Randomized, prospective, multicenter, open-label, controlled, parallel-group interventional trial to test the adjunctive effect of therapeutic plasma exchange in patients with early septic shock.
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to an infection; in septic shock profound circulatory, cellular and metabolic abnormalities are associated with an even higher mortality. Sepsis is a major healthcare problem, affecting millions of individuals around the world each year. Its incidence appears to be rising, and the mortality caused by septic shock in Germany in 2015 remains extraordinarily high (58.8%). It is well known - from the pathophysiological point of view - that these patients do not die from their infection per se but rather from multiple organ failure caused by their own overwhelming host response. This fact is so fundamental that it has been implemented as a key part of the 2016 sepsis definition (SEPSIS-3). Despite tremendous efforts during the last decades, innovative approaches targeting this fundamental hallmark of the disease, thereby reducing organ dysfunction, are lacking. Undoubtedly, there is an unmet need to expand the current standard of care for these patients by a more specific intervention. The investigators hypothesize that early Therapeutic Plasma Exchange (TPE) in the most severely ill individuals will dampen the injurious maladaptive host response by removing injurious mediators thereby limiting organ dysfunction. The potential impact of this trial is of immense clinical relevance as it evaluates a promising adjunctive treatment option for a patient cohort suffering from an extraordinary high mortality. A positive trial result could truly change the current standard of care (SOC) - that is mostly supportive - of septic shock patients. Of note, there is neither a patent nor a direct commercial interest in such a trial.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
274
The TPE treatment will be initiated within 6 hrs after randomization. Duration of TPE treatment is approximately 120-180 minutes. An additional second TPE can be performed if the patient remains vasopressor dependent ≥ 0.4 ug/kg/min after 24 hours following the first TPE procedure. Both unfractionated heparin (UFH) and citrate may be used as anticoagulant medication. To ensure treatment comparability between different patients, we will replace plasma in a fixed ratio of 1.2 x the individual patient's total plasma fluid.
University Hospital Innsbruck
Innsbruck, Austria
28-day mortality
Time frame: from randomization up to 28 days following randomization
Mean daily Sequential Organ Failure Score (SOFA) score over the first 7 days (KEY secondary outcome)
Per-patient mean daily SOFA score over the first 7 days, ranging from 0-24 points with higher scores indicating more severe organ dysfunction
Time frame: from randomization up to 7 days following randomization
Organ support free days until day 28 (KEY secondary outcome)
total days free of invasive ventilation, vasopressors/inotrops and renal replacement therapy (RRT) until day 28
Time frame: from randomization up to 28 days following randomization
90-day mortality
Time frame: from randomization up to 90 days following randomization
Intensive Care unit (ICU) length of stay
total days in ICU
Time frame: from randomization until ICU discharge
Hospital length of stay
total days in hospital
Time frame: from randomization until hospital discharge
Basic Hemodynamics
includes: Norepinephrine- \[µg/kg/min\], Dobutamine \[µg/kg/min\], Epinephrine- \[µg/kg/min\] and Vasopressin-dose \[U/kg/min\], Vasocative-inotropic (VIS) Score with higher scores indicating higher vasopressor/inotropic support, Mean arterial pressure (MAP, \[mmHg\]), Heart Rate (HR, \[1/min\]), Central venous pressure (CVP, \[mmHg\]) and Central-Venous Oxygen Saturation (ScvO2, \[%\]) at 0 and 12 hrs, d1-7
Time frame: at days 1-7 following randomization
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
University Hospital Vienna
Vienna, Austria
NOT_YET_RECRUITINGSt. Joseph Hospital
Berlin, Germany
NOT_YET_RECRUITINGUniversity Hospital Berlin Charite
Berlin, Germany
NOT_YET_RECRUITINGUniversity Hospital Bonn
Bonn, Germany
RECRUITINGHospital Braunschweig
Braunschweig, Germany
NOT_YET_RECRUITINGHospital Bremerhaven
Bremerhaven, Germany
NOT_YET_RECRUITINGHospital Cologne Meerheim
Cologne, Germany
NOT_YET_RECRUITINGUniversity Hospital Cologne
Cologne, Germany
NOT_YET_RECRUITINGUniversity Hospital Erlangen
Erlangen, Germany
NOT_YET_RECRUITING...and 15 more locations
Extended Hemodynamics
includes: Cardiac Index (CI, \[l/min/m2\]), Global End-Diastolic Volume Index (GEDI, \[ml/m2\]), Sytemic Vascular Resistance Index (SVRI, \[dyn\*s\*cm-5\*m2\]), Stroke Volume Variation (SVV, \[%\] ), Extravascular Lung Water Index (ELWI, \[ml/kg\]) and Pulmonar Vascular Permeability Index (PVPI) at at 0 and 12 hrs, d1-7
Time frame: at days 1-7 following randomization
Arterial blood gas analysis
includes: pH, PCO2 \[mmHg\], HCO3- \[mmol\], PO2 \[mmHg\], Lactate \[mmol/l\] at 0 and 12 hrs, d1-7
Time frame: at days 1-7 following randomization
Respiratory function
includes: pO2/FiO2, Tidal Volume (VT, \[ml\]), Positive End-Exspiratory Pressure (PEEP, \[cmH2O\]), Peak-Pressure (Ppeak, \[cmH2O\]), Plateau-Pressure (Pplat, \[cmH2O\]), Respiratory Rate (RR, \[1/min\]), Inspiratory Time (Tinsp, \[s\]), Inspiratory-Flow and End-tidal-CO2 (etCO2, \[mmHg\]) at 0 and 12 hrs, d1-7
Time frame: at days 1-7 following randomization
Renal function
includes: Presence of Acute kindey injury (AKI), AKI stage (KDIGO definition) stage 1-3 with higher stage indicating worse renal function, Need for Renal Replacement Therapy (RRT), Estimated Glomerular Filtration Rate (eGFR following CKD-EPI equation) \[ml/min\], Fluid intake \[ml/d\], Urine output \[ml/d\], Ultrafiltration and Net daily fluid balance \[ml/d\] at 0 and 12 hrs, d1-7 and at ICU discharge
Time frame: at days 1-7 following randomization and at ICU discharge
Liver Function
includes: Bilirubin, Aspartate aminotransferase (AST, \[U/l\]), Alanine aminotransferase (ALT, \[U/l\]), Alkaline phosphatase (AP, \[U/l\]), Gamma-glutamyl transferase (GGT, \[U/l\]), Cholinesterase (CHE, \[kU/l\]) and Albumin \[g/l\] at 0 and 12 hrs, d1-7 and at ICU discharge
Time frame: at days 1-7 following randomization and at ICU discharge
Sepsis associated coagulopathy
includes: Differential blood count including schistocytes \[%\], Fibrinogen \[g/l\] , D-Dimer \[mg/l\], International Normalized Ratio (INR), Lactate dehydrogenase (LDH, \[U/l\]), Antithrombin-III (AT-III, \[%\]), Protein C \[%\] and International Society on Thrombosis and Hemostasis- Disseminated Intravscular Coagulation Score (ISTH-DIC, \[U/l\]) ranging from 0-8 points with higher values indication more severe DIC at 0 and 12 hrs, d1-7, A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13, \[%\]) and von-Willebrand-Factor Antigen (vWF:Ag,\[IU/l\]) at 0 and 24 hrs
Time frame: at days 1-7 following randomization
Inflammatory response
includes: C-reactive protein (CRP, \[mg/l\]), Procalcitonin (PCT, \[ug/l\]), Interleukin-6 (IL-6, \[ng/ml\]), Ferritin \[ug/l\] and Neutrophil/Lymphocyte ratio at 0 and 12 hrs, d1-7
Time frame: at days 1-7 following randomization
Cardiac function
includes: Creatine kinase (CK, \[U/l\]), Myoglobin \[ug/l\], Troponin T \[ng/l\], NT-proBNP \[ng/l\] at 0 and 12 hrs, d1-7 and at ICU discharge
Time frame: at days 1-7 following randomization and at ICU discharge
Secondary infections
includes: incidence and type of secondary infections until ICU and hospital discharge, incidence of viral (HSV, EBV, CMV) reactivation at d7 and d14
Time frame: from randomization until hospital discharge