p = 0.0735). We concluded that donors were actually selected based on the comparison of predicted vital capacity between donor and recipient. In double-lung transplantation, the post-transplant vital capacity was limited by the recipient's normal thoracic volume and was not influenced by underlying pulmonary disease. In single-lung transplantation with pulmonary fibrosis, the allograft transplanted in the left chest could expand to its own size, and the allograft transplanted in the right chest could expand to the recipient's normal thoracic volume as in double-lung transplantation.

Interference of corticosteroids with prostaglandin E2 synthesis at the level of cyclooxygenase-2 mRNA expression in kidney cells.

In the kidney, prostanoids play a role as vasoactive and immunomodulatory mediators. One of the main biosynthetic enzymes, the inducible cyclooxygenase-2 (EC 1.14.99.1, Cox-2), has been recognized as a target of glucocorticoids. Therefore, we investigated whether the physiologically active corticosteroid aldosterone in the kidney might also interfere with prostaglandin (PG) synthesis. In two cell types, an epithelial cell line of tubular origin (MDCK) and rat renal mesangial cells, PGE2, release, Cox activity and Cox mRNA expression were determined after stimulation with phorbol ester and IL-1 beta, respectively. An increase in PGE2 release and Cox activity was observed, which correlated with an increase in Cox-2 mRNA expression. In MDCK cells, both dexamethasone and aldosterone were equally effective, suppressing all parameters measured by approximately 60%. A similar effect of aldosterone was also seen in mesangial cells, whereas dexamethasone was far more potent (> 90% inhibition at 10(-6) M). Whole cell binding assays showed the same number of receptors for aldosterone in both cell types (approximately 70,000 receptors/cell) but more than ten times higher receptor numbers for dexamethasone in mesangial cells than in MDCK cells (90,000 vs. 6000 receptors/cell). Receptor affinities of the corticosteroids were comparable. Thus, interaction of the corticosteroids with their cognate receptors was not sufficient to explain their different potencies but indicated the involvement of more complex regulatory mechanisms. Pathophysiologically, inhibition of PGE2 synthesis by aldosterone may play a role in the induction of hypertension by high concentrations of aldosterone.

Regulation of prostaglandin synthesis in Madin Darby canine kidney cells: role of prostaglandin G/H synthase and secreted phospholipase A2.

The renal epithelial cell line MDCK (Madin Darby canine kidney) was used as a model system to investigate the contribution of the secreted phospholipase A2 type II(sPLA2) and cyclooxygenases to prostaglandin E2 (PGE2) synthesis. Activation of protein kinase C by the phorbol ester TPA led to an enhanced PGE2 synthesis within 1 hour, which continued for more than 20 hours. Treatment of the cells with TPA increased the activities of sPLA2 and cyclooxygenase. Activation of cyclooxygenase was reflected by an increase in cyclooxygenase-2 mRNA. Coincubation of the cells with TPA and a specific sPLA2 inhibitor (BM 16.2224) almost completely inhibited sPLA2 activity in the cell culture supernatants. TPA-induced PGE2 synthesis was reduced by the inhibitor to about 50%. The inhibitor had no effect on cyclooxygenase activity or expression, indicating an involvement of sPLA2 in PGE2 synthesis. These experiments show that in resting cells, even in the presence of exogenous arachidonic acid, PGE2 synthesis was limited by the low abundance of cyclooxygenase. Enhanced expression and activity of cyclooxygenase, however, was not sufficient for increased prostaglandin synthesis. Availability of the precursor arachidonic acid seemed to be rate limiting in prostaglandin synthesis in stimulated MDCK cells.

Malperfusion of the thoracoabdominal vasculature in aortic dissection.

Ischemic damage to vital organs supplied by the thoracoabdominal aorta greatly increases the overall risk of aortic dissection. Of 320 patients operated upon for aortic dissection since 1985, 33 (10.3%) underwent operations directed at the relief of malperfusion (15/158 acute type A; 9/18 acute type B; 4/78 chronic type A; 5/66 chronic type B). Organs affected were the kidneys in 32; the bowel in 20; and the spinal cord in 1, while critical lower extremity ischemia was present in 11 patients. In total, 64 vascular areas were affected. Fenestration of the dissecting membrane with or without infrarenal grafting was the procedure performed most frequently in 25, followed by replacement of the descending or thoracoabdominal aorta in 6, and bypass grafting or direct revascularization of individual side branches in 6. Six other operations targeted at the affected organs were done. Twenty-four patients underwent one-stage operation for malperfusion; in 11, early reoperation after primary aortic repair was necessary, while 2 patients were operated electively. Ten of 33 patients died in hospital, 7 of malperfusion-induced complications. Of three late deaths, one was related to sequelae of malperfusion. We conclude that immediate diagnosis and prompt relief of malperfusion offer the best prospects for patient survival. Membrane fenestration appears to be the method of choice for treating malperfusion in most patients, and must be directed to the level of aortic and/or side branch obstruction.

Emergency lung transplantation after extracorporeal membrane oxygenation.

In some patients with acute respiratory failure, the native lungs do not recover during extracorporeal membrane oxygenation (ECMO), or complications occur that preclude the meaningful continuation of ECMO therapy. In such cases, emergency lung transplantation (LTx) represents the only therapeutic alternative. Between May 1988 and April 1993, the authors have performed LTx after ECMO support in five of 111 lung or heart-lung transplantations (4.5%). Two patients presented with early graft failure after unilateral LTx. In these patients, ECMO was used as a bridging device to unilateral re-LTx for 1, resp. 11 days. One patient died 6 months post-operatively from chronic rejection; the other underwent a third LTx and is doing well after 42 months. In three further patients already treated with ECMO for 5 to 12 days for ARDS (n = 2) or acute respiratory failure after liver and kidney transplantation, the native lungs did not recover (n = 2) or pulmonary hemorrhage developed. The last patient (unilateral LTx) and one of the former (bilateral LTx for ARDS) are long-term survivors (12, 30 months). The remaining patient (unilateral LTx for ARDS) had severe multiorgan failure at the time of his operation and died intraoperatively. The authors conclude that ECMO no longer represents a contraindication to subsequent LTx. Their results also support the continued investigation of this combined therapeutic approach.

Intravascular oxygenation for advanced respiratory failure.

Severe acute respiratory failure of varying etiology may require the temporary use of artificial gas exchange devices. So far, extracorporeal membrane oxygenation and extracorporeal carbon dioxide removal have been used successfully for this purpose. A totally implantable intravascular oxygenator (IVOX) recently became available. The authors have used IVOX in three patients who presented with severe respiratory failure secondary to pneumonia (n = 2) and post-traumatic adult respiratory distress syndrome (n = 1). At the time of implantation, all patients had hypoxemia (PaO2 less than 60) despite a 100% inspired oxygen concentration and forced mechanical ventilation. The duration of IVOX therapy ranged from 12 to 71 hr. All patients initially showed improvement in arterial oxygenation, allowing for moderate reduction of ventilator therapy after several hours. In one patient the pulmonary status deteriorated further, and she died from multiple organ failure despite IVOX therapy. One patient could be stabilized but died from other causes. The third patient is a long-term survivor 18 months after IVOX therapy. Gas transfer capabilities of IVOX are limited when compared to extracorporeal membrane oxygenation, and this may restrict its clinical applicability in cases of severe adult respiratory distress syndrome. However, IVOX may be used successfully in selected patients with less severe respiratory failure.

Extracorporeal membrane oxygenation (ECMO): extended indications for artificial support of both heart and lungs.

Extracorporeal membrane oxygenation (ECMO) was used to achieve temporary artificial support in cardiac and pulmonary function in 22 patients from 1987 to September 1990. Standard indications were postcardiotomy cardiogenic shock (n = 4), neonatal (n = 1) and adult respiratory distress syndrome (n = 4). ECMO was also used for extended indications, such as graft failure following heart (n = 11) or lung transplantation (n = 2). In six of these cases ECMO was instituted as a bridge device to subsequent retransplantation of either the heart (n = 4) or one lung (n = 2). One out of nine patients supported by ECMO for standard indications, and two out of 13 patients supported for extended indications are long-term survivors. This series illustrates the results with ECMO in emergency situations, in patients under immunosuppressive protocols, or in patients with advanced lung failure requiring almost complete artificial gas exchange. In such complex situations, ECMO does provide stabilization until additional therapeutic measures are in effect. ECMO cannot be recommended for postoperative cardiogenic shock but short-term ECMO support is an accepted method in most cases with graft failure or pulmonary failure or other origin.

Management of thoracoabdominal malperfusion in aortic dissection.

Malperfusion of the thoracoabdominal aorta or its branches is a common complication of aortic dissection, often with a fatal outcome. Since 1985 we saw thoracoabdominal malperfusion in 13 patients with aortic dissection. During repair of an acute type A aortic dissection, the intimal flap was fenestrated in three cases in the abdominal aorta and one within the superior mesenteric artery. In two cases with acute type B aortic dissection fenestration was performed at the level of the aortic bifurcation, and in one the descending aorta was replaced. Six patients had chronic dilatation of a false lumen without distal reentry, compromising the true lumen, with malperfusion of viscera, kidneys, and lower extremities. Three patients underwent replacement of the descending aorta, two of them subsequent abdominal aortic replacement with revascularization of the kidneys. One patient had thoracoabdominal replacement, and in two an extra-anatomic bypass was implanted. Five patients with acute dissection died: two from sequelae of malperfusion, two of myocardial failure, and one late after stroke. Eight patients are alive 1 month to 5 years after operation. In acute aortic dissection fenestration of the intimal flap may relieve thoracoabdominal malperfusion. In chronic aortic dissection, pseudocoarctation is most likely to occur at the diaphragmatic hiatus. This is treated by replacement of the affected aortic segment. In high-risk patients an extra-anatomic bypass is also feasible.

Some aspects of changed histopathologic appearance of acute rejection in cardiac allografts after prophylactic application of OKT3.

The histopathologic findings of therapy-requiring acute rejection in the cardiac allograft observed in endomyocardial biopsy specimens taken from patients under prophylactic administration of OKT3 show certain differences in comparison with the classic description of acute rejection. These differences are characterized above all by a distinctly reduced cellularity of the infiltrates, with a relative decrease of T cells, as well as edema and retrogressive changes, up to necroses of myocytes with marked fragmentation; some patients also have increased vascular reactions. Furthermore, an earlier occurrence of and an increased frequency of changes corresponding to the so-called lymphoma-like lesions ("Quilty" effect) were observed in patients who received immunosuppressive prophylaxis with OKT3. The changed histopathologic findings of therapy-requiring acute rejection under prophylactic application of OKT3 may, to a certain extent, explain the discrepant results reported by different transplant groups with respect to the frequency of rejection episodes and the time when the first episode of therapy-requiring rejection occurs after heart transplantation.

A reevaluation of heparin requirements for cardiopulmonary bypass.

We wished to determine if reduction in the standard heparin administration for cardiopulmonary bypass could be accomplished safely with the use of membrane oxygenators. An experimental study was designed to evaluate two different heparin administration protocols for cardiopulmonary bypass with hollow-fiber membrane oxygenators. Two groups of six pigs were submitted to hypothermic cardiopulmonary bypass (28 degrees C) for 3 hours, then rewarmed, decannulated, and reassessed after 1 hour. In group I (control) heparin was administered to maintain the activated clotting time in excess of 450 seconds; in group II activated clotting time was maintained between 250 and 300 seconds. The mean total heparin administered was 41,000 units in group I and 25,000 units in group II. Concentration of coagulation factors II, V, and VIII, fibrinogen, and platelet count were determined before, during, and 1 hour after bypass. No significant difference in any of these coagulation parameters was observed between the groups. The performance of the oxygenators was similar in both groups, with no evidence of thrombosis. Thus reduced heparin administration, enough to keep activated clotting time between 250 and 300 seconds, was not related either to major coagulation factors and platelet consumption or to derangements in the oxygenator's performance.

Extracorporeal membrane oxygenation as a bridge to lung transplantation.

The occurrence of severe graft failure after lung transplantation which appears refractory to conventional treatment represents a difficult situation with regard to the therapeutic strategies available. Of 17 patients undergoing single lung transplantation at our center, 2 developed early graft failure. In both, temporary artificial cardiopulmonary support by means of extracorporeal membrane oxygenation became necessary as a bridge to retransplantation. Both patients were successfully retransplanted after 8 h and 232 h, respectively, of extra-corporeal support. Postoperatively, there was a variety of complications. The first patient completely recovered from temporary severe cerebral dysfunction diagnosed as "locked-in syndrome". She was discharged from hospital on the 93rd postoperative day and remains alive and well 10 months after her operation. The other patient recovered well early after retransplantation. Later, however, airway problems developed, requiring the implantation of endotracheal stents. Cachexia and several episodes of viral pneumonia contributed to the progressive deterioration of her clinical status. She finally died after being hospitalized for 5 months after the original operation. These two cases illustrate the feasibility of using extracorporeal membrane oxygenation as a bridge to pulmonary transplantation.

Donor selection for single and double lung transplantation. Chest size matching and other factors influencing posttransplantation vital capacity.

In six single lung transplant (SLT) and six double lung transplant (DLT) recipients, the relationships of the recipient's posttransplantation vital capacity (posttx VCR) to the recipient's predicted normal vital capacity (pred VCR) and the donor's predicted normal vital capacity (pred VCD) were investigated. After left SLT the left posttx VCR was correlated with the left predicted VCD (r = 0.83; p less than 0.05); however, no correlation was found between these after DLT. In contrast, there was a tendency toward correlation between the posttx VCR and the predicted VCR after DLT (r = 0.75; p less than 0.1), but no such trend was apparent after SLT. These results suggest that posttx VCR depends primarily on predicted VCD after SLT and on pred VCR after DLT. Therefore, in donor-recipient size matching for lung transplantation a donor with a pred VCD greater than the pred VCR should be chosen for a left SLT recipient, whereas a donor with a pred VCD near the pred VCR would be suitable for a DLT recipient.