Septic Shock
Conditions
Keywords
Septic Shock, Sepsis, Multi-organ failure, Extracorporeal therapy, Plasmapheresis
Brief summary
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.
Detailed description
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.
Interventions
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.
Sponsors
Hannover Medical School
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* New onset of septic shock (\< 24 hrs), (SEPSIS-3 definition) * Norepinephrine (NE) dose ≥ 0.4 μg/kg/min ≥ 30 min OR NE ≥ 0.3 μg/kg/min + vasopressin (any dose) * Established vascular access suitable for plasma exchange independent of study inclusion (due to established indication of RRT, expected need for RRT within the next 48 hours or other medical reasons as assessed by treating physician team)
Exclusion criteria
* Age \< 18 or \> 80 years * Urogenital focus of infection * Pregnancy * Heparin-induced thrombocytopenia * Known reaction against fresh frozen plasma (FFP)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 28-day mortality | from randomization up to 28 days following randomization |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean daily Sequential Organ Failure Score (SOFA) score over the first 7 days (KEY secondary outcome) | from randomization up to 7 days following randomization | Per-patient mean daily SOFA score over the first 7 days, ranging from 0-24 points with higher scores indicating more severe organ dysfunction |
| Organ support free days until day 28 (KEY secondary outcome) | from randomization up to 28 days following randomization | total days free of invasive ventilation, vasopressors/inotrops and renal replacement therapy (RRT) until day 28 |
| 90-day mortality | from randomization up to 90 days following randomization | — |
| Intensive Care unit (ICU) length of stay | from randomization until ICU discharge | total days in ICU |
| Hospital length of stay | from randomization until hospital discharge | total days in hospital |
| Basic Hemodynamics | at days 1-7 following randomization | 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 |
| Extended Hemodynamics | at days 1-7 following randomization | 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 |
| Respiratory function | at days 1-7 following randomization | 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 |
| Renal function | at days 1-7 following randomization and at ICU discharge | 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 |
| Liver Function | at days 1-7 following randomization and at ICU discharge | 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 |
| Sepsis associated coagulopathy | at days 1-7 following randomization | 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 |
| Inflammatory response | at days 1-7 following randomization | 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 |
| Cardiac function | at days 1-7 following randomization and at ICU discharge | 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 |
| Secondary infections | from randomization until hospital discharge | includes: incidence and type of secondary infections until ICU and hospital discharge, incidence of viral (HSV, EBV, CMV) reactivation at d7 and d14 |
| Arterial blood gas analysis | at days 1-7 following randomization | includes: pH, PCO2 \[mmHg\], HCO3- \[mmol\], PO2 \[mmHg\], Lactate \[mmol/l\] at 0 and 12 hrs, d1-7 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Safety Endpoints | from randomization until day 7 following randomization | includes: Incidence of bleeding, allergic reactions, Transfusion associated lung injury (TRALI), severe thrombocytopenia (\< 5000/µl) and (other) severe adverse events (SAEs) |
Countries
Austria, Germany, Switzerland
Contacts
Primary ContactSascha David, Prof. Dr.
Backup ContactKlaus Stahl, PD Dr.
Outcome results
None listed