A randomized clinical trial of unfractioned heparin for treatment of sepsis (the HETRASE study): design and rationale [NCT00100308]

Jaimes, Fabián; Rosa, Gisela De La; Arango, Clara; Fortich, Fernando; Morales, Carlos; Aguirre, Daniel Camilo; Patiño, Pablo Javier

doi:10.1186/1745-6215-7-19

Cited by 12 publications

(9 citation statements)

References 35 publications

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“…22 A randomized study of unfractionated heparin administration in humans with sepsis currently is under way. 23 Finally, the present study also identified a significant decrease in PC activity from days 1 to 2, followed by a gradual increase in PC activity over time. In a study of humans with sepsis, serial PC measurements were significantly different between survivors and nonsurvivors.…”

Section: Discussionsupporting

confidence: 75%

“…In 1 study investigating heparin administration in rabbits with sepsis‐induced multiple organ failure and disseminated intravascular coagulation, heparin administration was associated with prevention of thrombocytopenia, leukopenia, and increases in plasma bilirubin and creatinine concentration 22 . A randomized study of unfractionated heparin administration in humans with sepsis currently is under way 23 …”

Section: Discussionmentioning

confidence: 99%

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Serial Evaluation of Protein C and Antithrombin in Dogs with Sepsis

Laforcade

Rozanski

Freeman

et al. 2008

Veterinary Internal Medicne

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Background: Protein C (PC) and antithrombin (AT) activities are decreased in humans with severe sepsis, and persistent changes are associated with decreased survival. In dogs with sepsis, PC and AT have been shown to be decreased at the time of diagnosis.Hypothesis: PC and AT activities change significantly over time in dogs with sepsis and may be related to outcome. Animals: Twelve dogs with naturally occurring sepsis.Methods: Blood was collected from 12 dogs with sepsis, defined as histopathologic or microbiologic confirmation of infection and two of the following: hypo-or hyperthermia, tachycardia, tachypnea, leukopenia, leukocytosis, or 43% bands. The time of 1st sampling was considered day 1 and sampling was repeated every 24 hours for 5 days or until discharge or death. Changes over time were analyzed by ANOVA with repeated measures, and the association between PC and AT and outcome was determined by a 2-equation treatment effects model.Results: Nine dogs and 11 dogs had decreased PC and AT activity on day 1, respectively (mean PC, 66.0 AE 25.8%; mean AT, 48.1 AE 16.5%). PC activity significantly decreased from day 1 to day 2 (P 5 .001), then increased over time. Changes in PC (P o .001) and AT (P o .001) over time were likely associated with outcome with nonsurvivors having lower PC and AT activities than survivors.Conclusion: Results of this preliminary study show that PC and AT activities change significantly over time in dogs with sepsis and both are likely related to survival.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Serial Evaluation of Protein C and Antithrombin in Dogs with Sepsis

Laforcade

Rozanski

Freeman

et al. 2008

Veterinary Internal Medicne

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“…In some studies, those therapies have even worsened the mortality or caused adverse events. These include: antithrombin concentrates (KyberSept trial) [24]; activated protein C (PROWLESS trial) [25]; Drotecognin Alfa (ADDRESS and PROWLESS-SHOCK trials) [26,27]; tissue factor pathway inhibitor (OPTIMIST trial) [28]; and anticoagulants [29,30]. ART-123 is a relatively new therapy aimed at restoring deleterious coagulation.…”

Section: Discussionmentioning

confidence: 99%

Human Soluble Recombinant Thrombomodulin, ART-123, Resolved Early Phase Coagulopathies, but Did Not Significantly Alter the 28 Day Outcome in the Treatment of DIC Associated with Infectious Systemic Inflammatory Response Syndromes

Mori

Sera

et al. 2019

JCM

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Disseminated intravascular coagulation (DIC) is a catastrophic systemic disorder of coagulation, resulting in uncontrollable bleeding, multiple organ failure, and death. Sepsis is one of the common causes of DIC. Despite many attempts to correct these coagulation pathologies, no adjunctive treatments have been shown to improve the mortality of DIC associated with sepsis. Although some clinical studies showed a recently developed human recombinant thrombomodulin, ART-123, might be effective in the treatment of DIC, few randomized, placebo-controlled studies have been conducted. In this study, we treated 60 DIC patients associated with systemic inflammatory response syndrome (SIRS) using ART-123 (n = 29) or saline as a placebo (n = 31). The basal clinical characteristics were similar in both groups. We compared clinical severity scores and DIC score in acute phase, and 28 day mortality between the two groups. Our study demonstrated the DIC score improved a few days earlier in the ART-123 group than the placebo group, and there were no major life-threatening adverse events in both groups. The overall survival rate at day 28 was not significantly altered. In conclusion, ART-123 can be used safely in DIC associated with infectious SIRS patients; however, its true efficacy in the treatment of DIC needs to be further investigated.

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“…Low-dose heparin infusion of 500 units/hour has been studied and confirmed efficacy versus placebo in patients with sepsis ( 17 ). This dose was preferred according to the best risk/benefit ratio to produce optimum heparin plasma concentration to activate antithrombin and decrease fibrin production without full anticoagulation and increased risk of bleeding ( 17 ). It is recommended to administer 10,000 - 15,000 units heparin per day as thromboprophylaxis in high-risk patients ( 10 ).…”

Section: Discussionmentioning

confidence: 99%

“…Endotoxin production in sepsis can cause a rise in the plasma PAI- level ( 17 ). The plasminogen activator inhibitor-1 acts as a proinflammatory mediator and up-regulates inflammatory state during sepsis ( 18 ).…”

Section: Discussionmentioning

confidence: 99%

Comparison of the Effects of Subcutaneous Versus Continuous Infusion of Heparin on Key Inflammatory Parameters Following Sepsis

et al. 2016

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BackgroundSepsis is the result of the interaction between inflammatory mediators and coagulation pathway. Unfractionated heparin may play a role as an anti-inflammatory agent beyond its anticoagulatory effect in sepsis. As a result, it may cause reduction in organ failure rate in patients with sepsis due to its impact on both inflammatory and coagulation process.ObjectivesThe aim of this study was to evaluate the anti-inflammatory effects of heparin in sepsis. Plasma plasminogen activator inhibitor-1 (PAI-1) as an inflammatory mediator and urinary necoutrophil gelatinase-associated lipocalin (NGAL) as a marker of kidney injury were investigated.Patients and MethodsThis prospective, randomized controlled trial was conducted in a 32-bed intensive care unit. Thirty patients with sepsis were randomized to receive heparin infusion of 500 units/hour or 5000 units of heparin three times a day, subcutaneously. The plasma level of PAI-1 and urinary level of NGAL were determined at day 0, 2 and 7.ResultsThe infusion group had a lower plasma PAI-1 level compared to the subcutaneous group at day 7 (11.3 ± 1.6 vs. 16.5 ± 4.2; P = 0.003). The urinary NGAL level was lower in the infusion group at day 2 (131.3 ± 11.9 vs. 151.2 ± 20.6; P = 0.014); however, at day 7 the NGAL level was decreased in the subcutaneous group as much as the infusion group and there was no significant difference between the two groups. There was no significant difference in the acute physiology and chronic health evaluation (APACHE) II and sequential organ failure assessment (SOFA) scores between the two groups at day 0, 2 and 7.ConclusionsLow-dose heparin infusion compared to subcutaneous heparin can decrease the plasma PAI-1 and urinary NGAL levels more rapidly. It can be related to anti-inflammatory effects of heparin, which may be more prominent in infusion route.

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A randomized clinical trial of unfractioned heparin for treatment of sepsis (the HETRASE study): design and rationale [NCT00100308]

Cited by 12 publications

References 35 publications

Serial Evaluation of Protein C and Antithrombin in Dogs with Sepsis

Serial Evaluation of Protein C and Antithrombin in Dogs with Sepsis

Human Soluble Recombinant Thrombomodulin, ART-123, Resolved Early Phase Coagulopathies, but Did Not Significantly Alter the 28 Day Outcome in the Treatment of DIC Associated with Infectious Systemic Inflammatory Response Syndromes

Comparison of the Effects of Subcutaneous Versus Continuous Infusion of Heparin on Key Inflammatory Parameters Following Sepsis

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