Medizin - Open Access LMU - Teil 08/22 Archiv

Intraoperative administration of the proteinase Inhibitor aprotinin causes reduction in blood loss and homologous blood requirement in patients undergoing cardiac surgery. To ascertain the blood-saving effect of aprotinin and to obtain further information about the mode of action, 40 patients undergoing primary myocardial revascularization were randomly assigned to receive either aprotinin or placebo treatment. Aprotinin was given as a bolus of 2 X 105 kallikrein inactivator units (KIU) before surgery followed by a continuous infusion of 5 X 105 KIU/h during surgery. Additionally, 2 X 105 KIU were added to the pump prime. Strict criteria were used to obtain a homogeneous patient selection. Total blood loss was reduced from 1,431 +/- 760 ml in the control group to 738 +/- 411 ml in the aprotinin group (P < 0.05) and the homologous blood requirement from 838 +/- 963 ml to 163 +/- 308 ml (P < 0.05). In the control group, 2.3 +/- 2.2 U of homologous blood or blood products were given, and in the aprotinin group, 0.63 +/- 0.96 U were given (P < 0.05). Twenty-five percent of patients in the control group and 63% in the aprotinin group did not receive banked blood or homologous blood products. The activated clotting time as an indicator of inhibition of the contact phase of coagulation was significantly Increased before heparinization in the aprotinin group (141 +/- 13 s vs. 122 +/- 25 s) and remained significantly Increased until heparin was neutralized after cardiopulmonary bypass (CPB). The concentration of the thrombin-antithrombin III complex was significantly decreased at the end of CPB in the aprotinin group, indicating less thrombin generation in the aprotinin-treated group. The total concentration of the fibrinogen-fibrin split products (FSP) and the split products of the cross-linked fibrin (D-dimers) were also significantly reduced due to attenuated proteolytic activities of thrombin and plasmin. The results of the fibrin plate assay revealed higher fibrinolytic activity during CPB in the control group. The results demonstrate the beneficial effect of high-dose aprotinin treatment on blood loss and homologous blood requirement. This effect can be attributed to the inhibition of the contact phase of coagulation and the consequently reduced thrombotic and fibrionolytic activity during and after CPB.

Hemodialysis treatment is associated with activation of neutrophil granulocytes. Pentoxifylline has been shown to inhibit neutrophil activation in vitro and in vivo. We investigated the effect of pentoxifylline on leukocyte and platelet counts and on plasma levels of extracellularly released neutrophil elastase and lactoferrin during a four-hour hemodialysis treatment. Eight patients received 400 mg of pentoxifylline or placebo orally twice a day over 14 days and an additional dose of 400 mg of pentoxifylline intravenously during hemodialysis. Each subject served as his own control in a randomized, double-blind, cross-over study. Combined oral and intravenous treatment with pentoxifylline prevented neither leukopenia nor neutrophil degranulation during the time interval studied. Elastase plasma levels paralleled the drop in leucocyte counts and thereafter increased similarly in both groups. Lactoferrin plasma levels exhibited less increase in the treated group; however, this effect was not statistically significant. This may be due to the small number of cases studied and to difficulties in reaching effective plasma levels without side effects.

Lithium treatment reduces the renal kallikrein excretion rate. Lithium salts are widely used agents for the prophylactic treatment of affective disorders. Lithium salts may be associated with distal nephron dysfunction. Kallikrein is a protease which is generated by the distal nephron. We used an amidolytic assay of chromatographically purified enzyme to determine the urinary excretion rate of active kallikrein in relation to lithium treatment. All plasma lithium concentrations were within the therapeutic range (0.4 to 0.9 mmol/liter). In 15 patients the urinary excretion rate of active kallikrein was 267.4 65.6 mU/24 hrs before lithium treatment, and fell to 117.8 39.6 mU/24 hrs (P < 0.05) on day 14 of lithium treatment. This reduction was associated with a decrease of immunoreactive kallikrein in the same urines by 66%. In another 15 patients who had undergone lithium therapy for an average period of 5.6 years, the urinary excretion rate of active kallikrein was 86.1 14.5 mU/24 hrs, while 21 age-matched healthy controls had an excretion rate of 364.1 58.4 mU/24 hrs (P < 0.05). Measurements of immunoreactive kallikrein in the same urine samples demonstrated a reduction of kallikrein after long-term lithium treatment by 78%. These observations could not be attributed to changes in creatinine clearance, renal sodium or potassium excretion rates or plasma concentrations of aldosterone and vasopressin. Addition of lithium to the urine in vitro had no demonstrable effect on kallikrein measurement by amidolytic assay. We conclude that lithium in therapeutic plasma concentrations may directly suppress the secretion of kallikrein by renal connecting tubule cells.