Septic Shock
Conditions
Keywords
Septic shock, hemoadsorption, blood purification, MODS, Endotoxemia
Brief summary
Hemoadsorpion in Patients With Septic Shock: Efficacy and Safety Evaluation. A Pilot Multicenter Randomized Controlled Trial. The goal of this clinical trial is the estimation of the efficacy and safety of hemoadsorption procedures (LPS (Lipopolysaccharide) and inflammatory mediators adsorption) in participants with septic shock. The main questions it aims to answer are: Does hemoadsorption decrease the severity of MODS (multiple organ disfunction syndrome)? The study will include participants aged 18 to 80 years with a verified diagnosis of septic shock according to SEPSIS 3 criteria, diagnosed within 12 hours, and a SOFA (sequential organ failure assessment) score of 9 or more. In addition to Standard of Care (SOC), blood purification, including hemoadsorption, will be used. The minimum waiting time after diagnosis of septic shock and initiation of basic therapy before inclusion of the patient in the study therapy is 4 hours. The choice of procedure will be based on the EAA (Endotoxin Activity Assay) result: * for an EAA level of 0.6-0.9, selective lipopolysaccharide (LPS) adsorption with duration from 2 to 10 hours; * for an EAA level less than 0.6, inflammatory mediator adsorption with duration from 6 to 12 hours. The choice of a specific adsorbers within the LPS and inflammatory mediator adsorption group will be based on randomization. The use of LPS adsorption is planned based on randomization: Toramyxin R-20 or Efferon LPS. The use of inflammatory mediator adsorption is planned based on randomization: Jafron (HA 330) or CytoSorb.
Detailed description
Every participant will receive 2 adsorption procedures. The second procedure will be initiated no later than 24 hours after the initiation of the first procedure. LPS adsorption will be performed in 38 participants (Efferon LPS in 19 participants and Toramyxin in 19 participants), two procedures per participant. Inflammatory mediator adsorption will be performed in 38 participants (Jafron HA 330 in 19 participants and CytoSorb in 19 participants), two procedures per participant. Sample size calculations were performed separately for each treatment cohort. For the endotoxemia cohort (EAA level of 0.6-0.9), this randomized trial is designed to compare Efferron LPS and Toraymyxin with respect to change in SOFA score at 72 hours. At present, no universally accepted minimal clinically important difference (MCID) has been established for the SOFA score in participants with septic shock. Therefore, the assumed treatment effect was derived from published evidence and expert clinical judgment. In the EUPHAS trial, polymyxin B hemoperfusion was associated with a mean reduction in SOFA score of approximately 3.4 points at 72 hours, whereas minimal change was observed in the control group. Similarly, the LASSO study demonstrated substantial improvement in organ dysfunction following endotoxin adsorption therapy. For the inflammatory mediator adsorption cohort (EAA level less than 0.6), this randomized trial is designed to compare CytoSorb and Jafron HA 330 with respect to change in SOFA score at 72 hours. In the retrospective study Mehta et al., CytoSorb hemoperfusion was associated with a mean reduction in SOFA score of approximately 2.0 points after treatment in survival group. Similarly, the case series Onuk et al. demonstrated substantial improvement in organ dysfunction following inflammatory adsorption therapy with Jafron HA 330 with a mean reduction in SOFA score of approximately 3.5 points at 72 hours. A between-group difference of 2.5 SOFA points was considered clinically meaningful for both Endotoxin hemoadsorption and inflammatory mediators hemoadsorption because it represents a substantial proportion of the treatment effect observed in previous hemoperfusion studies and corresponds to a clinically relevant difference in the degree of organ dysfunction improvement. The sample size for both groups (LPS and inflammatory mediator adsorption) was calculated based on the following assumption: the primary endpoint was the change in SOFA score at 72 hours (ΔSOFA); the expected between-group difference - 2.5 points on the SOFA score; standard deviation of ΔSOFA - 2.5 points; equal allocation ratio (1:1); two-sided significance level (α) of 0.05; statistical power of 80%. Sample size estimation was performed in R using the power.t.test() function. The calculation yielded a required sample size of 16.7 participants per group. Therefore, a minimum of 17 participants per group (34 participants in total) is required to achieve the planned statistical power. To account for an anticipated 10% dropout rate, the final sample size will be 19 patients per group (38 participants in total for LPS+ 38 participants in total for Inflammatory mediators adsorption. 76 participants in total).
Interventions
DEVICEEfferon LPS
Blood purification with Efferon LPS
DEVICEToramyxin PMX 20R
Blood purification with Toramyxin PMX 20R
DEVICEJafron HA 330
Blood purification with Jafron HA 330
DEVICECytoSorb
Blood purification with Jafron HA 330
Sponsors
Moscow Multidisciplinary Clinical Center "Kommunarka"
Petrovsky National Research Centre of Surgery
Bakulev Scientific Center of Cardiovascular Surgery
City clinical hospital named after S. S. Yudin, Moscow City Health
Sklifosovsky Institute of Emergency Care
City Clinical Hospital No 52, Moscow, Russia
Rostov Regional Clinical Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Masking description
Double (Investigator, Outcomes Assessor)
Intervention model description
Prospective, pilot, multicenter, parallel-group randomized controlled trial. Participants are independently stratified into 2 parallel groups based on the Endotoxin activity Assay (EAA) level: Group 1- inflammatory mediatiors adsorption (EAA\<0.6), group 2- Endotoxin adsorption (EAA 0.6-0.9). Within each distinct group, participants are randomized in a 1:1 ratio to receive either a CytoSorb (subgroup 1)/Jafron HA 330 (subgroup 2) in group 1 or Toramyxin PMX 20R (subgroup 3)/Efferon LPS (subgroup 4) in group 2. Every patient will receive 2 procedures of hemoadsorption
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Septic shock according to SEPSIS-3 criteria * Age: 18-80 years * SOFA ≥9 points * Diagnosis of septic shock established \<12 hours ago * Invasive hemodynamic monitoring * Norepinephrine dose \>0.2 mcg/kg/min
Exclusion criteria
* Absolute neutrophil count less than 500 cells/μL * Pregnancy * End-stage heart failure (NYHA stage IV) * Pulmonary embolism with obstructive shock * Ongoing bleeding * Atonic coma * More than 30 points on the MELD scale, class C on the Child-Pugh scale * HIV infection * Burns over 10% of the body surface area * Patients with oncohematological diseases * Patients with a recognized palliative status or the definition of "metastatic cancer" * RRT using membranes with a high cutoff point and increased adsorption capacity within 72 hours from the initiation of the first hemoadsorption procedure * Use of plasma exchange within 72 hours from the initiation of the first hemoadsorption procedure
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| SOFA (sequential organ failure assessment) score | Assessed at 72 hours after hemoadsorption initiation | MODS (multiple organ disfunction syndrome) dynamics majored by SOFA (sequential organ failure assessment) score. SOFA score ranges from 0 (best) to 24 (worst) points. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Vasoactive Inotropic Score (VIS) dynamics | Assessed at 4 time points: before hemoadsorption initiation (baseline); 24 hours, 48 hours and 72 hours after hemoadsorption initiation | Vasoactive Inotropic Score (VIS) dynamics VIS = dopamine dose (mcg∕kg∕ min ) + dobutamine dose (mcg∕kg∕ min ) + 100 × epinephrine dose (mcg∕kg∕ min ) + 10 × milrinone dose (mcg∕kg∕ min ) + 10,000 × vasopressin dose (units∕kg∕ min ) \+ 100 × norepinephrine dose (mcg∕kg∕ min ) |
| Norepinephrine dose dynamics | Assessed at 4 time points: before hemoadsorption initiation (baseline); 24 hours, 48 hours and 72 hours after hemoadsorption initiation | Norepinephrine dose dynamics (mcg/kg/min) |
| Hemodynamic index dynamics | Assessed at 4 time points: before hemoadsorption initiation (baseline); 24 hours, 48 hours and 72 hours after hemoadsorption initiation | Hemodynamic index: Mean arterial pressure (MAP) to Vasoactive Inotropic Score (VIS); VIS = dopamine dose (mcg∕kg∕ min ) + dobutamine dose (mcg∕kg∕ min ) + 100 × epinephrine dose (mcg∕kg∕ min ) + 10 × milrinone dose (mcg∕kg∕ min ) + 10,000 × vasopressin dose (units∕kg∕ min ) + 100 × norepinephrine dose (mcg∕kg∕ min ) |
| Horowitz index dynamics | Assessed at 4 time points: before hemoadsorption initiation (baseline); 24 hours, 48 hours and 72 hours after hemoadsorption initiation | Arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (FiO2) ratio (Horowitz index) dynamics |
| Lactate level dynamics | Assessed at 4 time points: before hemoadsorption initiation (baseline); 24 hours, 48 hours and 72 hours after hemoadsorption initiation | Lactate level dynamics (mmol/l) |
| Total bilirubin level dynamics | Assessed at 4 time points: before hemoadsorption initiation (baseline); 24 hours, 48 hours and 72 hours after hemoadsorption initiation | Total bilirubin level dynamics (mcmol/l) |
| Indirect bilirubin level dynamics | Time Frame: Assessed at 4 time points: before hemoadsorption initiation (baseline); 24 hours, 48 hours and 72 hours after hemoadsorption initiation | Indirect bilirubin level dynamics (mcmol/l) |
| Direct bilirubin level dynamics | Time Frame: Assessed at 4 time points: before hemoadsorption initiation (baseline); 24 hours, 48 hours and 72 hours after hemoadsorption initiation | Direct bilirubin level dynamics (mcmol/l) |
| Ferritin level dynamics | Time Frame: Assessed at 4 time points: before hemoadsorption initiation (baseline); 24 hours, 48 hours and 72 hours after hemoadsorption initiation | Ferritin level dynamics (mcg/l) |
| Procalcitonin (PCT) level dynamics | Time Frame: Assessed at 4 time points: before hemoadsorption initiation (baseline); 24 hours, 48 hours and 72 hours after hemoadsorption initiation | Procalcitonin (PCT) level dynamics (ng/ml) |
| C- reactive protein (CRP) level dynamics | Time Frame: Assessed at 4 time points: before hemoadsorption initiation (baseline); 24 hours, 48 hours and 72 hours after hemoadsorption initiation | C- reactive protein (CRP) level dynamics (mg/l) |
| NLR (neutrophil-to-lymphocyte ratio) dynamics | Time Frame: Assessed at 4 time points: before hemoadsorption initiation (baseline); 24 hours, 48 hours and 72 hours after hemoadsorption initiation | NLR (neutrophil-to-lymphocyte ratio) dynamics |
| PLR (Platelet-to-lymphocyte ratio) dynamics | Assessed at 4 time points: before hemoadsorption initiation (baseline); 24 hours, 48 hours and 72 hours after hemoadsorption initiation | PLR (Platelet-to-lymphocyte ratio) dynamics |
| TNF (Tumor necrosis factor-alpha) level dynamics | Assessed at 3 time points: before hemoadsorption initiation (baseline); 48 hours and 72 hours after hemoadsorption initiation | TNF (Tumor necrosis factor-alpha) level dynamics (pg/ml) |
| IL 6 (Interleukin 6) level dynamics | Assessed at 3 time points: before hemoadsorption initiation (baseline); 48 hours and 72 hours after hemoadsorption initiation | IL 6 (Interleukin 6) level dynamics (pg/ml) |
| IL 10 (Interleukin 10) level dynamics | Time Frame: Assessed at 3 time points: before hemoadsorption initiation (baseline); 48 hours and 72 hours after hemoadsorption initiation | IL 10 (Interleukin 10) level dynamics (pg/ml) |
| 28 - days mortality | Will be calculated for 28 days after hemoadsorption initiation | 28 - days mortality |
| 90 - days mortality | Will be calculated for 90 days after hemoadsorption initiation | 90 - days mortality |
| SOFA (sequential organ failure assessment) dynamics | Assessed at 4 time points: before hemoadsorption initiatioin (baseline); at 24, 48 and 120 hours after hemoadsorption initiation | MODS (multiple organ disfunction syndrome) dynamics majored by SOFA (sequential organ failure assessment) score |
| SOFA 2 (sequential organ failure assessment) dynamics | Assessed at 5 time points: before hemoadsorption initiatioin (baseline); at 24, 48, 72 and 120 hours after hemoadsorption initiation | MODS (multiple organ disfunction syndrome) dynamics majored by SOFA 2 (sequential organ failure assessment) score |
Countries
Russia
Contacts
CONTACTAleksandr Burov, PHD
STUDY_DIRECTORDenis Protsenko, MD, PHD
Moscow Multi-disciplinary Clinical Center "Kommunarka"
Outcome results
None listed