Use of antithrombin III in critical patients. Antithrombin therapy for severe preeclampsia: results of a double-blind, randomized, placebo-controlled trial. BI51.017 Study Group. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. Treatment of severe preeclampsia with antithrombin concentrate: results of a prospective feasibility study. Effect of antithrombin concentrate on haemostatic variables in critically ill patients. Controlled trial of antithrombin III supplementation in fulminant hepatic failure. A placebo-controlled randomized trial of antithrombin therapy in neonatal respiratory distress syndrome. Antithrombin III supplementation in severe sepsis: beneficial effects on organ dysfunction. A pilot study of antithrombin replacement in intensive care management: the effects on mortality, coagulation and renal function. Antithrombin III supplementation during orthotopic liver transplantation in cirrhotic patients: a randomized trial. High-dose antithrombin III treatment of severely injured patients: results of a prospective study. Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia. Results of the PAARKA study. Antithrombin III (ATIII) replacement therapy in patients with sepsis and/or postsurgical complications: a controlled double-blind, randomized, multicenter study. Antithrombin treatment in patients with traumatic brain injury: a pilot study. A prospective randomized double-blind trial of antithrombin III concentrate in the treatment of multiple-organ dysfunction syndrome during hematopoietic stem cell transplantation. Can the administration of antithrombin III decrease the risk of cerebral hemorrhage in premature infants? Double-blind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. Antithrombin III and local serum application: adjuvant therapy in peritonitis. Antithrombin III in patients with severe sepsis. A randomized, placebo-controlled, double-blind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with antithrombin III in severe sepsis.
To evaluate the effect of the AT III concentrates upon the clinical evolution and hemostatic parameters.
                Prospective, open, randomized trial.
                Septic and multiple trauma patients admitted to our Intensive Care Unit.
                Levels of AT III below 70% were used as criteria to choose 36 patients, 20 of whom received treatment with AT III and 16 did not.
                AT III concentrates were administered at an initial dose of 60 U/kg followed by 10 U/kg every six hours.
                The administration of AT III neither contributes to alterations in haemostasis, nor the clinical evolution (evaluated according to Apache II score).
                The results suggest that the administration of AT III concentrates to critical patients with acquired low levels, but without manifest DIC, may not be justified; although further studies on a larger population are required to establish definite conclusions. A double-blind, randomized, placebo-controlled trial was conducted to evaluate whether treatment with Antithrombin (AT) concentrates improved the clinical and perinatal outcome in patients with severe preeclampsia. Severe preeclamptic patients (24 to 35 weeks of gestation. Gestosis Index (GI) > or = 6 points) were randomized into two groups: 66 received AT and 67 received placebo. There were no statistical differences in the clinical profiles of the two groups. Study drugs were given intravenously once daily for 7 consecutive days. Maternal symptoms were evaluated from the difference of GI between before and after treatment, and fetal findings were evaluated from the changes of the biophysical profile score and the estimated fetal weight gain. Improvement was significantly greater in the AT group for both the GI (p = 0.020) and the estimated fetal weight gain (p = 0.029). The improvement of coagulation parameters was also evaluated. The D-dimer levels increased significantly in the placebo group (p = 0.026), but did not change in the AT group. Gestation was significantly prolonged (p = 0.007), and the number of low-birth weight infants was significantly smaller (p = 0.011) in the AT group. No adverse events related to AT were observed. It is revealed that AT concentrate therapy for preeclampsia is effective and safe, leading to an improved perinatal outcome. 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.
                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.
                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.
                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).
                All-cause mortality 28 days after initiation of study medication.
                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).
                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. The prospective feasibility study was designed to determine whether treatment with antithrombin (AT) concentrates could be used for patients with severe preeclampsia to provide clinical efficacy without the full systemic antihypertensive drug. Twenty-nine severe preeclamptic patients (24 to 36 weeks of gestation, gestosis index [GI] >/= 6 points) were randomized to receive AT (1500 U/day) or not. AT was given intravenously once daily for 7 consecutive days. Twenty-four hours of continuous infusion of 5000 U/day of unfractionated heparin was given simultaneously in both groups. There were no statistical differences in the clinical profiles of the two groups. Maternal symptoms were evaluated from the difference of GI before and after treatment, and fetal findings were evaluated from the changes of the biophysical profile score. Improvement was significantly greater in the AT group for both the GI ( P = 0.046) and the biophysical profile score ( P = 0.022). The improvement of coagulation parameters was also evaluated. The improvement of plasmin-plasmin inhibitor complex (PPIC), D-dimer levels, and platelet counts was observed in the AT group compared with the non-AT group. The coagulation index as a composite coagulation test parameter showed a significantly improvement in the AT group. No adverse events related to AT were observed. Given that AT plus heparin was significantly better than treatment with heparin alone for improvement of both GI and biophysical profile of infant, it is suggested that therapy with AT alone might be effective enough for severe preeclampsia. In a controlled pilot study of 32 critically ill patients, we have attempted prospectively to identify laboratory variables which can be used to select and monitor patients on antithrombin (AT) therapy. Patients with plasma AT levels less than 70% of normal were randomized to receive (AT group) or not to receive AT concentrate (non-AT group). The groups did not differ in median age, sex, median APACHE II and TISS scores, number of days spent in the Intensive Care Unit or mortality rate. At the time of inclusion all patients had activated coagulation and fibrinolysis demonstrated as high levels of soluble fibrin, thrombin-antithrombin complexes and fibrin-D-dimers (twice, four and ten times the upper reference range, respectively). In the AT group these levels decreased faster and the prothrombin complex concentration increased more rapidly to normal (i.e. the prothrombin time decreased). The level of C-reactive protein which was high in both groups on inclusion (139 and 98 mg/l, respectively) decreased by 40% in the AT group but did not change in the control group. Our study indicates that laboratory variables normalize faster in seriously ill patients who have activated coagulation and fibrinolysis when they receive AT concentrate and that the variables mentioned above seem to be useful for monitoring the treatment. Patients with fulminant hepatic failure have severe circulatory disturbances which may be due to fibrin and cellular plugs in micro-vessels which are a consequence of intravascular coagulation and which can lead to multiorgan failure. Since antithrombin III supplementation has been shown to be beneficial in animal models of septic shock with disseminated intravascular coagulation, a controlled study was performed to investigate the effect of antithrombin III supplementation in fulminant hepatic failure. Twenty-five patients in grade III or IV coma were selected on the basis of evidence of sepsis, intravascular coagulation and a high risk of developing multiorgan failure. Thirteen patients received 3000 units of antithrombin III (Kybernin P; Behringwerke), followed by a further 1000 units every 6 h. Antithrombin III activity increased from 0.26 +/- 0.04 SE U/ml to 0.82 +/- 0.07 U/ml at 3 h post infusion (normal range 0.80-1.20 U/ml) and remained greater than 0.80 U/ml throughout the study without any apparent increase in the frequency of bleeding. However, survival was not improved and markers of intravascular coagulation remained similar between the two groups. Thus, although the antithrombin III deficiency in fulminant hepatic failure can be corrected by supplementation with antithrombin III concentrate, its use in the prevention of intravascular coagulation and to avoid microvessel plugging needs to be studied at an earlier stage in the disease. Neonatal respiratory distress syndrome (RDS) is associated with decreased plasma activity of antithrombin (AT) and increased formation of thrombin. We tested whether AT reduces thrombin formation, improves gas exchange, and decreases the duration of mechanical ventilation and supplemental oxygen. One hundred twenty-two infants were randomized to pasteurized AT concentrate or to placebo. Two ml/kg (equivalent to 100 IU AT/kg) were followed by 1 ml/kg (50 IU/kg) every 6 h for 48 h. Outcome measures included plasma AT activity, thrombin-AT (TAT) complex, prothrombin fragment (F1+2), the ratio of arterial to alveolar oxygen pressure [(a/A)PO2], and the ventilator efficiency index (VEI). In the AT group (n = 61), mean (SD) birth weight was 1,198 (301) g, mean (SD) gestational age (GA) was 28.3 (2.0) wk, 54% were male. In the placebo group (n = 61), mean (SD) birth weight was 1,201 (315) g, mean (SD) GA was 28.8 (2. 3) wk, 51% were male. In treated infants, AT activity was raised to means of 1.69 and 2.25 U/ml at 24 and 48 h, respectively. Corresponding means in control infants were 0.37 and 0.44 U/ml (p < 0.0001). F1+2, but not TAT, was significantly reduced by AT (p = 0. 004). VEI and (a/A)PO2 were similar in both groups throughout the first week of life. Median days receiving mechanical ventilation were 7.1 (AT) versus 4.8 (placebo), p = 0.0014. Median days receiving supplemental oxygen were 7.9 (AT) versus 5.5 (placebo), p < 0.0001. There were seven (11.5%) deaths in the AT group and three (4.9%) deaths in the placebo group. We conclude that treatment with AT cannot be recommended in premature infants with RDS. Activation of thrombin and of the coagulation system plays an important role in the pathophysiology of sepsis-associated organ dysfunction. Antithrombin III (AT III) is a natural inhibitor of thrombin, a central procoagulatory factor with pleiotropic activities. Experimental supplementation of AT III improved coagulation parameters and ameliorated organ dysfunction. To determine whether long-term AT III supplementation has beneficial effects on organ function, we conducted a randomized, prospective study in surgical patients with severe sepsis. The study evaluated the long-term effect of AT III supplementation (duration of treatment: 14 days). After randomization (AT III vs. control group), AT III was infused continuously over 14 days to obtain plasma AT III activities > 120%. Forty consecutive patients were recruited (20 AT III/20 control group). Eleven patients had a rapid fatal course and did not met the criterion of a 14 day treatment period. From these 11 patients, 8 patients (5 AT III/3 control group) died within 72 h due to septic shock. The remaining 14 AT III patients and 15 controls survived 14 days and showed no differences in baseline parameters of organ function. AT III caused a disappearance of disseminated intravascular coagulation (DIC) in all patients with DIC, whereas in control patients, the frequency of DIC remained constant (p < .05). In AT III patients a progressive increase in oxygenation index (PaO2/FiO2 ratio) and a continuous decrease in pulmonary hypertension index (mean pulmonary artery pressure/mean arterial pressure (PAP/MAP) ratio) indicated an improvement of lung function (p < .05 vs. control). AT III prevented the continuous rise in total serum bilirubin concentration observed in control patients and diminished the frequency of artificial renal support therapy (p < .05). Long-term supplementation with AT III may improve lung function and prevent the development of septic liver and kidney failure in patients with severe sepsis. A prospective, randomized, controlled trial to examine the effects of antithrombin supplementation on mortality, coagulation and renal function has been carried out on 132 intensive care patients. Antithrombin activity was measured in all patients on admission to the intensive care unit (ICU). Patients with an antithrombin activity of less than 70% were randomized to either receive antithrombin replacement or to act as controls. Antithrombin activity was maintained above 70% in the treated patients throughout their stay on ICU. Ninety-three patients had an antithrombin activity of less than 70% and 35 received replacement therapy. Patients with antithrombin activity below 70% remained on the ICU significantly longer and had a significantly higher mortality rate than patients with antithrombin activity above 70%. Antithrombin supplementation neither reduced mortality nor shortened the intensive care stay. Fifty patients with reduced antithrombin activity remained on the ICU for at least 4 days, 25 received antithrombin and 25 acted as controls; coagulation parameters and renal function have been monitored in these patients. Fibrinogen concentration and platelet count were unaffected by antithrombin replacement. Antithrombin supplementation did not appear to reduce the incidence of impaired renal function in sepsis, trauma and postoperative patients. The creatinine clearance fell below 20 ml/min in eight patients in the no-treatment arm while by comparison only three patients in the treatment arm developed impaired renal function. Our study does not demonstrate a clear role for the use of antithrombin supplementation in intensive care, however the finding that antithrombin reduced renal impairment is encouraging and a larger study to confirm this finding is at present underway. Severe intraoperative bleeding is one of the main problems during liver transplantation. Acquired hemostatic defects, namely primary or secondary hyperfibrinolysis, are considered significant pathogenetic events. Antithrombin III (ATIII), the main physiological serine protease inhibitor, has a critical role in the regulation of hemostasis. 29 patients with post necrotic cirrhosis undergoing liver transplantation were randomized to receive or not ATIII replacement therapy before the induction of anaesthesia and thereafter throughout surgery. Activation of both coagulation and fibrinolysis (increase of thrombin-antithrombin complexes, fibrin and fibrinogen degradation products) were demonstrated in both groups. Blood loss and transfusion requirements were not affected by ATIII administration. Antithrombin III (AT III) treatment has been shown to reduce disseminated intravascular coagulation and to inhibit thrombin, which plays a central role in the activation of platelets and other inflammatory systems in conditions with severe inflammation. The objective of this study was to evaluate the influence of early and high-dose administration of AT III to patients with severe multiple injuries on the inflammatory response and outcome.
                In a placebo-controlled, double-blind study, 40 consecutive patients with Injury Severity Scores of 29 or greater who met the inclusion criteria were randomized to receive either AT III or placebo within 360 minutes after trauma. Twenty patients were administered AT III for a period of 4 days, aiming to achieve AT III concentrations of 140% of normal.
                The AT III and placebo groups were comparable with respect to Injury Severity Score, age, incidence of blood pressure less than 80 mm Hg on admission, initial base deficit, and start of the test drug. The patients in the AT III group received a total of about 20,000 IU during the first 4 days. AT III levels of 130 to 140% could be achieved by this regimen, whereas in the control group the AT III concentration averaged about 70%. In the AT III group prothrombin tended to be elevated and prothrombin fragment F1+2 as well as thrombin-AT III complex tended to be lower on the first day. No differences between groups, however, could be observed with respect to partial thromboplastin time, prothrombin time, platelets, plasminogen activator inhibitor I, soluble tumor necrosis factor receptor II, neutrophil elastase, interleukin (IL)-1 receptor antagonist, IL-6, and IL-8. Mortality (15 vs. 5%), incidence of respiratory failure (55 vs. 55%), duration of mechanical ventilation (13 vs. 12 days), and length of stay in the surgical intensive care unit (19 vs. 21 days) were also similar in both treatment groups. The duration of organ failure, however, was shorter in the patients receiving AT III.
                The early and high-dose administration of AT III to patients with severe blunt trauma appears not to attenuate the posttraumatic inflammatory response or to significantly improve outcome. An association has been reported between thrombotic events and the use of L-asparaginase (ASP) in children with acute lymphoblastic leukaemia (ALL). The mechanism for thrombosis is likely related to an acquired antithrombin deficiency. Since a primary prophylaxis using antithrombin concentrates may prevent thrombosis, the PARKAA (Prophylactic Antithrombin replacement in kids with ALL treated with L-asparaginase) study was performed. The objectives of PARKAA were to determine if there was a trend to efficacy and safety of antithrombin treatment as assessed by 1) incidence of thrombosis 2) incidence of bleeding and 3) plasma markers of endogenous thrombin generation as surrogate outcomes for thrombosis. The study was not powered to answer the question of efficacy and safety, but rather to detect a trend. PARKAA was an open, randomised, controlled study in children with ALL being treated with ASP. Children were randomised to receive antithrombin infusions or no antithrombin treatment. All thrombotic events were confirmed using bilateral venography, ultrasound, echocardiography and MRI. The incidence of thrombosis in patients treated with antithrombin was 28% (95% CI 10-46%), compared to 37% (95% CI 24-49%) in the non treated arm. Two minor bleeds occurred in patients in the treated arm, but were not considered to be related to antithrombin. No significant differences were seen in plasma markers by the treatment group. In conclusion, treatment with antithrombin concentrate shows a trend to efficacy and safety. In contrast, there was no difference in surrogate markers for thrombosis. Carefully designed clinical trials are needed to test the efficacy and safety of antithrombin in this population. ATIII is decreased in sepsis and/or shock and its baseline value correlates with mortality. The efficacy of ATIII therapy on mortality was assessed in a selected group of patients admitted to the intensive care unit (ICU) in a double-blind, randomized, multicenter study.
                120 patients admitted to the ICU with an ATIII concentration < 70% were randomized to receive ATIII (total dose 24000 units) or placebo treatment for 5 days; 56 patients had septic shock.
                ATIII concentrations in the treated group remained constant throughout the treatment period (range 97-102%). The Kaplan-Meier analysis showed no difference in overall survival between the two groups: 50 and 46% for ATIII and placebo, respectively. Septic shock and hemodynamic support were unbalanced in the two groups at admission. Therefore the Cox analysis was carried out after adjusting for these two variables. Treatment with ATIII decreases the risk of death with an odds ratio (OR) of 0.56. Of the covariates analyzed, septic shock and the baseline multiple organ failure score were negatively associated with survival and plasma activity level was positively associated with survival with an OR of 0.97 for each 1% increase in the ATIII plasma concentration at baseline.
                The results of ATIII treatment in this population of patients suggests that replacement therapy reduces mortality in the subgroup of septic shock patients only. This study will determine if early administration of antithrombin concentrate to patients with traumatic brain injury (TBI) can inhibit or significantly shorten the time of coagulopathy. The progress of brain injury monitored by computed tomographic scan (CT) was also assessed, as was the time needed for intensive care and outcome related to Glasgow outcome scale (GOS). Twenty-eight patients with isolated brain trauma verified with CT were included in either of two parallel groups. The Glasgow coma score (GCS) was mean 7.5, and median 7.0; signifying a moderate to severe traumatic brain injury but with a mortality of only 3.5%. The patients randomized to antithrombin treatment received a total of 100 U/kg BW during 24 hours. To measure hypercoagulability, soluble fibrin (SF), D-dimer (D-d), and thrombin-antithrombin complex (TAT) were assessed together with antithrombin (AT) and routine coagulation tests. Before treatment, SF, D-d, and TAT were markedly increased in both groups. Soluble fibrin and D-dimer (measured after treatment began) appeared to decrease faster in the AT group, and there was a statistically significant difference between the groups at 36 hours for SF and at 36 hours, 48 hours, and at Day 3 for D-d. Thrombin-antithrombin complex levels were very high in both groups but, surprisingly, showed no significant difference between the groups. The authors conclude that antithrombin concentrate administered to patients with severe TBI resulted in a marginal reduction of hypercoagulation. We could not detect any obvious influence by antithrombin on brain injury progress, on CT, or on outcome or time needed for intensive care. Many of the complications of high-dose therapy with hematopoietic stem cells are caused by or lead to the multiple-organ dysfunction syndrome (MODS). In hematopoietic stem cell transplantation (HSCT), acquired antithrombin III (ATIII) deficiency is independently associated with MODS to the exclusion of transplant type, preparative regimen, and bacteremia. In experimental settings, replacement of ATIII can ameliorate the severity of MODS that develops in response to a variety of pathologic stimuli, suggesting that ATIII supplementation might improve the clinical course of MODS in patients undergoing HSCT. We performed a study to determine if ATIII can improve the morbidity of MODS in HSCT. Forty-nine patients undergoing HSCT, who developed pulmonary dysfunction (oxygen saturation of <90%), central nervous system dysfunction (drop of >4 points in the mini-mental status exam), or hepatic dysfunction (bilirubin >34 micromol/L [2.0 mg%], weight gain of >5% over baseline, and abdominal pain, possibly of hepatic origin) with a concomitant ATIII activity of <84% were double-blind randomized to receive ATIII concentrate, 70 units/kg within 24 hours of recognition of initial organ dysfunction followed by 50 units/kg 8, 16, 48, and 72 hours later, or albumin placebo. The group randomized to ATIII had a lower severity-of-illness score (15.7 +/- 19.2 vs. 28.6 +/- 25.2, p = 0.03), shorter duration of hospitalization (14.9 +/- 16.7 vs. 25.7 /- 17.9 days, p = 0.03), and lower hospital charges ($138,700 +/- $23,500 vs. $206,400 +/- $34,000). ATIII concentrate was associated with improved morbidity of MODS in patients undergoing HSCT when given early in the evolution of the syndrome. This study was carried out to determine whether the administration of antithrombin III decreases the risk of intraventricular hemorrhage in premature infants. In a randomized study, 60 infants born before 30 weeks of gestation were assigned to receive a loading dose of antithrombin III or placebo. There was no significant difference in the incidence of intraventricular hemorrhage between the antithrombin III and the placebo group (27.5 vs. 32%). Partial thromboplastin time, Quick's prothrombin time and platelet count were also not significantly different between the 2 groups. We conclude that the administration of antithrombin III during the first 2 days of life does not decrease incidence of intraventricular hemorrhage. Antithrombin III is a very expensive therapy and its benefits should be carefully investigated before being recommended as valuable therapy.
                Copyright 2003 S. Karger AG, Basel Septic shock is frequently complicated by a syndrome of disseminated intravascular coagulation (DIC). Numerous uncontrolled clinical studies have reported that antithrombin III (ATIII) substitution might prevent DIC and death in septic shock.
                We conducted a randomized double-blind placebo-controlled trial in patients with a documented septic shock and DIC. The patients received either a placebo or ATIII (90 to 120 IU/kg in loading dose, then 90 to 120 IU/kg/d during 4 days). Administration of fresh frozen plasma, platelets, and fibrinogen concentrates was restricted to patients with hemorrhages and severe decreases in prothrombin time, platelet count, and fibrinogen levels.
                Thirty-five patients entered the study (18 placebo, 17 ATIII). Both groups were well balanced for all demographic, hemodynamic, and biologic data. Three patients were excluded before the treatment allocation code was broken. In the ATIII group, ATIII levels were rapidly corrected and remained over normal levels until day 10; sequential protein C and protein S levels were not modified. The duration of DIC was significantly reduced: in the ATIII group, 64 percent of patients were cured of DIC at day 2, and 71 percent were cured at the end of treatment vs in the placebo group, 11 percent (p < 0.01) and 33 percent (p < 0.05), respectively. In the 32 included patients, the mortality in ICU was reduced by 44 percent in the ATIII group (p = 0.22, NS). Care loads and transfusion requirements were not different. No side effect was observed.
                Mortality was reduced by 44 percent in this trial, but the difference did not reach the statistical significance. Circulating protein C and protein S levels were not modified by ATIII supplementation. High doses of ATIII concentrates significantly improved sepsis-induced DIC during septic shock. The trend toward improved survival suggests further randomized studies. Patients with diffuse peritonitis show an overall mortality of about 20%, probably caused by the breakdown of local defence mechanisms combined with a systemic outspread of bacteria and toxins, which often results in sepsis syndrome.
                In a prospective, randomized, controlled study 50 patients with diffuse secondary peritonitis were included. Patients in the therapy group were treated with an adjuvant medication consisting of a continuous intravenous infusion of antithrombin III and two intraperitoneal instillations of fresh frozen human donor serum. The aim of the study was the reduction of mortality and incidence of multiple organ failure.
                Mean antithrombin III plasma levels in the therapy group were raised above 140% for 4 days and were significantly higher than in the control group. With the intraperitoneal application of fresh frozen serum and antithrombin III opsonic capacity as well as thrombin, inhibitory activity in the exudate could be significantly elevated over 2 days. The 90-day-mortality rate was 6/26 (23%) in the control group and 6/24 (25%) in the therapy group. Although no improvement of mortality was achieved, a slight but not significant reduction of the severity of the multiple organ failure was seen.
                The chosen therapeutic approach was feasible and showed no side-effects. Yet, neither mortality nor multiple organ failure were significantly improved by the applied short-term adjuvant therapy. Thus, for future trials in severely-ill patients a longer treatment period and/or combinations of antithrombin III with other anti-inflammatory agents should be considered. To evaluate the safety and potential efficacy of antithrombin III (AT III) in reducing mortality in patients with severe sepsis.
                Prospective, randomized, placebo-controlled, double-blind, phase II, multicenter, multinational clinical trial.
                Seven academic medical center intensive care units (ICU) in Belgium, Denmark, the Netherlands, Norway and Sweden.
                42 patients with severe sepsis who received standard supportive care and antimicrobial therapy, in addition to the administration of AT III or placebo.
                Patients received either an intravenous loading dose of 3000 IU AT III followed by a maintenance dose of 1500 IU every 12 h for 5 days or equivalent amounts of placebo.
                All patients were evaluated for safety and for 30-day all-cause mortality.
                The administration of AT III was safe and well-tolerated. It was followed by a 39 % reduction in 30-day all-cause mortality (NS). The reduction in mortality was accompanied by a considerably shorter stay in the ICU. Patients treated with AT III exhibited a better performance in overall severity of illness and organ failure scores (Acute Physiology and Chronic Health Evaluation II, multiple organ failure, organ system failure), which was noticeable soon after initiation of treatment. Patients treated with AT III demonstrated a better resolution of pre-existing organ failures and a lower incidence of new organ failures during the observation period. A meta-analysis comprising this and two other double-blind, placebo-controlled trials with AT III with a total of 122 patients suffering from severe sepsis confirms the positive trend. The results of the meta-analysis demonstrate a 22.9 % reduction in 30-day all-cause mortality in patients treated with AT III. Although still too small to be confirmative, the meta-analysis clearly points to the fact that a sufficiently powered phase III trial is warranted to prove whether AT III has a beneficial role in the treatment of severe sepsis.
AT III cannot be recommended for critically ill patients based on the available evidence. A randomized controlled trial of AT III, without adjuvant heparin, with prespecified inclusion criteria and good bias protection is needed.