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Context: Activation of the coagulation system and depletion of endogenous anticoagulants are frequently found in patients with severe sepsis and septic shock. Diffuse microthrombus formation may induce organ dysfunction and lead to excess mortality in septic shock. Antithrombin III may provide protection from multiorgan failure and improve survival in severely ill patients.Objective: To determine if high-dose antithrombin III (administered within 6 hours of onset) would provide a survival advantage in patients with severe sepsis and septic shock.Design and Setting: Double-blind, placebo-controlled, multicenter phase 3 clinical trial in patients with severe sepsis (the KyberSept Trial) was conducted from March 1997 through January 2000.Patients: A total of 2314 adult patients were randomized into 2 equal groups of 1157 to receive either intravenous antithrombin III (30 000 IU in total over 4 days) or a placebo (1% human albumin).Main Outcome Measure: All-cause mortality 28 days after initiation of study medication.Results: Overall mortality at 28 days in the antithrombin III treatment group was 38.9% vs 38.7% in the placebo group (P =.94). Secondary end points, including mortality at 56 and 90 days and survival time in the intensive care unit, did not differ between the antithrombin III and placebo groups. In the subgroup of patients who did not receive concomitant heparin during the 4-day treatment phase (n = 698), the 28-day mortality was nonsignificantly lower in the antithrombin III group (37.8%) than in the placebo group (43.6%) (P =.08). This trend became significant after 90 days (n = 686; 44.9% for antithrombin III group vs 52.5% for placebo group; P =.03). In patients receiving antithrombin III and concomitant heparin, a significantly increased bleeding incidence was observed (23.8% for antithrombin III group vs 13.5% for placebo group; P<.001).Conclusions: High-dose antithrombin III therapy had no effect on 28-day all-cause mortality in adult patients with severe sepsis and septic shock when administered within 6 hours after the onset. High-dose antithrombin III was associated with an increased risk of hemorrhage when administered with heparin. There was some evidence to suggest a treatment benefit of antithrombin III in the subgroup of patients not receiving concomitant heparin. [ABSTRACT FROM AUTHOR]

To establish whether a general dysfunction, i.e., an increase in permeability, had occurred in 16 trauma patients (6 with adult respiratory distress syndrome [ARDS]), we measured beta 2-microglobulin (beta 2MG), myoglobin (MG), immunoglobulin G (IgG), and transferrin (TF) concentrations in bronchoalveolar lavage fluid (BAL), serum, and urine as well as extravascular lung water content (EVLW) over a period of 14 days. Our results show a positive correlation (p = 0.03) between increases of EVLW, reflecting lung edema, and beta 2MG concentrations in urine of all patients with ARDS, indicating systemically increased permeability. Generalized increase of permeability can also explain the elevation of MG urine concentrations (p = 0.03) together with an EVLW increase, and an increase of BAL protein concentrations (IgG, TF, p less than 0.01) in the early post-trauma phase during the first 48 h after admission. In contrast, commonly used kidney function tests remained unchanged over the time course of 14 days.

The effect of cimetidine, a histamine H2 receptor antagonist, was investigated in 12 healthy volunteers over a period of six weeks. Cimetidine was administered orally in a daily doses of 1,600 mg during the first three weeks of evaluation. Significant alterations in values of immunoglobulins (IgG, IgA), complement (C3), B-lymphocytes and T-helper cell counts were found after cimetidine intake. The in vitro lymphocyte proliferation response to plant mitogens was increased. In contrast to results obtained from a previous study with healthy volunteers who were given 800 mg cimetidine, we found no significant increase in the CD4/CD8 ratio and no decrease in the CD8 but a significant increase in the CD4 cell count. Whereas the peripheral blood immune system showed signs of immune system activation following 800 and 1,600 mg cimetidine intake, reactivity patterns of skin immune system, however, differed in both studies. The data suggests that cimetidine has a dose and time dependent effect on the immune system.

Lymphocyte subpopulations were determined in blood samples from blood donors (40 women and 45 men) using immunofluorescence microscopy and flow cytometric methodologies. The study demonstrates the value of both methods for the enumeration of lymphocyte subpopulations. The advantages of employing an automated flow cytometer system are better precision and speed. The automated systems require a large initial technical and financial burden and are therefore probably destined to be reserved for the larger laboratory. There is a need for an adequate lymphocyte standard which shows little variation between aliquots and can be used for interlaboratory comparisons.

Changes in the expression of T-lymphocyte membrane antigens are seen in many diseases, particularly in autoimmune diseases. The reliability of these parameters, as well as their changes associated with age and sex, were examined in 232 healthy subjects using monoclonal antibodies of the OKT series. The precision of the indirect immunofluorescence method for determining the T3, T4 and T8 antigens (corresponding antibodies OKT 3, OKT 4, OKT 8) is within a range expected for biological testing methods (median variation coefficients 7-20%). In both sexes a statistically significant reduction of the T3+ cells (P = 0.0001; T-lymphocytes) and of the T8+ cells (P = 0.0004; T-suppressor lymphocytes) was seen with increasing age. In women (n = 115) the rate of T3+ and T4+ cells was 2-5% higher on the average (the T4+ cell population contains T-helper lymphocytes). According to these findings there is a statistically significant increase of the T4+ to T8+ cell ratio (P = 0.0001); due to the greater number of helper cells, the average T4/T8 quotients are greater in women than in men (P = 0.0076). The changes in the ratio of T-helper to T-suppressor cells are discussed as predisposing factors in the genesis of autoimmune diseases.