Masako K. Nishijima

Gabexate mesilate (FOY) therapy of disseminated intravascular coagulation due to sepsis.

Gabexate mesilate (FOY), a synthetic serine proteinase inhibitor, has an anticoagulant activity in the absence of antithrombin-III. We investigated FOY therapy for the treatment of disseminated intravascular coagulation (DIC) associated with sepsis in 15 patients (group F), and compared it with heparin therapy in 8 patients (group H). Successful treatment was observed in 13 patients in group F and in 4 patients in group H. The efficacy of the therapy in both groups was not significantly different. However, in patients whose antithrombin-III values were less than 20 mg/dl at the initiation of the therapy, FOY therapy was successful in 6 of 7 patients, whereas heparin therapy was not at all successful in 4 patients (p < 0.05). We conclude that FOY can be used as effectively as heparin for the treatment of DIC, and that FOY therapy is superior to heparin therapy in DIC associated with decreased antithrombin-III.

Serial changes in cellular immunity of septic patients with multiple organ-system failure.

Total lymphocyte count, lymphocyte cell-surface markers (OKT3, OKT4, OKT8, and B-1), serum complement factors (C3 and C4), immunoglobulins (IgG, IgA, and IgM), ceruloplasmin (Crl), and transferrin (Trf) were determined weekly for nine septic postoperative patients, all of whom had multiple organ-system failure. The peripheral blood total lymphocyte count, its subpopulation, T-cell subset, and proliferative responses of lymphocyte to phytohemagglutinin (PHA) and concanavalin A (Con A) decreased in all patients. OKT3 and B-l decreased progressively in the four nonsurvivors compared with the five survivors. Although immunoglobulin levels were within the normal range in both groups, they tended to increase in survivors and decrease in nonsurvivors. Serial levels of C3, C4, Crl, and Trf increased in survivors but did not change in nonsurvivors. T-cell function and antibody-producing activity diminished progressively in nonsurvivors. These changes in cellular immunity may represent another manifestation of multiple organ-system failure during sepsis.

New approach to regional anticoagulation in hemodialysis using gabexate mesilate (FOY).

Gabexate mesilate (FOY), a synthetic serine proteinase inhibitor, prevented and controlled bleeding during hemodialysis of 3 patients with active bleeding sites and/or hemorrhagic tendencies. The effectiveness of regional anticoagulation was evaluated by activated coagulation time (ACT). The ACTs of blood sampled from the outlet of dialyzer were significantly prolonged; however, systemic ACTs were almost normal. ACTs immediately after dialysis were not prolonged compared with those before dialysis. In 1 patients, renal function was improved after dialysis. No harmful side effects of FOY were observed. We consider FOY to be superior to other drugs for hemodialysis in that: (1) it can provide sufficient regional anticoagulation; (2) it has a very short half-life and need not be antagonized after dialysis; and (3) it can be used in patients with sepsis and/or disseminated intravascular coagulation (DIC) because it inhibits proteinase and also prevents platelet aggregation.

Application of HPLC measurement of plasma concentration of gabexate mesilate

The plasma concentration of gabexate mesilate (ethyl-p-(6-guanidinohexanoyloxy) benzoate) methanesulfonate (GM), FOY, was measured on a high performance liquid chromatography. GM concentrations ranging from 1 to 50 micrograms/ml of whole blood were able to be determined with this method. The half-life of GM in plasma was 55 seconds and the minimum concentration of GM which affected the activated coagulation time of whole blood (ACT) was 10 micrograms/ml. This method is sensitive and accurate to provide us with the pharmacodynamic basis for the determination of the effective plasma concentration of GM with respect to its anticoagulant activity.

Amino acids and thiobarbituric acid reactive substances in cerebrospinal fluid and plasma of patients with septic encephalopathy.

Amino acids and thiobarbituric acid reactive substances (TBARs) in the cerebrospinal fluid (CSF) and plasma were identified and assayed in 5 patients with septic encephalopathy. Levels of all the high molecular weight neutral amino acids (LNAAs) appeared to increase in the CSF. CSF levels of phenylalanine (PHE) and methionine (MET) increased significantly by factors of 20.9 and 9.5, respectively, and the plasma PHE level increased 7.5-fold. No significant changes in branched-chain amino acids were observed in either the CSF or plasma. The CSF/plasma ratios of valine (VAL), tyrosine (TYR), PHE, and MET significantly increased to 0.21, 0.46, 0.52, and 0.52, respectively. TBAR levels increased 4-fold in the CSF and also were slightly increased in the plasma, suggesting that lipid peroxidation in the central nervous tissues is markedly increased. We conclude that increases in LNAA levels and in lipid peroxidation in the central nervous tissues may play important roles in the development of septic encephalopathy.

Effects of driving pressure and respiratory rate on airway pressure and PaCO2 in rabbits during high-frequency jet ventilation.

The effects of driving pressure (DP) and respiratory rate (RR) on mean airway pressure (Paw), Paco2, and other respiratory variables were studied during high-frequency jet ventilation (HFJV) in anesthetized rabbits. The animals were tracheotomized and paralyzed, and various combinations of RR (4, 8, 12, and 16 Hz) and DP (0.5, 1.0, and 2.0 kg/cm2) were applied randomly with an inspiratory/expiratory ratio of 1.0. HFJV was delivered via a 2.5-Fr catheter through a T-attachment, using 100% oxygen, and a hot-wire flowmeter was connected to the outlet of the T-attachment for measurement of the minute volume (MV). Heart rate, arterial BP and CVP, respiratory variables, and arterial blood gases were monitored during the study. There were no direct correlations between Paco2 and DP, MV, or RR. However, there was an inverse correlation between Paco2 and tidal volume, and linear correlations were found between Paw and DP, and between DP and MV. It is concluded that HFJV over an RR range of 4 to 16 Hz depends mainly upon tidal volume. When the desired Paco2 and Paw are determined, DP and RR can be calculated following the equations established in this study.

High-frequency jet ventilation for differential lung ventilation

High-frequency jet ventilation using a jet injector located at the right mainstem bronchus was superimposed on standard mechanical ventilation to ventilate the injured lung of a patient with unilateral massive atelectasis secondary to pulmonary hemorrhage. This technique of differential ventilation markedly improved arterial oxygenation in this patient and may prove to be a simpler modality of respiratory support in patients who have respiratory failure from unilateral lung disease.

Elimination of false-positive limulus amebocyte lysate tests in patients with hyperlipidemia.

Varying concentrations of lipopolysaccharide (LPS) and mannan suspensions were mixed with either saline or plasma from normal volunteers, heated to 100 degrees C for 10 min, and then subjected to the limulus amebocyte lysate test (LAL). A positive LAL in saline required minimum LPS and mannan concentrations of 10(-11) and 10(-5) g/ml, respectively, while the minimum concentrations premixed with plasma were 10(-13) and 10(-9) g/ml, respectively. Thus, use of plasma instead of saline increased assay sensitivity 100-fold for LPS and 10,000-fold for mannan. In the second part of the experiment, normal plasma was separated into lipid and nonlipid phases by Folchs method. LAL analysis of each phase revealed equal sensitivity for LPS and mannan in the nonlipid phase, but no sensitivity in the lipid extract. Subsequently, 200 ml of a fat emulsion (Intralipos) was administered to the normal volunteers, and LAL and lipid analyses were performed. The LAL turned positive in all volunteers. When LAL was positive, triglycerides (TG), chylomicron (Chyl), and very low-density lipoprotein (VLDL) increased significantly compared with when LAL was negative. It is concluded that plasma lipids increase the sensitivity of LAL and directly activate LAL when TG, Chyl, and VLDL concentrations are high. This effect of plasma lipids on LAL can be eliminated by extracting LPS and mannan in the nonlipid phase.