Septic Shock
Conditions
Keywords
sepsis, septic shock, cytosorb, cytokine removal
Brief summary
Sepsis and septic shock have mortality rates between 20-50%. When standard therapeutic measures fail to improve patients' condition, additional therapeutic alternatives are applied to reduce morbidity and mortality. One of the most recent alternatives is extracorporeal cytokine hemoadsorption. One of the most tested devices is CytoSorb, however, there are a lot of open questions, such timing, dosing and of course its overall efficacy. This study aims to compare the efficacy of standard medical therapy (Group A, SMT) and continuous extracorporeal cytokine removal with CytoSorb therapy in patients with early refractory septic shock. Furthermore, we compare the dosing of CytoSorb adsorber device - as the cartridge will be changed in every (12 Group B) or 24 hours (Group C).
Interventions
COMBINATION_PRODUCTStandard medical therapy
Standard medical therapy (according to the Surviving Sepsis Campaign) will include standard monitoring (pulseoximetry, 5-lead ECG, continuous invasive blood pressure monitoring, central venous cannulation and 24 with PiCCO-technology. Norepinephrine as a vasopressor and dobutamine - if needed - as an inotrope will be administered by the attending physician.
DEVICEStandard medical therapy plus cytokine removal treatment using Cytosorb, with the adsorber changed in every 12 hours
Standard medical therapy, as discussed above will be applied. Furthermore, Cytosorb will be administered as soon as it is possible after randomization but not later than 2 hour (start of the treatment, T0). In a blood pump circuit in pre-haemofilter position, using a kidney replacement device of Fresenius Multifiltrate as a solo therapy or in combination with renal replacement therapy. It will be run in CVVHD, CVVHDF or CVVH mode with a 150 and 200 ml/min blood flow. Anticoagulation will be applied intravenously with heparin, low molecular weight heparin or citrate. The aim of the pump flow rate will be 100-400 mL/min, and the flow rate will be recorded. Possible shock reversal will be assessed by the physician attending. Adsorber cartridges will be changed in every 12 hours. End of the study period (Te): 12 hours after shock reversal, death of the patient, or maximum of five days, whichever happens first.
DEVICEStandard medical therapy plus cytokine removal treatment using Cytosorb, with the adsorber changed in every 24 hours
The standard medical therapy and method of Cytosorb treatment as detailed above will be applied. Adsorber cartridges will be changed in every 24 hours.
Sponsors
University of Pecs
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
No masking is applied in this study, as it is impossible to blind the medical personnel and participants. Statisticians will be blinded to allocation
Intervention model description
Prospective, randomized, controlled, three-arm, open-label, international, multi-centre, phase III study
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Septic shock as defined by the Sepsis-3 criteria * Septic shock both medical or surgical ethiology (except for re-operation) * APACHE \> 25 * Mechanical ventilation * Norepinephrine requirement ≥0.4 µg/kg/min for at least 30 minutes, when hypovolemia is highly unlikely as indicated by invasive hemodynamic measurements assessed by the attending physician * Invasive hemodynamic monitoring to determine cardiac output and derived variables * Procalcitonin level ≥ 10 ng/ml * Inclusion within 6 - 24 hours after the onset of vasopressor need and after all standard therapeutic measures have been implemented without clinical improvement (i.e.: the shock is considered refractory)
Exclusion criteria
* Patients under 18 years and over 80 * Lack of health insurance * Pregnancy * Standard guideline-based medical treatment not exhausted (detailed below at 3.6) standard medical therapy) * End stage organ failure * New York Heart Association Class IV. * Chronic renal failure with eGFR \< 15 ml/min/1,73 m2 * End-stage liver disease (MELD score \>30, Child-Pugh score Class C * Unlikely survival for 24 hours according to the attending physician * Acute onset of hemato-oncological illness * Post cardiopulmonary resuscitation care * Re-operation in context with the septic insult * Immunosuppression * systemic steroid therapy (\>10 mg prednisolon/day) * immunosuppressive agents (i.e.: methotrexate, azathioprine, cyclosporin, tacrolimus, cyclophosphamide) * Human immunodeficiency virus infection (active AIDS): HIV-VL \> 50 copies/mL * Patients with transplanted vital organs * Thrombocytopenia (\<20.000/ml) * More than 10%-of body surface area with a third-degree burn * Acute coronary syndrome
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Shock reversal | At the time of shock reversal assessed up to 5 days | Proportion of patients achieving shock reversal, defined as follows: no need (or minimal need, meaning max. the 10% of the maximum dose) of vasopressore for 3 hours, with haemodynamic measurements, and arterial, central venous blood gas analysis, arterial lactate level measurement, venous and arterial pCO2-gap and O2 saturation measurements to confirm cardiorespiratory stability |
| Time to shock reversal | From the start of the treatment until shock reversal assessed up to 5 days | The time from the start of the treatment (T0) until shock reversal |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Interleukin-6 level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Absolute level of interleukin-6 |
| Change in interleukin-6 level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Change in interleukin-6 level from the start of the treatment until the end of the study period |
| C-reactive protein level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Absolute level of C-reactive protein |
| Change in C-reactive protein level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Change in C-reactive protein level from the start of the treatment until the end of the study period |
| Interleukin-1 level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Absolute level of interleukin-1 |
| Change in interleukin-1 level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Change in interleukin-1 level from the start of the treatment until the end of the study period |
| Interleukin-1ra level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Absolute level of interleukin-1ra |
| Change in interleukin-1ra level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Change in interleukin-1ra level from the start of the treatment until the end of the study period |
| Interleukin-8 level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Absolute level of interleukin-8 |
| Change in interleukin-8 level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Change in interleukin-8 level from the start of the treatment until the end of the study period |
| Interleukin-10 level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Absolute level of interleukin-10 |
| Change in interleukin-10 level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Change in interleukin-10 level from the start of the treatment until the end of the study period |
| Tumor necrosis factor alpha level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Absolute level of tumor necrosis factor alpha |
| Change in tumor necrosis factor alpha level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Change in tumor necrosis factor alpha level from the start of the treatment until the end of the study period |
| Syndecan-1 level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Absolute level of syndecan-1 |
| Procalcitonine level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Absolute level of procalcitonine |
| Heparan sulphate level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Absolute level of heparan sulphate |
| Change in heparan sulphate level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Change in heparan sulphate level from the start of the treatment until the end of the study period |
| Arterial lactate levels | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Absolute level of arterial lactate levels |
| Change in arterial lactate levels level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Change in arterial lactate level from the start of the treatment until the end of the study period |
| Change in SOFA score | From the start of the treatment until the end of the treatment assessed up to 5 days | Change in SOFA score from the start of the treatment until the end of the study period |
| Change in extravascular lung water (EVLW) | From the start of the treatment until the end of the treatment assessed up to 5 days | Change in extravascular lung water (EVLW) from the start of the treatment until the end of the study period |
| Duration of mechanical ventilation | From the start of the treatment until the end of the treatment assessed up to 5 days | Duration of mechanical ventilation given in days |
| Duration of catecholamine requirement | From the start of the catecholamine requirement until the end of the catecholamine requirement assessed up to 5 days | Duration of catecholamine requirement given in days |
| Duration of renal replacement therapy | From the start of the renal replacement therapy requirement until the end of the renal replacement therapy requirement assessed up to 90+/-7 days at the second follow-up visit | Duration of renal replacement therapy given in days |
| Need for dialysis | day 28±7, day 90±7 | Rate of patients, who require dialysis |
| Length of internsive care unit stay | From admission to intensive care unit until the end of intensive care unit assessed at study completion an avarage of 90 days | Length of intensive care unit stay given in days |
| Length of hospital stay | From admission to the hospital until the end of hospital stay assessed at study completion an avarage of 90 days | Length of hospital stay given in days |
| Survival | Rate if surviving patients assessed at death, or study completion which ever happens first, up to 90 +/-7 days | Rate of surviving patients |
| Adverse events | Recorded at the occurrance of adverse events, and study completion up to 90 +/- 7 days | Rate of patients experiencing adverse events, or device deficiencies |
| Change in syndecan-1 level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Change in syndecan-1 level from the start of the treatment until the end of the study period |
| Change in procalcitonine level | 0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit | Change in procalcitonine level from the start of the treatment until the end of the study period |
Countries
Hungary
Outcome results
None listed