OBJECTIVES: Systemic inflammatory response variability displays differing degrees of organ damage and differing outcomes of sepsis. C1-esterase inhibitor, an endogenous acute-phase protein, regulates various inflammatory and anti-inflammatory pathways, including the kallikrein-kinin system and leukocyte activity. This study assesses the influence of high-dose C1-esterase inhibitor administration on systemic inflammatory response and survival in patients with sepsis. DESIGN: Open-label randomized controlled study. SETTING:Surgical and medical intensive care units of nine university and city hospitals. PATIENTS::Sixty-one patients with sepsis. INTERVENTIONS: Patients were randomized to receive either 12,000 U of C1-esterase inhibitor infusions in addition to conventional treatment or conventional treatment only (n = 41 C1-esterase inhibitor, 20 controls). Blood samples for measurement of C1-esterase inhibitor, complement components C3 and C4, and C-reactive protein concentrations were drawn on days 1, 3, 5, 7, 10, and 28. MEASUREMENTS AND MAIN RESULTS: Quartile analysis of C1-esterase inhibitor activity in sepsis subjects revealed that the lowest quartile subgroup had similar activity levels(0.7-1.2 U/L), when compared to healthy volunteers (p >.05). These normal-level C1-esterase inhibitor sepsis patients nevertheless displayed increased C-reactive protein(p =.04) production and higher likelihoods of a more severe sepsis(p =.001).Overall, infusion of C1-esterase inhibitor increased C1-esterase inhibitor(p <.005 vs. control on days 2, 3, and 5) functional activity, resulted in higher C3 levels(p <.05 vs. control on days 2 and 3), followed by decreased C-reactive protein(p <.05 vs. control on days 3 and 10). Simultaneously,C1-esterase inhibitor infusion in sepsis patients was associated with reduced all-cause mortality(12% vs. 45% in control, p =.008) as well as sepsis-related mortality(8% vs. 45% in control, p =.001) assessed over 28 days. The highest absolute reduction risk of 70% was achieved in sepsis patients with Simplified Acute Physiology Score II scores >27. CONCLUSION: In the present study, patients in the lowest quartile of C1-esterase inhibitor activity in combination with high C-reactive protein demonstrated a higher risk of developing severe sepsis. In general, high-dose C1-esterase inhibitor infusion down-regulated the systemic inflammatory response and was associated with improved survival rates in sepsis patients, which could have important treatment and survival implications for individuals with C1-esterase inhibitor functional deficiency.
RCT Entities:
OBJECTIVES: Systemic inflammatory response variability displays differing degrees of organ damage and differing outcomes of sepsis. C1-esterase inhibitor, an endogenous acute-phase protein, regulates various inflammatory and anti-inflammatory pathways, including the kallikrein-kinin system and leukocyte activity. This study assesses the influence of high-dose C1-esterase inhibitor administration on systemic inflammatory response and survival in patients with sepsis. DESIGN: Open-label randomized controlled study. SETTING: Surgical and medical intensive care units of nine university and city hospitals. PATIENTS: : Sixty-one patients with sepsis. INTERVENTIONS:Patients were randomized to receive either 12,000 U of C1-esterase inhibitor infusions in addition to conventional treatment or conventional treatment only (n = 41 C1-esterase inhibitor, 20 controls). Blood samples for measurement of C1-esterase inhibitor, complement components C3 and C4, and C-reactive protein concentrations were drawn on days 1, 3, 5, 7, 10, and 28. MEASUREMENTS AND MAIN RESULTS: Quartile analysis of C1-esterase inhibitor activity in sepsis subjects revealed that the lowest quartile subgroup had similar activity levels (0.7-1.2 U/L), when compared to healthy volunteers (p > .05). These normal-level C1-esterase inhibitorsepsispatients nevertheless displayed increased C-reactive protein (p = .04) production and higher likelihoods of a more severe sepsis (p = .001). Overall, infusion of C1-esterase inhibitor increased C1-esterase inhibitor (p < .005 vs. control on days 2, 3, and 5) functional activity, resulted in higher C3 levels (p < .05 vs. control on days 2 and 3), followed by decreased C-reactive protein (p < .05 vs. control on days 3 and 10). Simultaneously, C1-esterase inhibitor infusion in sepsispatients was associated with reduced all-cause mortality (12% vs. 45% in control, p = .008) as well as sepsis-related mortality (8% vs. 45% in control, p = .001) assessed over 28 days. The highest absolute reduction risk of 70% was achieved in sepsispatients with Simplified Acute Physiology Score II scores >27. CONCLUSION: In the present study, patients in the lowest quartile of C1-esterase inhibitor activity in combination with high C-reactive protein demonstrated a higher risk of developing severe sepsis. In general, high-dose C1-esterase inhibitor infusion down-regulated the systemic inflammatory response and was associated with improved survival rates in sepsispatients, which could have important treatment and survival implications for individuals with C1-esterase inhibitor functional deficiency.
Authors: Juan S Danobeitia; Tiffany J Zens; Peter J Chlebeck; Laura J Zitur; Jose A Reyes; Michael J Eerhart; Jennifer Coonen; Saverio Capuano; Anthony M D'Alessandro; Jose R Torrealba; Daniel Burguete; Kevin Brunner; Edwin Van Amersfoort; Yolanda Ponstein; Cees Van Kooten; Ewa Jankowska-Gan; William Burlingham; Jeremy Sullivan; Arjang Djamali; Myron Pozniak; Yucel Yankol; Luis A Fernandez Journal: Am J Transplant Date: 2020-02-20 Impact factor: 8.086
Authors: A Landsem; E W Nielsen; H Fure; D Christiansen; J K Ludviksen; J D Lambris; B Østerud; T E Mollnes; O-L Brekke Journal: Clin Exp Immunol Date: 2013-08 Impact factor: 4.330