***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND Disseminated intravascular coagulation ( DIC ) is a serious complication of sepsis that is associated with a high mortality . OBJECTIVES Using the adapted International Society on Thrombosis and Haemostasis ( ISTH ) diagnostic scoring algorithm for DIC , we evaluated the treatment effects of high-dose antithrombin ( AT ) in patients with severe sepsis with or without DIC . PATIENTS AND METHODS From the phase III clinical trial in severe sepsis ( KyberSept ) , 563 patients were identified ( placebo , 277 ; AT , 286 ) who did not receive concomitant heparin and had sufficient data for DIC determination . RESULTS At baseline , 40.7 % of patients ( 229 of 563 ) had  DIC . DIC in the placebo-treated patients was associated with an excess risk of mortality ( 28-day mortality : 40.0 % vs. 22.2 % , P < 0.01 ) . AT-treated patients with DIC had an absolute reduction in 28-day mortality of 14.6 % compared with placebo ( P = 0.02 ) whereas in patients without DIC no effect on 28-day mortality was seen ( 0.1 % reduction in mortality ; P = 1.0 ) . Bleeding complications in AT-treated patients with and without DIC were higher compared with placebo ( major bleeding rates : 7.0 % vs. 5.2 % for patients with DIC , P = 0.6 ; 9.8 % vs. 3.1 % for patients without DIC , P = 0.02 ) . CONCLUSIONS High-dose AT without concomitant heparin in septic patients with DIC may result in a significant mortality reduction . The adapted ISTH DIC score may identify patients with severe sepsis who potentially benefit from high-dose AT 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 Objectives : To evaluate the safety , pharmacokinetics , and the practicability of two different antithrombin III ( AT III ) high-dose regimens in patients with severe sepsis.¶ Design : Prospect i ve , open , r and omized , 2 parallel groups , multinational clinical trial.¶ Setting : Eleven academic medical center intensive care units ( ICU ) in Austria , Belgium , Denmark , Germany , Norway and Sweden.¶ Patients : Thirty-three patients with severe sepsis who received st and ard supportive care and antimicrobial therapy , in addition to the administration of AT III.¶  Interventions : Patients received an intravenous loading dose of 6,000 IU AT III followed by either intermittent bolus infusions of 1,000 IU AT III every 4 h or a continuous infusion of 250 IU AT III/h for 4 days , result ing in a total dose for both dosage regimens of 30,000 IU AT III.¶ Measurements : All patients were evaluated for safety and all but one for pharmacokinetics.¶ Results and conclusions : The administration of AT III was safe and well tolerated . The overall 28-day all-cause mortality was 30 % ( 43 % intermittent bolus infusions ; 21 % continuous infusion ) . The mean probability of dying according to the SAPS II was 48 % . The difference in mortality between both groups was within the range of chance . AT III plasma levels were elevated from low baseline levels to above 120 % soon after onset of AT III therapy and remained at these levels for the treatment phase of 4 days . Functional and immunologic levels of AT III corresponded very well . With an overall median volume of distribution of 4.5 l ( range : 2.4–6.5 l ) , AT III only moderately extended beyond plasma . The overall median elimination half-life was 18.6 h ( range : 5.1–37.4 ) . Overall , median response was 1.75 % per IU/kg ( range : 1.14–2.8).¶The variability of elimination parameters was quite noteworthy ( CV = 41–59 % ) , whereas distribution-related parameters showed a moderate variability ( CV = 24 % ) . In spite of this variability , both high-dose IV regimens reliably provided AT III levels above 120 % for all but one patient . An increased mortality was observed for patients with a distribution volume exceeding 4.5 l ( or a response < 1.7 % per IU/kg ) . AT III distribution volumes above 4.5 l might indicate a capillary leak phenomenon . The continuous infusion regimen was slightly preferred by the investigators with regard to practicability 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 r and omized , prospect i ve study in surgical patients with severe sepsis . The study evaluated the long-term effect of AT III supplementation ( duration of treatment : 14 days ) . After r and omization ( 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 prospect i ve , r and omized , 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 r and omized 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 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 r and omized 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 AT-III LLC , a joint venture between Genzyme Transgenics ( GTC ) and Genzyme General , is developing transgenic recombinant human antithrombin III ( rhAT-III ) as a potential treatment for sepsis and other disorders involving thrombosis . It is in phase III clinical trials in the US and Europe as an anticoagulant in patients undergoing elective cardiac surgery such as cardiopulmonary bypass Objective : Sepsis is frequently associated with coagulatory activation , which may contribute to deteriorated organ function . Antithrombin is one important endogenous coagulation inhibitor that is therapeutically applied during sepsis . This study investigates the effect of 14-day antithrombin application on coagulatory variables . Design : Prospect i ve study . Setting : Surgical intensive care unit of a university hospital . Patients : Forty patients with severe sepsis . Interventions : Patients with severe sepsis were r and omly assigned to receive either conventional intensive care treatment ( n = 20 , controls ) or antithrombin substitution that aim ed at a plasma antithrombin activity ≥120 % during a long-term ( 14-day ) study period ( n = 20 , antithrombin ) . To allow comparative analysis of laboratory variables over time , all patients who did not survive the 14-day-period ( five controls and six antithrombin 
    Output:
    
In sepsis patients with DIC , administration of antithrombin concentrate may increase overall survival .