Extended Evaluation of Recombinant Human Activated Protein C United States Trial (ENHANCE US)

Bernard, Gordon R.; Margolis, Benjamin D.; Shanies, Harvey M.; Ely, E. Wesley; Wheeler, Arthur P.; Levy, Howard; Wong, Kar; Wright, Theressa J.

doi:10.1378/chest.125.6.2206

Cited by 144 publications

(17 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Despite confirmation of the results for severe sepsis patients with a high risk of death in the ENHANCE US trial, the absence of an effect of APC on mortality in patients with sepsis with a lower risk of death in the ADDRESS trial indicates that the currently employed APC therapeutic regimen has its limitations (49,50). Implementation of more aggressive APC dosing regimen to increase its therapeutic efficacy is hampered by a low but significant increase in serious bleeding events associated with administration of APC for sepsis (18,51).…”

Section: Discussionmentioning

confidence: 99%

Activated Protein C Mutant with Minimal Anticoagulant Activity, Normal Cytoprotective Activity, and Preservation of Thrombin Activable Fibrinolysis Inhibitor-dependent Cytoprotective Functions

Mosnier

Yang

Griffin

2007

Journal of Biological Chemistry

110

127

View full text Add to dashboard Cite

Activated protein C (APC) reduces mortality in severe sepsis patients and exhibits beneficial effects in multiple animal injury models. APC anticoagulant activity involves inactivation of factors Va and VIIIa, whereas APC cytoprotective activities involve the endothelial protein C receptor and protease-activated receptor-1 (PAR-1). The relative importance of the anticoagulant activity of APC versus the direct cytoprotective effects of APC on cells for the in vivo benefits is unclear. To distinguish cytoprotective from the anticoagulant activities of APC, a protease domain mutant, 5A-APC (RR229/230AA and KKK191-193AAA), was made and compared with recombinant wild-type (rwt)-APC. This mutant had minimal anticoagulant activity but normal cytoprotective activities that were dependent on endothelial protein C receptor and protease-activated receptor-1. Whereas anticoagulantly active rwt-APC inhibited secondaryextended thrombin generation and concomitant thrombindependent activation of thrombin activable fibrinolysis inhibitor (TAFI) in plasma, secondary-extended thrombin generation and the activation of TAFI were essentially unopposed by 5A-APC due to its low anticoagulant activity. Compared with rwt-APC, 5A-APC had minimal profibrinolytic activity and preserved TAFI-mediated anti-inflammatory carboxypeptidase activities toward bradykinin and presumably toward the anaphlatoxins, C3a and C5a, which are well known pathological mediators in sepsis. Thus, genetic engineering can selectively alter the multiple activities of APC and provide APC mutants that retain the beneficial cytoprotective effects of APC while diminishing bleeding risk due to reduction in APC's anticoagulant and APC-dependent profibrinolytic activities.

show abstract

Section: Discussionmentioning

confidence: 99%

Activated Protein C Mutant with Minimal Anticoagulant Activity, Normal Cytoprotective Activity, and Preservation of Thrombin Activable Fibrinolysis Inhibitor-dependent Cytoprotective Functions

Mosnier

Yang

Griffin

2007

Journal of Biological Chemistry

110

127

View full text Add to dashboard Cite

show abstract

“…A 36-hour window was allowed to establish a clinical diagnosis of sepsis, obtain the necessary written informed consent from the patients and randomize the patients. The diagnosis of sepsis was made on the basis of the criteria previously defined by Bone et al [24] and as modified by Bernard et al [25]. The following were considered exclusion criteria: severe sepsis (sepsis associated with at least one organ failure) and septic shock (sepsis associated with hypotension despite adequate fluid resuscitation) at baseline, a clinical diagnosis of sepsis for more than 36 hours, pregnancy or breastfeeding, patients younger than 18 years of age, significant limitation of survival prognosis (patients expecting with a life survival expectancy less than 28 days because of a chronic and/or incurable disease such as uncontrolled cancer or other terminal disease), preexisting chronic renal insufficiency and need of hemodialysis or peritoneal dialysis, body mass index (BMI) ≥ 29, acute pancreatitis without established origin, participation in other clinical trials less than 6 months before this trial, head trauma with a Glasgow Coma Scale score ≤ 5, recent stroke or subarachnoid hemorrhage (less than 3 months), severe immunologic suppression (defined as a leukocyte count below 5,000 cells/mm 3 ), HIV infection, no indication for enteral feeding or imminent need for parenteral nutrition, partial parenteral nutrition to achieve caloric goals, presence of uncontrolled diarrhea, recent gastrointestinal bleeding, physician's decision to exclude patients on the basis of the study protocol, or the presence of respiratory failure (defined as evidence of acute pulmonary dysfunction with a ratio of partial pressure of oxygen to fraction of inspired oxygen (PaO 2 /FiO 2 ratio) < 300 and, if measured, pulmonary capillary wedge pressure not suggestive of central volume overload).…”

Section: Methodsmentioning

confidence: 99%

Enteral nutrition with eicosapentaenoic acid, γ-linolenic acid and antioxidants in the early treatment of sepsis: results from a multicenter, prospective, randomized, double-blinded, controlled study: the INTERSEPT Study

et al. 2011

View full text Add to dashboard Cite

IntroductionEnteral nutrition (EN) with eicosapentaenoic acid (EPA)/γ-linolenic acid (GLA) is recommended for mechanically ventilated patients with severe lung injury. EPA/GLA has anti-inflammatory benefits, as evidenced by its association with reduction in pulmonary inflammation, improvement in oxygenation and improved clinical outcomes in patients with severe forms of acute lung injury. This study was a prospective, multicenter, randomized, double-blinded, controlled trial designed to investigate whether EPA/GLA could have an effective role in the treatment of patients with early sepsis (systemic inflammatory response syndrome with confirmed or presumed infection and without any organ dysfunction) by reducing the progression of the disease to severe sepsis (sepsis associated with at least one organ failure) or septic shock (sepsis associated with hypotension despite adequate fluid resuscitation). Secondary outcomes included the development of individual organ failure, increased ICU and hospital length of stay, need for mechanical ventilation and 28-day all-cause mortality.MethodsRandomization was concealed, and patients were allocated to receive, for seven days, either an EPA/GLA diet or an isocaloric, isonitrogenous control diet not enhanced with lipids. Patients were continuously tube-fed at a minimum of 75% of basal energy expenditure × 1.3. To evaluate the progression to severe sepsis and/or septic shock, daily screening for individual organ failure was performed. All clinical outcomes were recorded during a 28-day follow-up period.ResultsA total of 115 patients in the early stages of sepsis requiring EN were included, among whom 106 were considered evaluable. Intention-to-treat (ITT) analysis demonstrated that patients fed the EPA/GLA diet developed less severe sepsis and/or septic shock than patients fed the control diet (26.3% versus 50%, respectively; P = 0.0259), with similar results observed for the evaluable patients (26.4% versus 50.9% respectively; P = 0.0217). The ITT analysis demonstrated that patients in the study group developed cardiovascular failure (36.2% versus 21%, respectively; P = 0.0381) and respiratory failure (39.6% versus 24.6%, respectively; P = 0.0362) less often than the control group. Similarly, when considering only the evaluable patients, fewer patientsdeveloped cardiovascular failure (20.7% versus 37.7%, respectively; P = 0.03) and respiratory failure (26.4% versus 39.6%, respectively; P = 0.04). The percentage of patients fed the EPA/GLA diet requiring invasive mechanical ventilation was reduced compared with controls (ITT patients: 18.9% versus 33.9%, respectively; P = 0.394; evaluable patients: 17.5% versus 34.5%, respectively; P = 0.295). Patients nourished with the EPA/GLA diet remained in the ICU fewer days than the control population (ITT patients: 21.1 ICU-free days versus 14.7 ICU-free days, respectively; P < 0.0001; evaluable patients: 20.8 ICU-free days versus 14.3 ICU-free days, respectively; P < 0.0001) and fewer days at the hospital (ITT patients: 19.5 hospital-f...

show abstract

“…One would then expect sepsis therapies to have differential success depending on the primary site of infection, which has been confirmed clinically (Bernard et al 2001). Adding to the difficulty is that timing of therapy is critical in a rapidly evolving disease, also eloquently demonstrated in sepsis (Rivers et al 2001; Bernard et al 2004). Unfortunately, time zero of an infection is truly not known in a typical patient, in contrast to an animal experiment.…”

Section: Discussionmentioning

confidence: 99%

Systems engineering medicine: engineering the inflammation response to infectious and traumatic challenges

Clermont

2010

J. R. Soc. Interface.

View full text Add to dashboard Cite

The complexity of the systemic inflammatory response and the lack of a treatment breakthrough in the treatment of pathogenic infection demand that advanced tools be brought to bear in the treatment of severe sepsis and trauma. Systems medicine, the translational science counterpart to basic science's systems biology, is the interface at which these tools may be constructed. Rapid initial strides in improving sepsis treatment are possible through the use of phenomenological modelling and optimization tools for process understanding and device design. Higher impact, and more generalizable, treatment designs are based on mechanistic understanding developed through the use of physiologically based models, characterization of population variability, and the use of control-theoretic systems engineering concepts. In this review we introduce acute inflammation and sepsis as an example of just one area that is currently underserved by the systems medicine community, and, therefore, an area in which contributions of all types can be made.

show abstract

Extended Evaluation of Recombinant Human Activated Protein C United States Trial (ENHANCE US)

Cited by 144 publications

References 27 publications

Activated Protein C Mutant with Minimal Anticoagulant Activity, Normal Cytoprotective Activity, and Preservation of Thrombin Activable Fibrinolysis Inhibitor-dependent Cytoprotective Functions

Activated Protein C Mutant with Minimal Anticoagulant Activity, Normal Cytoprotective Activity, and Preservation of Thrombin Activable Fibrinolysis Inhibitor-dependent Cytoprotective Functions

Enteral nutrition with eicosapentaenoic acid, γ-linolenic acid and antioxidants in the early treatment of sepsis: results from a multicenter, prospective, randomized, double-blinded, controlled study: the INTERSEPT Study

Systems engineering medicine: engineering the inflammation response to infectious and traumatic challenges

Contact Info

Product

Resources

About