T. E. Ruud

Studies on the Plasma Kallikrein-Kinin System in Peritoneal Exudate and Plasma during Experimental Acute Pancreatitis in Pigs

Acute pancreatitis was induced in pigs by retrograde injection of Na-taurocholate into the pancreatic duct. By means of chromogenic peptide substrate assays, increased plasma kallikrein activity, parallel with a reduction of plasma prekallikrein and functional kallikrein inhibition values, was found in peritoneal exudate. In plasma, however, no changes in the kallikrein-kinin system were found during the 6-h observation time. The study demonstrates the presence of components of the plasma kallikrein-kinin system in peritoneal fluid and suggests that the peritoneal cavity to a great extent is a functionally separate compartment from plasma. Activation of the plasma kallikrein-kinin system in peritoneal exudate during acute experimental pancreatitis appears to be of importance for the initial symptoms and the development of shock seen during this condition.

Effects on peritoneal proteolysis and hemodynamics of prophylactic infusion with C1 inhibitor in experimental acute pancreatitis.

Acute pancreatitis was induced in pigs by manual retrograde injection of Na-taurocholate into the pancreatic duct. Chromogenic peptide substrate assays showed increased trypsin (TRY) and plasma kallikrein activities (KK), parallel with a reduction of prekallikrein (PKK) levels and functional plasma kallikrein inhibition (KKI), in the peritoneal exudate in untreated animals. Pretreatment with C1 inhibitor (C1 INH) concentrate significantly increased the KKI capacity, parallel with unchanged KK and TRY activities in the peritoneal exudate. Furthermore, C1 INH pretreatment significantly improved the hemodynamic performance and the survival rate during a 6-h observation period. The study underlines the pathophysiological importance of trypsin and the plasma kallikrein-kinin system during acute pancreatitis. C1 INH concentrates given intravenously prevent activation of this system locally in the peritoneal exudate during experimental acute pancreatitis.

Effects on peritoneal proteolysis and hemodynamics of prophylactic and therapeutic infusions of high doses of aprotinin in experimental acute pancreatitis.

Acute pancreatitis was induced in pigs by retrograde injection of Na-taurocholate into the pancreatic duct. Chromogenic peptide substrate assays showed increased trypsin (TRY) and plasma kallikrein activity (KK), parallel with a reduction of plasma prekallikrein (PKK) and functional kallikrein inhibition (KKI) values, in the peritoneal exudate in untreated animals. Intravenous high-dose pretreatment or therapy with aprotinin starting 3 h after the induction of acute pancreatitis resulted in significantly increased KKI capacity and unchanged KK and TRY activities in the peritoneal exudate. In test animals receiving aprotinin intravenously a significantly increased survival rate and improved cardiac output and arterial blood pressure were found during the 6-h observation period. All animals treated with aprotinin survived the observation period, whereas 63% of the untreated animals died. The study emphasizes the pathophysiological importance of the plasma kallikrein-kinin system in acute pancreatitis.

Evaluation of patients with acute pancreatitis by means of chromogenic peptide substrate assays and the proenzyme functional inhibition index

Using chromogenic peptide substrate assays the severity and clinical course were evaluated in 37 patients with acute pancreatitis. Retrospective clinical evaluation revealed that 20 patients had a severe disease, whereas 17 patients had mild acute pancreatitis. Seven of the patients with severe acute pancreatitis died. The proenzyme functional inhibition index (PFI index) is defined as the sum of deviations from the normal plasma pool values of plasma prekallikrein, functional kallikrein inhibition, plasminogen, antiplasmin, prothrombin and antithrombin III. Increased values are counted as positive, whereas reductions compared with the normal plasma pool values are recognized as negative. During the second day after admission the PFI index revealed significantly more negative values in severe cases than in patients with mild acute pancreatitis, -159 in severe case, -74 in mild cases (median values, P less than 0.05). The PFI index values were maintained strongly negative for the following 3 days in severe cases whereas the index was brought to positive values during the same period in patients with mild acute pancreatitis. The fatal cases revealed strongly negative PFI index values for the whole observation period. The patients with severe acute pancreatitis were earlier identified by means of the PFI index than by individual parameters also used for calculating the index. The results show that by means of the PFI index severity of acute pancreatitis can be recognized during early stages of the disease.

Effects on Peritoneal Proteolysis and Hemodynamics by High Doses of Methyl-Prednisolone in Experimental Acute Pancreatitis

Acute pancreatitis was induced in 15 anesthetized pigs by injection of Na-taurocholate into the pancreatic duct. Seven animals were pretreated with methyl-prednisolone sodium succinate 30 mg/kg intravenously. Using chromogenic peptide substrate assays, values of trypsin (TRY), plasma prekallikrein (PKK), plasma kallikrein (KK) and functional plasma kallikrein inhibition capacity (KKI) were studied in the peritoneal exudate. Cardiac output (CO) and arterial pressure (AP) were regularly monitored before and during a six hour observation period. In acute untreated pancreatitis a 40% reduction of PKK levels was found paralleled by an increased KK activity and a reduction of KKI capacity. High TRY levels were found in several animals. The mortality rate was 63%. The pretreated animals all survived. CO and AP were significantly less reduced than in the untreated animals. Components of the plasma kallikrein-kinin system and TRY in the exudate remained mainly unchanged. Methyl-prednisolone given as pretreatment significantly improves hemodynamic parameters and increases the survival rate. Methyl-prednisolone suppresses generation of trypsin activity and activation of the plasma kallikrein-kinin system in the peritoneal exudate which may be of significant importance to the outcome.

Studies on pathological plasma proteolysis in severely burned patients using chromogenic peptide substrate assays: a preliminary report.

Changes in components of the plasma proteolytic enzyme systems were studied in nine patients with severe burns using chromogenic peptide substrate assay technique. All patients were critically ill and five died during a four week observation period. Plasma prekallikrein, plasminogen, prothrombin and platelet values decreases regularly in all patients after the injury. These changes were seen together with a high frequency of increases serum FDP values and presence of soluble fibrin. During critical illness extensive plasma proteolysis occurred, indicated by elevated plasma kallikrein and plasmin activities combined with lowered functional plasma kallikrein inhibition, prekallikrein and plasminogen values. The study confirms that plasma pathological proteolysis occurs in patients with severe burns, and indicates that close monitoring of components of the plasma proteolytic enzyme systems can give information of prognostic and therapeutic value in the severely burned patient.

STUDIES ON THE KALLIKREIN-KININ SYSTEM IN PLASMA AND PERITONEAL FLUID DURING EXPERIMENTAL PANCREATITIS

Using chromogenic peptide substrate assay technique, components of the plasma kallikrein-kinin system and trypsin activity were studied in plasma and peritoneal exudate during acute pancreatitis in pigs. In the plasma no significant changes occurred, but increased kallikrein activity was found in the peritoneal exudate. This finding was paralleled by a reduction in prekallikrein levels and functional kallikrein inhibition values. The trypsin activity in peritoneal exudate, however, increased inconstantly. These results emphasize the significance of peritoneal protease-antiprotease imbalance during acute pancreatitis.

Changes in Components of The Plasma Kallikrein-Kinin and Fibrinolytic Systems Induced by a Standardized Surgical Trauma

Trauma might lead to pathological plasma proteolysis. In recent studies we found that several components of the plasma proteolytic enzyme systems becomes markedly reduced in patients with multiple trauma (1). Furthermore, these studies revealed significantly more pronounced decreases within the first week after injury in the fatal cases than in the patients that survived. In order to further evaluate these changes, components of the plasma kallikrein-kinin and fibrinolytic systems were studies in patients with a standardized surgical trauma.

Haemodynamic effects of intravenous injection of peritoneal exudate in experimental acute pancreatitis

The haemodynamic effects of intravenous injection into the test animals themselves of peritoneal exudate obtained during experimental acute pancreatitis in pigs were studied. The exudate had a distinct but moderate vasodilating effect when injected into the test animal. This decrease in afterload and a slight compensatory increase in heart rate led to a small increase in cardiac output. The profound hypotensive effect of intravenous injection of peritoneal pancreatic exudate observed by others when injecting the exudate into healthy animals could not be reproduced. In an organism severely affected by pancreatitis, the added pharmacological insult of peritoneal exudate intravenously seems to be of little haemodynamic consequence. Some of the effects previously reported may be caused by trypsin added to the fluid injected intraductally to produce the ailment.