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Cardiac surgery with cardiopulmonary bypass (CPB) is associated with the development of a systemic inflammatory response that can often lead to dysfunction of major organs. The systemic inflammation can be assessed intra- and postoperatively by measuring concentrations of inflammatory mediators in plasma and tissues. These concentrations, however, do not always correlate with the degree of observed organ dysfunction. Various strategies have been used to reduce inflammatory phenomena in patients undergoing CPB. Cardiac surgery without CPB has been performed increasingly with satisfactory results over the past few years. Attenuation of systemic inflammation and improved outcome in high risk patients are potential benefits of this technique. The emergence and expanding performance of cardiac surgical procedures without the use of CPB has given us an excellent tool to investigate the relative importance of CPB as a cause of systemic inflammation. Aprotinin is a protease inhibitor which is used in cardiac surgical patients for its haemostatic effects. Aprotinin has anti-inflammatory properties, the nature of which have not been completely clarified. This article presents a summary of the published literature investigating inflammatory response and organ dysfunction in patients who have cardiac surgery without CPB. It also presents an overview of recent data on the anti-inflammatory action mechanisms of aprotinin.

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Lung carcinoma is the most frequently diagnosed malignancy in the world, with the incidence increasing through the 20 th century. Presentation may be as a tumor mass primarily obstructing the central bronchial lumen, or a mass infiltrating lung tissue. Cryosurgery can be used as a method of palliative treatment for both these endobronchial and extrabronchial presentations. The aim of this study is two-fold: to present data relating to our extensive experience in treating obstructing endobronchial tumors and to present our initial results of direct cryosurgery to infiltrating lung tumor masses.During a nine-year period, 521 consecutive patients (male:female ratio 1.8:1) with a mean age of 67.9 years who had advanced obstructive tracheobronchial malignant tumors underwent cryosurgery with a mean of 2.4 treatments per patient. Hemoptysis, cough, dyspnoea and chest pain improved by at least one class in 76.4%, 69.0%, 59.25% and 42.6% (p<0.01) of symptomatic patients respectively. Quality of life studies showed that the mean Karnofsky score improved from 60 ± 7 to 75 ± 8 and the mean WHO score from 3.04 ± 0.7 to 2.20 ± 0.56. There were 7 (1.2%) in-hospital deaths, and 2-year survival was 15.9%.Direct cryosurgery to carcinoma of the lung was performed on 15 patients at exploratory thoracotomy. Results showed an increase in FEV1 from 1.80 ± 0.6 liters to 1.95 ± 0.8 (8.3%) liters and in FVC from 2.50 ± 0.8 to 2.68 ± 0.8 liters (7.2%). The Karnofsky score improved from 68 ± 9 to 78 ± 10 and the WHO score from 2.63 ± 0.81 to 2.38 ± 0.78 (9.6%).Major symptoms including cough, dyspnoea, and hemoptysis were assessed and showed improvement in 77.8%, 66.7%, and 100% (p<0.01) of symptomatic patients respectively.Patients were followed for a mean period of 18 months (range 4-84 months). Median survival from the date of surgery (Kaplan-Meier, 95%Cl) was 11.6 (6.8 to 18.2) months, range 1 to 84 months.Cryosurgery provides a safe and effective method for the palliation of advanced central bronchial obstructive tumors, and compares favorably with other methods in terms of safety, cost, and complications. Initial experience suggests that similar palliation may be achieved by cryosurgery applied to advanced parenchymal tumor masses.

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The purpose of inflammation is to combat various agents that may injure the tissues. Conditions such as CPB can often cause systemic inflammation and dysfunction of major organs. Pulmonary, renal, myocardial and intestinal function may suffer various degrees of impairment during and after cardiac surgery. Although changes in major organs usually remain clinically insignificant, severe organ failure is not uncommon. The process of systemic inflammation proceeds through activation of serum proteins, activation of leucocytes and endothelial cells, secretion of cytokines, leucocyte-endothelial cell interaction, leucocyte extravasation and tissue damage. Several anti-inflammatory strategies have already been used, some of which have given promising results pertaining to further reduction in the rate of the inflammation-related complications in cardiac surgical patients.

The final stage in the migration of leukocytes to sites of inflammation involves movement of leukocytes through the endothelial cell layer and the perivascular basement membrane. Both platelet-endothelial cell adhesion molecule-1 (PECAM-1/CD31) and the integrin αvβ3 have been implicated in this process, and in vitro studies have identified αvβ3 as a heterotypic ligand for PECAM-1. In the present study we have addressed the roles of these molecules by investigating and comparing the effects of PECAM-1 and αvβ3 blockade on leukocyte migration in vivo. For this purpose we have examined the effects of neutralizing Abs directed against PECAM-1 (domain 1-specific, mAb 37) and β3 integrins (mAbs 7E3 and F11) on leukocyte responses in the mesenteric microcirculation of anesthetized rats using intravital microscopy. The anti-PECAM-1 mAb suppressed leukocyte extravasation, but not leukocyte rolling or firm adhesion, elicited by IL-1β in a dose-dependent manner (e.g., 67% inhibition at 10 mg/kg 37 Fab), but had no effect on FMLP-induced leukocyte responses. Analysis by electron microscopy suggested that this suppression was due to an inhibition of neutrophil migration through the endothelial cell barrier. By contrast, both anti-β3 integrin mAbs, 7E3 F(ab′)2 (5 mg/kg) and F11 F(ab′)2 (5 mg/kg), selectively reduced leukocyte extravasation induced by FMLP (38 and 46%, respectively), but neither mAb had an effect on IL-1β-induced leukocyte responses. These findings indicate roles for both PECAM-1 and β3 integrins in leukocyte extravasation, but do not support the concept that these molecules act as counter-receptors in mediating leukocyte transmigration.

Our studies have therefore revealed a novel anti-inflammatory mechanism of aprotinin operating at the level of leukocyte extravasation. These findings may be relevant in the prevention of systemic inflammation after cardiopulmonary bypass through the use of protease inhibitors.