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.

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.

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.

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.

Oxygen-derived free radical scavengers for amelioration of reperfusion damage in heart transplantation.

In this study we tried to define the possible benefits of the oxygen-derived free radical scavengers after 3 hours of cold myocardial global ischemia, as required in the setting of cardiac transplantation. Twenty-one pig hearts were harvested after preservation with a cold cardioplegic solution (St. Thomas' Hospital solution) and topical cooling. Normothermic reperfusion with blood was achieved with a special heart-lung machine preparation, which allows the heart to beat in a working or nonworking mode. Twelve hearts served as control hearts (group I), and nine (group II) were subjected to superoxide dismutase and catalase. Superoxide dismutase was applied at a dose of 40 U/ml of cardioplegic solution and 1500 U/kg body weight with the start of reperfusion. Catalase was added to the cardioplegic solution in a dose of 100 U/kg and 3500 U/kg body weight with the start of reperfusion. After 15 minutes of retrograde reperfusion, both left ventricular developed pressure and its first derivative were significantly higher in group II (137 +/- 7.6 mm Hg, 2467 +/- 162 mm Hg/sec) than in group I (105 +/- 6 mm Hg, 1676 +/- 231 mm Hg/sec, p less than 0.05 for each). In addition, a considerably higher coronary blood flow was observed in group II throughout the 180-minute period of reperfusion (p = 0.047). We therefore conclude that the combined administration of superoxide dismutase and catalase during the initial period of cardioplegic arrest and during early reperfusion of donor hearts submitted to 3 hours of cold ischemia has a beneficial effect on myocardial performance.

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.

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.

Cardiac innervation after double lung transplantation. Toronto Lung Transplant Group.

Double lung transplantation has been successfully introduced for patients with end-stage pulmonary disease and preserved cardiac function. An advantage of this operation compared with heart-lung transplantation is retention of the recipient's heart. The operative dissection, however, may lead to interruption of sympathetic and parasympathetic pathways to the heart and consequent denervation of the native heart. The cardiac innervation of seven double lung transplant recipients was investigated by the heart rate response to carotid sinus massage, the Valsalva maneuver, intravenous injection of atropine, and exercise. Five single lung and two heart-lung transplant recipients were studied for comparison. Of the seven double lung transplant recipients, three had abnormal responses to carotid sinus massage, six to the strain phase of the Valsalva maneuver, and five to the release phase of the Valsalva maneuver. Three of six double lung transplant recipients tested had no response to intravenous injection of atropine, and five of seven patients had an abnormal recovery of heart rate after maximal exercise. No patient had a normal response to all interventions, and three patients had responses compatible with complete cardiac denervation. It is concluded that cardiac denervation may occur after double lung transplantation, most likely caused by surgical interruption of sympathetic and parasympathetic pathways during dissection of the recipient's trachea.

Cardiopulmonary exercise testing after single and double lung transplantation.

The cardiopulmonary response to exercise was investigated in six single and six double lung transplant recipients using a three-minute incremental work rate protocol on a cycle ergometer. Maximum VO2 averaged 44.2 +/- 9.2 percent and 48.5 +/- 5.0 percent of predicted maximal VO2 in the single and double lung transplant groups, respectively. No evidence of ventilatory limitation to exercise was found in either group. Circulatory factors that may have limited exercise capacity included anemia and submaximal heart rates. There was a strong correlation between VO2/kg at venous blood lactate level of 2.2 mEq/L and vital capacity/body surface area in the single, but not in the double, lung recipients. Maximum VO2 in these lung transplant recipients was comparable to previously published values in heart-lung transplant recipients. The factors that limit maximum exercise capacity after lung transplantation deserve further study.

The effect of ischemic time and temperature on lung preservation in a simple ex vivo rabbit model used for functional assessment.

Despite 25 years of research in lung transplantation, little progress has been made in methods for improving lung preservation. To evaluate many factors that may affect lung function after preservation, we have developed a simple, reliable, and inexpensive animal model. This consists of an isolated rabbit lung preparation perfused with blood and ventilated with a closed-circuit system. Heart-lung blocks were harvested and the left lung was assessed after ligation of the right pulmonary artery and right main-stem bronchus. On completion of a storage period, the left lung was ventilated and perfused with fresh rabbit venous blood at a rate of 40 ml/min for 10 minutes. Assessment of lung function included gas analysis of infused and effluent blood, oxygen uptake, mean pulmonary artery perfusion pressure, and mean airway pressure. A control group and six preservation groups were evaluated, each with different storage temperatures (38 degrees C, 34 degrees C, 23 degrees C, 15 degrees C, 10 degrees C, and 4 degrees C). For each temperature, ischemic periods ranging from 1 to 30 hours were studied. In the control group, the lungs were assessed immediately after being harvested. In the preservation groups, the lungs were kept partially inflated, stored at a predetermined temperature by immersion, and later assessed after variable ischemic periods. Our studies demonstrated the following: (1) The degree of impaired lung function produced by ischemia is reflected by a decrease in oxygen uptake and in oxygen tension of the effluent pulmonary venous blood and an increase in pulmonary artery perfusion pressure; (2) hypothermia improves ischemic tolerance; (3) preservation of lung at 10 degrees C is superior to preservation at 15 degrees C and 4 degrees C. This screening model has allowed evaluation of independent multiple factors and methods pertinent to lung preservation and enables one to assess lung function reliably and rapidly.

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.

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.

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.

Pulmonary reperfusion injury: evidence for oxygen-derived free radical mediated damage and effects of different free radical scavengers.

Blood granulocyte-mediated reactions involving generation of oxygen-derived free radicals have recently been shown to be capable of causing injury to the lungs. These findings suggest a similar mechanism also to be involved in the development of pulmonary ischemia/reperfusion injury. In the present study, therefore, the effects of three oxygen-derived free radical scavengers, superoxide dismutase (SOD; 1 mg/kg), catalase (20,000 IU/kg) and allopurinol (45 mg/kg), were evaluated during reperfusion in a rabbit model after 2 h normothermic ischemia of the lung. During reperfusion, ischemic lungs were found to have an elevated pulmonary vascular resistance, increased total and extravascular lung water content, and decreased arterial oxygen tension (PaO2) compared to control animals. SOD and catalase, but not allopurinol, were able to reduce pulmonary injury by lowering the pulmonary vascular resistance, but could not prevent pulmonary damage as shown by total lung water (TLW) or PaO2. It is concluded that oxygen-derived free radicals such as hydrogen peroxide and the superoxide anion may play an important role in precipitating pulmonary injury after ischemia. The failure of xanthine oxidase inhibition (allopurinol) to exert protective effects may suggest that oxygen-derived free radical generation following pulmonary ischemia occurs predominantly via leukocyte-mediated reactions.

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.

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.

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.

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.

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.