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Steroids in Septic Shock
Published in Stephen M. Cohn, Alan Lisbon, Stephen Heard, 50 Landmark Papers, 2021
However, in the same issue of the New England Journal of Medicine was another study (APROCCHSS) where patients (n = 1241) with septic shock were treated with either placebo or hydrocortisone plus fludrocortisone. (Drotrecogin alfa was initially included in the 2 × 2 study design but was dropped when the drug was removed from the market.) the investigators found that treatment with 50 mg of IV hydrocortisone every 6 hours and 50 mg of fludrocortisone via nasogastric tube every day resulted in lower 90-day mortality. In addition, vasopressor-free and organ-failure-free days were significantly higher in the steroid group.
Septic shock
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Bryan E. Freeman, Michael R. Foley
Activated protein C therapy [also known as recombinant human activated protein C (rhAPC), drotrecogin alfa] should be based upon the diagnosis of the patient and their Acute Physiology and Chronic Health Evaluation (APACHE) II score. The APACHE II score is a tool used to assess the severity of disease in adults admitted to intensive care units and is based upon physical assessment of patients during the first 24 hours of their admission. Patients with severe sepsis, an APACHE II score >25 or multiple organ failure, and who are deemed to be at high risk of death should receive rhAPC, assuming that they have no contraindications. On the other hand, patients with severe sepsis, an APACHE II score <20 or single organ failure, and who are at low risk for death should not receive rhAPC therapy (12). These recommendations are consistent with conclusions from the Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group, published in 2005 (16).
Complications of Hypovolemic and Septic Shock
Published in Stephen M. Cohn, Matthew O. Dolich, Complications in Surgery and Trauma, 2014
Meghann L. Kaiser, Matthew O. Dolich
The coagulopathy associated with septic shock is typified by diffuse intravascular coagulation (DIC), a consumptive exhaustion of clotting factors and platelets compounded by microvascular obstructive thrombi, thus worsening end-organ hypoperfusion. Diagnosis of DIC can be made on the basis of the International Society on Thrombosis and Haemostasis (ISTH) scoring system incorporating platelet count, fibrinogen level, prothrombin time, and fibrin split product level. A peripheral blood smear demonstrating megakaryocytes and schistocytes supports the diagnosis. Knowledge of this pathogenesis prompted an interest in recombinant activated protein C (drotrecogin alpha), to inhibit disordered coagulation. While initial experience with this therapy in the PROWESS trial showed potential to improve organ function, the follow-up multicenter randomized controlled PROWESS–SHOCK trial as well as a Cochrane meta-analysis demonstrated no survival benefit. In light of the risk of associated bleeding complications, drotrecogin alpha was withdrawn from the market in 2011.36 The OPTIMIST trial of tissue factor pathway inhibitor (TFPI, or tifacogin) for septic shock was likewise disappointing, as were monoclonal antibodies to TNF-α. Investigators continue to pursue other avenues, but addressing the underlying etiology of sepsis remains the best therapeutic approach for DIC at this time.
Role of the inflammatory response in community-acquired pneumonia: clinical implications
Published in Expert Review of Anti-infective Therapy, 2022
Alexander Rombauts, Gabriela Abelenda-Alonso, Guillermo Cuervo, Carlota Gudiol, Jordi Carratalà
The modulation of coagulation pathways has been studied extensively in animal models, with evidence that an attenuated coagulant response is related to increased survival. However, most studies performed in humans have failed to reproduce these results and did not show clear benefits. Tifacogin, a recombinant tissue factor pathway inhibitor, acts as an anticoagulant that prevents thrombin generation and proinflammatory intracellular signaling, thus reducing endothelial injury. A phase II study showed a small reduction in mortality [142]. Unfortunately, the large CAPTIVATE multicenter clinical trial showed a negative result, even when using well-defined subgroups [143]. Drotrecogin alfa (activated) is a recombinant form of activated protein C that has antithrombotic and anti-inflammatory properties. The PROWESS-SHOCK trial, in which the lung was the primary site of infection in almost half of the patients, also failed to demonstrate any benefit [144], resulting in drotrecogin being shelved. The SCARLET trial, involving 816 patients, also showed that giving a human recombinant thrombomodulin could not reduce 28-day all-cause mortality [145].
Non-antibiotic therapies for sepsis: an update
Published in Expert Review of Anti-infective Therapy, 2019
Jean-Louis Vincent, Wasineenart Mongkolpun
Another general host response target has been the coagulation system. Drotrecogin alfa is no longer available after a negative trial in patients with shock [46], but thrombomodulin has been studied recently with some encouraging results. Thrombomodulin is a cofactor in the activation of protein C and has anticoagulant, anti-fibrinolytic and anti-inflammatory properties [47]. A phase II study indicated that patients with sepsis and coagulopathy may perhaps benefit from recombinant human soluble thrombomodulin [48] and a large study in 800 patients has been recently completed which indicated a 9% relative reduction in mortality (26.8 vs. 29.4%) [49]; although not a statistically significant difference, these results are still encouraging – a subgroup analysis indicated that patients with persisting coagulopathy at the time of initiation of therapy may benefit most (Vincent JL, presented at ESICM, 24 October 2018). The particularity about this immunomodulatory therapy is that a biomarker is available (coagulopathy) that can help to identify patients who will respond to the therapy, which has been missing for many of our past interventions.
Emerging therapeutic targets for sepsis
Published in Expert Opinion on Therapeutic Targets, 2021
Elizabeth W. Tindal, Brandon E. Armstead, Sean F. Monaghan, Daithi S. Heffernan, Alfred Ayala
Drotrecogin alfa is a recombinant form of human activated protein C (APC) and was FDA-approved in 2001 for use in sepsis after the PROWESS study demonstrated a mortality benefit [34]. However, further study including the follow up PROWESS-SHOCK trial failed to confirm these findings even in the highest risk septic patients and the drug was ultimately removed from the market in 2011(Table 1) [35].