Septic Shock
Conditions
Keywords
sepsis, septic shock, hemoadsorption, CytoSorb, endothelial dysfunction, syndecan-1, vasoplegia
Brief summary
This study aims to investigate the effects of adjunctive CytoSorb hemoadsorption therapy versus standard medical treatment on endothelial dysfunction in patients with refractory septic shock. The investigators hypothesize that hemoadsorption mitigates endothelial and glycocalyx injury by removing inflammatory mediators and other injurious circulating molecules, promoting hemodynamic stabilization.
Detailed description
This is a prospective, randomised, controlled, open-label, monocentric, proof-of-concept trial. Patients will be randomly assigned in a 1:1 ratio to receive either standard medical therapy alone or standard therapy plus continuous CytoSorb hemoadsorption for 24 hours. Blood samples will be collected at baseline, 6, 12, 18, and 24 hours, and then daily for 5 days to analyze endothelial markers, microRNAs, and inflammatory parameters. An adaptive group sequential design allows for an interim unblinded sample size re-estimation after the first 30 evaluable patients.
Interventions
DEVICECytoSorb hemoadsorption
Target blood flow rate of 1.5 ml/kg/min, implemented either as a standalone extracorporeal treatment or integrated into a CRRT circuit (CVVHDF mode, preferably with regional citrate anticoagulation).
Standard Medical Therapy according to local protocols based on the current international 'Surviving Sepsis Campaign' guidelines.
Sponsors
Semmelweis University
Ludwig Boltzmann Institute for Traumatology - The research center in cooperation with AUVA
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
* Septic shock as defined by Sepsis-3 criteria. * Serum lactate levels \>2 and \<8 mmol/L at screening. * Fluid unresponsiveness: Objectively confirmed via dynamic tests or fluid challenges following initial resuscitation. * Vasopressor Dose Threshold: Norepinephrine base equivalent (NEE) dose \> 0.5 µg/kg/min. * Systemic corticosteroid treatment on board for at least 30 minutes. * Tissue perfusion impairment: Persistently elevated serum lactate AND/OR prolonged capillary refill time (\> 3 seconds) despite standard therapy. * Alternative causes of shock (e.g., obstructive or cardiogenic) must be ruled out using critical care ultrasonography (CCUS). * Arterial, central venous catheters and an invasive hemodynamic device (PiCCO, Getinge) in place. * Inclusion within a maximum of 12 hours after the onset of vasopressor need. * High likelihood of a dysregulated immune response (PCT ≥ 5 ng/mL AND/OR IL-6 ≥ 1000 pg/mL AND/OR Ferritin ≥ 1000 ng/mL). * Written informed, retrospective or prospective consent.
Exclusion criteria
* Patients under 18 years of age and over 80. * Unlikely to survive for 24 hours (Moribund). * Pregnancy. * SOFA-2 score ≥ 16 at ICU admission. * Source control is uncertain. * Thrombocytopenia (\<20,000/µL). * Criteria of standard guideline-based medical treatment not exhausted. * End-stage organ failure (chronic renal failure (estimated glomerular filtration rate (eGFR) \<15 mL/min/1.73 m2), chronic liver failure (MELD Score \>30, ChildPugh score class C.), chronic heart failure (New York Heart Association class IV.); severe chronic pulmonary disease (chronic obstructive pulmonary disease: GOLD D)). * Expected need to disconnect CytoSorb therapy for more than 2 hours (e.g., surgery, CT transfer).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Syndecan-1 serum levels | Baseline (T0), 6, 12, 18, and 24 hours, and then daily up to 5 days (including pre- and postadsorbent samples in the CytoSorb group) | Serum Syndecan-1, a marker of endothelial glycocalyx injury, will be measured in arterial blood samples. The outcome is the log-scale change from baseline to the T24 post-baseline Syndecan-1 value in ng/mL. If the T24 value is missing, the value will be considered missing. Negative values indicate a decrease from baseline. Syndecan-1 values will be analysed on the natural logarithmic scale due to expected right skew. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Sequential Organ Failure Assessment (SOFA)-2 score | Baseline (T0), 24 hours, and then daily up to 5 days. | Sequential Organ Failure Assessment (SOFA)-2 is an organ dysfunction score used in critically ill patients. SOFA-2 includes 6 organ systems with total score ranging from 0 to 24 (higher scores indicate worse organ dysfunction). Change from baseline will be calculated at each post-baseline assessment and reported in score points. |
| Change from baseline in arterial blood concentrations of endothelial and glycocalyx-specific markers (Glypican-1, Heparan-sulfate, sICAM-1, sVCAM-1, soluble E-selectin, soluble P-selectin) | Baseline (T0), 6, 12, 18, and 24 hours, and then daily up to 5 days. | Arterial blood concentrations of glypican-1, heparan sulfate, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin/CD62E), and soluble P-selectin (sP-selectin) will be measured in ng/mL. For each biomarker, the change from baseline (T0) will be calculated at each post-baseline assessment. Results will be reported separately for each biomarker; no composite score will be calculated. |
| Change from baseline in arterial blood concentrations of endothelial markers (MCP-1, VEGF) | Baseline (T0), 6, 12, 18, and 24 hours, and then daily up to 5 days. | Arterial blood concentrations of monocyte chemoattractant protein-1/C-C motif chemokine ligand 2 (MCP-1/CCL2) and vascular endothelial growth factor (VEGF) will be measured in pg/mL. For each biomarker, the change from baseline (T0) will be calculated at each post-baseline assessment. Results will be reported separately for each biomarker; no composite score will be calculated. |
| Change from baseline in quantification cycle values of selected microRNAs associated with endothelial function, vascular homeostasis, and inflammation (miR-126, miR-92a, miR-155, miR-21, miR-23a) | Baseline (T0) and 6, 12, 18, 24, 48, 72, 96, and 120 hours after T0 | Expression of miR-126, miR-92a, miR-155, miR-21, and miR-23a will be measured in arterial blood samples by quantitative reverse-transcription polymerase chain reaction and reported as quantification cycle (Cq) values. For each microRNA, change from baseline at each post-baseline time point will be calculated as the Cq value at that time point minus the corresponding Cq value at baseline (T0). Results will be analyzed and reported separately for each microRNA; no composite or aggregated microRNA score will be calculated. Hemolyzed samples will be excluded from the microRNA analyses. |
| Change from baseline in arterial lactate levels | Baseline (T0) and 6, 12, 18, 24, 48, 72, 96, and 120 hours after T0 | Arterial lactate concentration will be measured in arterial blood samples and reported in mmol/L. at each post-baseline time point will be calculated as the arterial lactate concentration at that time point minus the arterial lactate concentration at baseline (T0). Changes at each time point will be reported separately. |
| Change from baseline in procalcitonin concentration | Baseline (T0) and 6, 12, 18, 24, 48, 72, 96, and 120 hours after T0 | Procalcitonin (PCT) concentration will be measured in arterial blood samples and reported in ng/mL. For each participant, change from baseline at each post-baseline time point will be calculated as the PCT concentration at that time point minus the PCT concentration at baseline (T0). Changes at each time point will be reported separately. |
| Change from baseline in C-reactive protein concentration | Baseline (T0) and 6, 12, 18, 24, 48, 72, 96, and 120 hours after T0 | C-reactive protein (CRP) concentration will be measured in arterial blood samples and reported in mg/L. For each participant, change from baseline at each post-baseline time point will be calculated as the CRP concentration at that time point minus the CRP concentration at baseline (T0). Changes at each time point will be reported separately. |
| Change from baseline in white blood cell count | Baseline (T0) and 6, 12, 18, 24, 48, 72, 96, and 120 hours after T0 | White blood cell count (WBC) will be measured in arterial blood samples and reported in G/L. For each participant, change from baseline at each post-baseline time point will be calculated as the WBC count at that time point minus the WBC count at baseline (T0). Changes at each time point will be reported separately. |
| Change from baseline in ferritin concentration | Baseline (T0) and 6, 12, 18, 24, 48, 72, 96, and 120 hours after T0 | Ferritin concentration will be measured in arterial blood samples and reported in ng/mL. For each participant, change from baseline at each post-baseline time point will be calculated as the ferritin concentration at that time point minus the ferritin concentration at baseline (T0). Changes at each time point will be reported separately. |
| Change from baseline in tumor necrosis factor alpha concentration | Baseline (T0) and 6, 12, 18, 24, 48, 72, 96, and 120 hours after T0 | Tumor necrosis factor alpha (TNF-α) concentration will be measured in arterial blood samples and reported in pg/mL. For each participant, change from baseline at each post-baseline time point will be calculated as the TNF-α concentration at that time point minus the TNF-α concentration at baseline (T0). Changes at each time point will be reported separately. |
| Change from baseline in interleukin-1 beta concentration | Baseline (T0) and 6, 12, 18, 24, 48, 72, 96, and 120 hours after T0 | Interleukin-1 beta (IL-1β) concentration will be measured in arterial blood samples and reported in pg/mL. For each participant, change from baseline at each post-baseline time point will be calculated as the IL-1β concentration at that time point minus the IL-1β concentration at baseline (T0). Changes at each time point will be reported separately. |
| Change from baseline in interleukin-8 concentration | Baseline (T0) and 6, 12, 18, 24, 48, 72, 96, and 120 hours after T0 | Interleukin-8 (IL-8) concentration will be measured in arterial blood samples and reported in pg/mL. For each participant, change from baseline at each post-baseline time point will be calculated as the IL-8 concentration at that time point minus the IL-8 concentration at baseline (T0). Changes at each time point will be reported separately. |
| Change from baseline in extravascular Lung Water Index (EVLWI) | Baseline (T0) and 6, 12, 18, 24, 48, 72, 96, and 120 hours after T0 | Extravascular Lung Water Index willl be measured using invasive hemodynamic monitoring and reported in ml/kg. Change from baseline at each post-baseline time point will be calculated as the EVLWI at that time point minus the EVLWI at baseline |
| Change from baseline in Vasoactive-Inotropic Score (VIS) | Baseline (T0) and 6, 12, 18, 24, 48, 72, 96, and 120 hours after T0 | The Vasoactive-Inotropic Score (VIS) quantifies the amount of cardiovascular support a patient receives through vasoactive and inotropic medications. The VIS is calculated as: VIS = dopamine (µg/kg/min) + dobutamine (µg/kg/min) + 100 × epinephrine (µg/kg/min) + 100 × norepinephrine (µg/kg/min) + 10 × milrinone (µg/kg/min) + 10 × vasopressin (U/kg/min) at each time point. Higher score indicates worse outcome. VIS at each post-baseline time point will be calculated as the VIS at that time point minus the VIS at baseline (T0). Changes at each time point will be reported separately. |
| Daily fluid balance through Day 28 | From T0 through Day 28, assessed every 24 hours | Daily fluid balance will be calculated for each 24-hour period as total fluid intake minus total fluid output. Negative values indicate that fluid output exceeded fluid intake during the corresponding 24-hour period. Daily fluid balance will be reported in mL at each assessment day. |
| Time to first negative daily fluid balance | From T0 through Day 28 | Time to first negative daily fluid balance will be calculated as the time from T0 to the end of the first 24-hour assessment period during which total fluid output exceeds total fluid intake, corresponding to a daily fluid balance of less than zero. Time will be reported in days. Participants who do not achieve a negative daily fluid balance by Day 28 will be censored at Day 28. |
| Cumulative fluid balance through Day 28 | From T0 through Day 28, assessed every 24 hours | Cumulative fluid balance will be calculated as the sum of fluid intake minus fluid output from T0 through each assessment time point. Negative values indicate that cumulative fluid output exceeded cumulative fluid intake since T0. Cumulative fluid balance will be reported in mL at each assessment day. |
| Time to first negative cumulative fluid balance | From T0 through Day 28 | Time to first negative cumulative fluid balance will be calculated as the time from T0 to the first assessment at which cumulative fluid output since T0 exceeds cumulative fluid intake since T0, corresponding to a cumulative fluid balance of less than zero. Time will be reported in days. Participants who do not achieve a negative cumulative fluid balance by Day 28 will be censored at Day 28. |
| Vasopressor-free days through Day 28 | Day 1 through Day 28 | Vasopressor-free days will be calculated as the number of days from Day 1 through Day 28 during which the participant is alive and free from vasopressor treatment. A day will be counted as vasopressor-free only when no vasopressor is administered during that day. The possible range is 0 to 28 days, with higher values indicating more days alive without vasopressor support. |
| Mechanical ventilation-free days through Day 28 | Day 1 through Day 28 | Mechanical ventilation-free days will be calculated as the number of days from Day 1 through Day 28 during which the participant is alive and free from mechanical ventilation. A day will be counted as ventilation-free only when no mechanical ventilation is provided during that day. The possible range is 0 to 28 days, with higher values indicating more days alive without mechanical ventilatory support. |
| Continuous renal replacement therapy-free days through Day 28 | Day 1 through Day 28 | Continuous renal replacement therapy (CRRT)-free days will be calculated as the number of days from Day 1 through Day 28 during which the participant is alive and free from CRRT. A day will be counted as CRRT-free only when no CRRT is administered during that day. The possible range is 0 to 28 days, with higher values indicating more days alive without CRRT. |
| Intensive Care Unit length of stay through Day 28 | From ICU admission through ICU discharge, death in the ICU, or Day 28, whichever occurs first | Intensive Care Unit (ICU) length of stay will be calculated as the elapsed time in days from ICU admission to ICU discharge or death in the ICU, whichever occurs first. Participants who remain in the ICU on Day 28 will be censored at Day 28. |
| Survival rates (ICU survival, Hospital survival, and 28-day survival) | Up to 28 days. | ICU survival, hospital survival, and 28-day survival will be recorded separately as alive/deceased status at ICU discharge, hospital discharge, and Day 28 after randomization. Results will be reported as proportions of participants surviving at each time point. |
| Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) | From baseline up to 28 days. | Adverse events, serious adverse events, and device deficiencies will be recorded from baseline through Day 28. Events will be summarized by incidence, event type, severity, relationship to the study device or procedure, outcome, and seriousness. |
Countries
Hungary
Contacts
CONTACTTamás Tóth, Dr.
PRINCIPAL_INVESTIGATORZsolt Molnár, Prof. Dr.
Department of Anaesthesiology and Intensive Therapy, Semmelweis University, Budapest, Hungary
PRINCIPAL_INVESTIGATORPéter Hegyi, Prof. Dr.
Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
Outcome results
None listed