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Biomedical subjects

C R Wildevuur

Publications and source records attributed to C R Wildevuur.

At least 73 records · Page 4Linked to original sources
PubMed1991

Methylprednisolone prophylaxis protects against endotoxin-induced death in rabbits.

Endotoxemia in patients can lead to sepsis and shock by activation of cellular and plasmatic systems. Corticosteroids are described to have a beneficial effect on these phenomena. In this study of controlled endotoxic shock, we investigated the protective effects of prophylactic corticosteroid treatment against activation of cellular and plasmatic systems. In this respect, a low-dose methylprednisolone (1 mg/kg body wt) treatment was compared with that of a high-dose methylprednisolone (40 mg/kg body wt) treatment. Endotoxin infusion induced death of all rabbits, which was associated with leukopenia, thrombopenia, increased levels of beta-glucuronidase, and leukotriene B4 (LTB4) and decreased levels of complement total hemolytic activity (CH50) and tissue plasminogen activator (t-PA) activity. Both methylprednisolone regimens prevented death of the rabbits after endotoxin infusion, which correlated with a significant decrease of the granulocyte release product beta-glucuronidase (P less than 0.01). The early leukopenia and thrombopenia were not prevented; however, both cell numbers returned more rapidly to baseline values than in the placebo group (P less than 0.01, P less than 0.05). The LTB4 and CH50 concentration and t-PA activity did not differ significantly between the treated and placebo groups. These results indicate that although methylprednisolone has no inhibitory effect on the activation of the complement, arachidonic acid, and fibrinolytic systems, it protected the animals from the deleterious effects of endotoxin shock by inhibition of leukocyte activation. In this regard a low dosage of methylprednisolone is equally effective as the most often recommended high dose.

Animals↗
PubMed1991

Membrane oxygenator prevents lung reperfusion injury in canine cardiopulmonary bypass.

The effect of blood activation on lung reperfusion injury during cardiopulmonary bypass was investigated in 20 dogs with the use of a bubble oxygenator (n = 10) or a membrane oxygenator (n = 10). In the bubble oxygenator group, significant leukocyte and platelet right to left atrium gradients were found 15 minutes after lung reperfusion (p less than 0.05, p less than 0.01) accompanied by a sharp increase in plasma malondialdehyde concentration 5 minutes after lung reperfusion, whereas no significant right to left atrium gradient of leukocytes or platelets nor significant increase in plasma malondialdehyde concentration was observed in the membrane oxygenator group. In both the bubble oxygenator and membrane oxygenator group, similar mild to moderate lung histological changes were found before lung reperfusion. After lung reperfusion, however, more endothelial cell swelling (p less than 0.05), leukocyte (p less than 0.01) and platelet (p less than 0.01) accumulation in lung capillaries, leakage of erythrocytes into the alveolar space (p less than 0.05), and type I cell damage (p less than 0.05) were found only in the bubble oxygenator group. Eventually, a significantly higher lung water content was found in the bubble oxygenator group than in the membrane oxygenator group (p less than 0.01) after cardiopulmonary bypass. This study indicated that lung injury during cardiopulmonary bypass starts mainly after lung reperfusion, which was correlated with lung leukocyte and platelet sequestration associated with different types of oxygenators.

Animals↗
PubMed1991

Aprotinin reduces intraoperative and postoperative blood loss in membrane oxygenator cardiopulmonary bypass.

To determine whether aprotinin can provide a significant improvement of hemostasis in cardiopulmonary bypass using a membrane oxygenator, we tested this drug in a prospective, randomized, double-blind, placebo-controlled clinical trial. The subjects were 80 male patients undergoing cardiopulmonary bypass for coronary artery bypass grafting. Forty patients received aprotinin and 40 patients served as placebo controls. Aprotinin (4 x 10(6) KIU) was given as a continuous infusion, starting before operation and continuing until after cardiopulmonary bypass; additionally, 2 x 10(6) KIU aprotinin was added to the pump prime. Intraoperative and postoperative bleeding, respectively two thirds and one third of the total perioperative blood loss, were both significantly reduced in the aprotinin-treated group (p less than 0.01). The total average perioperative blood loss, corrected to a hemoglobin concentration of 7 mmol/L, was 550 mL in the aprotinin-treated patients versus 900 mL in the control patients. This reduction in blood loss, furthermore, significantly decreased the amount of postoperative blood transfusions (p less than 0.05) and increased the percentage of patients who did not receive postoperative donor blood from 42% to 68%. Aprotinin increased the activated clotting time significantly during cardiopulmonary bypass, which led to a reduction in heparin usage. The improved hemostasis during operation, despite the prolonged activated clotting time, might even abolish the need for heparin conversion with protamine at the end of cardiopulmonary bypass, thus allowing retransfusion through cardiotomy suction to be continued, which saves the blood that is currently lost with vacuum suction.

Aprotinin↗
PubMed1991

The role of different types of corticosteroids on the inflammatory mediators in cardiopulmonary bypass.

In a placebo-controlled double-blind study on patients undergoing cardiopulmonary bypass (CPB) we studied the inhibiting effects of dexamethasone, a high dose of methylprednisolone, and a low dose of prednisolone on the inflammatory reaction induced by CPB. During CPB two episodes of blood activation were noticed. First, the blood-material interaction caused a significant increase in complement C3a and elastase concentrations after the start of bypass (p less than 0.01). Secondly, the reperfusion of the ischemic heart, lungs, and peripheral tissue, after release of the aortic cross-clamp, caused an additional increase in C3a and elastase concentration and a statistically significant increase in leukotriene B4 (LTB4) concentration and tissue plasminogen activator (t-PA) activity (p less than 0.01, p less than 0.05, respectively). Dexamethasone treatment effectively inhibited the increase in LTB4 concentration and t-PA activity after release of the cross-clamp (significant differences to the placebo group, p less than 0.01, p less than 0.05, respectively). High-dose methylprednisolone treatment was almost as effective as dexamethasone treatment, whereas low-dose prednisolone treatment was less effective than methylprednisolone in the inhibition of the inflammatory mediators (DM greater than MP greater than P). None of the corticosteroid regimens was able to inhibit the increase in complement C3a and elastase. We therefore conclude that corticosteroids do not have an effect on complement activation during CPB. However, leukocyte activation and t-PA activity after release of the aortic cross-clamp are effectively inhibited by corticosteroid treatment, in a dose-dependent way. The inhibition of this inflammatory reaction will have a favourable effect on the postoperative course in patients who have undergone CPB.

Acute-Phase Proteins↗
PubMed1991

Reduction of granulocyte-mediated lung injury in canine cardiopulmonary bypass by anisodamine infusion.

The effect of infusing the M-cholinergic receptor blocker anisodamine during cardiopulmonary bypass (CPB) on granulocyte-mediated lung injury was evaluated in sixteen dogs undergoing CPB for 120 min with the aorta crossclamped for 90 min. The treated dogs (n = 8) received a total dose of 15 mg/kg anisodamine hydrochloride before and during CPB whereas the controls (n = 8) received saline only. A significantly reduced sequestration of granulocytes in the lungs was found in the treated dogs as indicated by a lower right-to-left atrium granulocyte gradient 15 minutes after pulmonary recirculation during CPB (p less than 0.05) and less granulocyte accumulation in the lung capillaries after CPB, as shown by histological examination (p less than 0.01). Moreover, oxygen free radical release as indicated by plasma malondialdehyde concentrations was significantly lower (p less than 0.05) in the treated dogs than in the controls towards the end of CPB. Finally, a significantly reduced lung-water content was found 30 min after CPB in the treated dogs as compared with the controls (p less than 0.01). These results suggest that anisodamine administration in this experimental model significantly inhibits pulmonary granulocyte sequestration in CPB and the consequent lung injury induced.

Animals↗
PubMed1991

Morphologic activation of lymphocytes in blood during rejection of heart and lung grafts in rats.

We investigated morphologic activation of lymphocytes in blood in a standardized, infection-free rat model and compared lymphocyte activation during rejection of heart grafts and that of lung grafts with other parameters of rejection. For heart grafts the other parameters were histology and palpation, and for lung grafts they were histology, bronchoalveolar lavage, and chest roentgenography. During acute rejection of heart grafts, lymphocyte activation in blood increased when histology of the heart grafts showed already moderate-to-severe rejection with myocyte necrosis. Lymphocyte activation in blood detected acute heart rejection clearly later than histology but somewhat earlier than palpation. During acute rejection of lung grafts, lymphocyte activation in blood increased when histology of the lung grafts showed the (early) vascular phase of rejection, without apparent tissue damage. Lymphocyte activation in blood detected acute lung rejection only slightly later than histology, at approximately the same time as bronchoalveolar lavage and earlier than chest roentgenograms. Lymphocyte activation was higher during acute lung rejection than during acute heart rejection. During "chronic" rejection of long-surviving heart grafts and lung grafts, lymphocyte activation in blood did not increase consistently. The early and strong increase of morphologic activation of lymphocytes in blood during acute lung rejection may imply for clinical transplantation that monitoring of lymphocyte activation in blood is more useful for early detection of acute rejection after lung transplantation than after heart transplantation.

Acute Disease↗
PubMed1991

Lung transplantation in the rat. A morphometric analysis of the gas exchange region.

Single-lung transplantation in the rat provides a model that allows investigators to study immunologic, cellular, and morphologic changes associated with allograft rejection. We performed morphometric analysis of transplanted and nontransplanted lungs removed from recipients having received isografts, allografts, or hilus-stripping up to six months previously, and having received cyclosporine on the first postoperative day, the second postoperative day, the first five days, or not at all. When CsA was not administered, there was extensive and rapid destruction of the alveolar septa with consolidation and rejection of the transplanted lung within one week. In contrast, the allografts from rats treated with CsA were not obviously changed compared with the control lung. To evaluate whether or not these CsA-treated allografts had even subtle injury to alveolar septal cells, a morphometric analysis using transmission electron microscopy was used. There were no significant changes between control (nontransplanted or hilus-stripped) lungs and isografted or allografted lungs for most parameters measured. Exceptions included type I epithelial cell volume, which increased in rats treated with CsA on postoperative day 1 only, and the tissue component of diffusing capacity, which decreased in rats treated with CsA on postoperative day 2 only. We conclude that CsA treatment of rats given lung allografts effectively blocks the development of injury in the gas exchange region. The effect is achieved when the CsA is given during the first five days following transplantation in rats, and may be influenced by the timetable of administration and cumulative dosage.

Animals↗
PubMed1991

Factors determining prolongation of rat heart allograft survival by perioperative injection of donor spleen cells.

Previously, we have shown that a perioperative injection of donor mononuclear cells in combination with cyclosporine treatment on day 2 after transplantation prolongs heart allograft survival in rats. In this study we determined whether the efficacy of this treatment was influenced by the same factors that have been shown to affect the efficacy of preoperative administration of donor cells. The effect of the following factors were investigated: dosage and repetition of the donor cell injection, viability of the donor cells, immunosuppressive drugs other than cyclosporine, and the rat strain combination. We found that there was an optimal dosage of donor cells; dosages of 4 x 10(7) or 1 x 10(8) cells gave the best heart graft survival. Repetition of the donor cell injection was not useful. Reducing viability of the cells by irradiation did not abrogate the prolonged graft survival, whereas killing of the cells did. Methylprednisolone, azathioprine, or cyclophosphamide in combination with the perioperative donor cell injection did not prolong heart graft survival in comparison with treatment with the drug only. The efficacy of this treatment was also influenced by the rat strain combination. In some combinations, this treatment prolonged graft survival, whereas in others an effect was absent or undetectable. Importantly, this treatment never adversely affected graft survival. We conclude that the efficacy of this treatment is influenced by similar factors as found for preoperative treatment with donor cells. A major advantage of this treatment over preoperative blood transfusions is that it avoids sensitization.

Animals↗
PubMed1991

The combi-effect--reduced rejection of the heart by combined transplantation with the lung or spleen.

The term combi-effect was introduced to describe the phenomenon of a reduction in rejection of heart grafts after combined transplantation with the lung. In this study in rats we investigated whether the combi-effect was an immunological process and whether it could also be induced by combined transplantation of the heart with the spleen or with a lymphocyte-depleted spleen. Heart and spleen grafts were transplanted into the abdomen; left lungs were transplanted into the thorax of recipient rats. To deplete spleens of their lymphocytes, prospective donor rats were irradiated. Cyclosporine was injected once, on day 2 after transplantation. All heart allografts transplanted alone and treated with cyclosporine were rejected acutely (median survival time [MST] of 14.5 days). In contrast, after combined transplantation of a donor lung or spleen with the heart, almost all heart grafts survived indefinitely. Transplantation of a syngeneic lung or third-party spleen had little effect on heart graft survival (MST of 22.5 days and 26.5 days, respectively). Without cyclosporine treatment, combined transplantation with a donor lung or spleen hardly prolonged heart graft survival. Transplantation of a lymphocyte-depleted spleen with the heart induced a combi-effect in cyclosporine-treated rats that was somewhat weaker: only two of six hearts survived indefinitely. We conclude that in the combi-effect an immunological mechanism reduces rejection of the heart. This mechanism is probably generated by the lymphoid tissue (bronchus-associated lymphoid tissue in lung and white pulp in spleen) in the combined transplant.

Animals↗
PubMed1991

Distribution of endotracheally instilled surfactant protein SP-C in lung-lavaged rabbits.

In lung-lavaged surfactant-deficient rabbits (n = 6) requiring artificial ventilation, porcine surfactant was instilled endotracheally. This resulted in improvement of lung function so that the animals could be weaned off artificial ventilation. The animals were killed 4 1/2 h after surfactant administration and the porcine surfactant protein was localized in the lung with a MAb. We found surfactant protein in all lobes of the lung but the distribution was not homogeneous. Surfactant protein C was found in less than 15% of the alveolar spaces and in less than 1% of the bronchi.

Animals↗
PubMed1991

Inhibition by dexamethasone of the reperfusion phenomena in cardiopulmonary bypass.

A placebo-controlled double-blind study of patients undergoing cardiopulmonary bypass was conducted, comparing the effects of dexamethasone and a placebo on the activation of the plasmatic systems and blood cells and on the postoperative course after cardiopulmonary bypass. In the placebo group two patterns of blood activation could be distinguished. From the start of bypass, blood-material interaction caused an increase in complement C3a and elastase concentration. After release of the aortic cross-clamp, a statistically significant increase was observed in tumor necrosis factor, leukotriene B4, and tissue plasminogen activator activity (p less than 0.01, p less than 0.05, p less than 0.05, respectively). Dexamethasone treatment was not able to inhibit complement activation and elastase release during cardiopulmonary bypass. However, dexamethasone treatment effectively inhibited the increase in tumor necrosis factor, leukotriene B4, and tissue plasminogen activator activity after release of the crossclamp (p less than 0.01 compared with the placebo group). In the postoperative period the patients in the placebo group had hyperthermia and hypotension and required considerable intravenous fluid administration and cardiotonic treatment. The dexamethasone-treated patients, however, showed normothermia (p less than 0.01), had significantly higher blood pressures (p less than 0.01) without supportive treatment, and consequently were in the intensive care unit for a shorter period of time. We conclude that dexamethasone prevents the hemodynamic instability after cardiopulmonary bypass and thus improves the postoperative course by inhibition of the leukocyte and tissue plasminogen activator activity generated after release of the aortic crossclamp.

Aged↗
PubMed1990

Vacuum cell seeding: a new method for the fast application of an evenly distributed cell layer on porous vascular grafts.

The study was to develop a method to induce rapid endothelial coverage of vascular prostheses by cell seeding. The method uses vacuum pressure and is therefore called vacuum cell seeding. A special seeding device was constructed, in which grafts of different length and/or inner diameter could be positioned. Microporosity of the grafts was a prerequisite for this method. Two types of commercially available microporous grafts were tested. The ePTFE graft routinely used clinically needed pretreatment to enable the method, whilst a polyurethane-based graft could be seeded as received. Vacuum cell seeding applied cells from a suspension in culture medium within 10 min in an evenly distributed cell layer on to the luminal graft surface. The adhering cells immediately started flattening, thereby completely covering the luminal surface. It was concluded that the vacuum cell seeding method rapidly introduced a confluent layer of seeded cells on porous vascular grafts in a simple way, which in the clinical setting could easily be performed on the operating table.

Animals↗
PubMed1990

Aprotinin protects platelets against the initial effect of cardiopulmonary bypass.

Remarkable improvement in hemostasis after cardiopulmonary bypass has been achieved by treatment with the proteinase inhibitor aprotinin, but the mechanism is still unclear. The present study is designed to elucidate the importance of platelet adhesive (glycoprotein Ib) or aggregatory (glycoprotein IIbIIIa) receptors on this hemostatic function in cardiopulmonary bypass and its improvement by aprotinin treatment. To determine whether the first pass of blood through the circuit or a continuous proteolytic attack is the main cause of platelet damage, we gave two different dose regimens of aprotinin treatment to patients undergoing coronary artery bypass grafting. Part I of the study consisted of a double-blind trial on 60 patients. Patients received placebo or aprotinin infusion (total 6.10(6) KIU) before and during bypass. A consecutive group of 22 matching patients received one single bolus of aprotinin in the pump prime (2.10(6) KIU). Blood samples were collected before and during operation to assess the effect of bypass and aprotinin on platelets and the activation of the various proteases in relation to hemostasis expressed in blood loss and blood requirements. The adhesive platelet membrane Ib glycoproteins were decreased by 50% in the untreated patients within 5 minutes of cardiopulmonary bypass and remained low during bypass, whereas glycoprotein Ib did not decrease in either group of aprotinin-treated patients. The platelet membrane IIbIIIa glycoproteins did not significantly change during bypass in either group, but fibrinogen binding to these receptors improved significantly in the 6.10(6) KIU aprotinin-treated group at the end of bypass as compared with initial values. The high continuous dose of 6.10(6) KIU aprotinin inhibited the clotting and kallikrein/kinin system throughout the operation; the pump prime dose of 2.10(6) KIU inhibited these systems only initially. Although the fibrinolytic activity was effectively inhibited in both aprotinin groups, fibrinolytic activity became apparent only at the end phase of bypass in the placebo group. However, improved hemostasis was observed intraoperatively from the start of bypass and resulted in a 40% lower blood loss intraoperatively and postoperatively and consequently a 40% lower total blood requirement in the aprotinin-treated patients than in the untreated patients. Our results therefore demonstrate that the improved hemostasis during and after bypass in patients treated with aprotinin has specifically to be attributed to a preserved adhesive capacity of platelets that was affected in the first pass of blood through the cardiopulmonary bypass circuit.

Aprotinin↗
PubMed1990

Increased anticoagulation during cardiopulmonary bypass by aprotinin.

In this prospective study, the effect of the antiproteinase aprotinin on anticoagulation during cardiopulmonary bypass was compared with placebo treatment in a randomized double-blind fashion. The kallikrein-inhibiting capacity was significantly increased in aprotinin-treated patients and decreased in the control patients. The intrinsic clotting system was also inhibited by aprotinin. We demonstrated during cardiopulmonary bypass and in vitro a significantly prolonged activated clotting time and a remarkable prolongation of the activated partial thromboplastin time by aprotinin at low heparin concentrations, whereas the antithrombin III consumption was significantly reduced. Aprotinin synergistically enhanced the anticoagulation by heparin, which allowed reduced heparinization. This is of clinical importance for use in both heparin-resistant and heparin-sensitive patients undergoing cardiopulmonary bypass and may also have advantages for routine use during bypass to reduce the adverse effects of heparin-protamine complexes.

Antithrombin III↗