tPA-PAl (tissue plasminogen activator—plasminogen activator inhibitor-1 complex) can be a predictive marker of multiple organ dysfunction syndrome in seriously ill acute patients with glucose intolerance — analysis under strict blood glucose control by artificial pancreas

Background and purpose

Recently close relationships between multiple organ dysfunction syndrome (MODS) and coagulopathy, particularly hvpercoagulability, have been reported in seriously ill acute patients. However, there are few studies suggesting which parameters related to coagulopathy are most intensively correlated with MODS, and whether the coagulopathy has a role of the cause of MODS or is only the result of it.

The purpose of this report is to (1) study whether PAI-1 related markers including tPA-PAI are parameters related to coagulopathy closely related to MODS, and (2) analyse whether the coagulopathy indicated by the elevation of the PAI-1 related markers is the cause of MODS in seriously ill acute septic patients with glucose intolerance. Patients under strict blood glucose control by artificial pancreas (AP) were selected in order to sample reliable PAI-1 values because fluctuation of blood glucose and scrum fat levels are believed to influence the blood levels of PAI-1 related parameters. AP used was STG-22 manufactured by NIKKISOH corporation in Japan.

Materials

Nine severe septic patients with glucose intolerance without NIDDM, aged 27-83 years were investigated. Primary diseases were, four patients with hepatobiliary diseases, two with gangrene of lower extremities, two with ARDS, and one with burn.

Analyzed items were (1) regarding to the MODS: MOF score (calculated from the MOF criteria of Japanese Association for Critical Care Medicine), (2) regarding to glucose intolerance: M value (mg/kg per min, measured by the euglycemic hyperinsulinemic glucose clamp method with AP. The clamped blood glucose level was 80 mg/dl with the insulin infusion rate of 3.36 mU/kg per min), as reported in the literature, (3) regarding coagulopathy: (i) DIC (disseminated intravascular coagulation) score calculated from the DIC criteria of the Ministry of Health and Welfare of Japan, (ii) PAI-1 related markers (PAI-1 activity, PAI-1 antigen, and tPA-PAl), (iii) platelet count (PLT), (iv) fibrinogen (Fb), (v) FDP, (vi) prothrombin time ratio (PT), (vii) TAT, (viii) D-dimer, (ix) PIC, (x) antithrombin-III (AT-III), (xi) protein-C activity (PC), (xii) protein-S activity (PS), (4) thrombomodulin (TM) as a parameter of endothelial cell injury, and (5) serum fat (free fatty acid, triglyceride, cholesterol).

Results

(1) Mean value of the daily mean blood glucose levels (BSm), and M values measured within a few days after admission were 165 ± 42 mg/dl (n = 35) and 7.4 ± 3.6 mg/kg per min (n = 8), respectively. (2) MOF score was correlated with DIC score (correlation coefficient: 0.86, n = 111), PIT (-0.60, n = 115), tPA-PAl (0.57, n = 37), TAT (0.49, n = 25), and D-dimer (0.46, n = 25), (3) DIC score was correlated with PIT (-0.75, n = 111) and TPA-PAl (0.49, n = 35). (4) tPA-PAl was correlated with PIT (-0.54, n = 38), PC (-0.54, n = 24), TAT (0.53, n = 24) and Fg (-0.52. n = 35). (5) TM was correlated with tPA-PAl (0.62, n = 33). (6) There were no definite relationships between tPA-PAl and BSm, blood insulin concentration, and serum fat levels. (7) The marked change of tPA-PAl levels apparently preceded those of MOF score in three out of eight patients and were parallel to them in four out of eight

Interpretation and conclusions

Several important relationships between tPA-PAI and DIC, hypercoagulability, endothelial cell injury, and MODS became evident. These analyses were thought to be possible because strict blood glucose control was performed by using AP. The degree of MODS correlated with that of DIC and/or hypercoagulability. Among parameters related to coagulopathy, tPA-PAl was not only a sensitive marker of DIC and hypercoabulability, but also correlated well with the severity of MODS and the endothelial cell injury. Moreover, hypercoagulable state indicated by the elevation of tPA-PAl was thought to be one of the causes of MODS, and treatment for the hypercoabulability may be justified as an important method.