Cytokine Storm, Septic Shock
Conditions
Keywords
Sepsis, Septic shock, Hemoperfusion, Blood purification, HA-330
Brief summary
Sepsis and septic shock are major causes of ICU admission worldwide. Despite recent advances in treatment, including targeted resuscitation and timely use of antimicrobial agents, mortality of ICU patients with septic shock remains steadily high. Especially in those requiring high dosage of vasopressors, whose 28-day mortality rate could reach 60%. The pathophysiology of septic shock emphasizes on the role of dysregulated host immune response towards inciting microbes, producing excessive inflammatory cytokines which lead to tissue damage and subsequent organ failures. Multiple therapies targeting the overwhelming inflammatory response in patients with septic shock have been studied (ref). While some showed promising results in modulating inflammation in observational studies (ref), none other than systemic corticosteroids lead to better clinical outcomes in the randomized controlled studies. The reasons for their failures are the complexity of the inflammation cascades, where treatments specifically targeting parts of the process may not be able to achieve meaningful effects. Extracorporeal blood purification therapy is an adjunctive treatment option more extensively studied over the last decade. By passing patients' blood or plasma through specifically developed absorber, various inflammatory cytokines are absorbed to resins inside the devices and removed from the circulation. Decreasing levels of inflammatory cytokines may subsequently attenuate systemic inflammation leading to shock reversal and better survival. HA-330 disposable hemoperfusion cartridge (Jafron®, China) is an absorber targeting hyper-inflammatory states including septic shock. It is designed to nonspecifically absorb molecules with molecular weight 10-60 kilo-Dalton, making it effective for removing various pro-inflammatory cytokines and potentially modulating the inflammatory cascade. Previous randomized study in patients with sepsis compared between the add-on 3 daily session of hemoperfusion with HA-330 adsorber and the standard therapy . .Circulating interleukin-6 and interleukin-8 levels of patients underwent hemoperfusion significantly reduced after two sessions when compared to baseline. Their values on day 3 were also significantly lower than those of the control group. Adjunctive hemoperfusion were associated with lower ICU mortality, butno significant difference in hospital and 28-day mortality between the two groups(ref). However, approximately 50% of enrolled patients had sepsis without shock. Generalization of the findings to more severe cohorts of septic shock patients are therefore limited. Patients with septic shock have higher cytokines level than septic patients without shock. Hence, they are theoretically more likely to benefit from therapies aiming to reduce cytokine levels. We hypothesize that adjunctive hemoperfusion with HA-330 adsorber would be associated with better outcomes in a more severe group of patients with septic shock.
Interventions
DEVICEHA-330 Disposable Hemoperfusion Cartridge (Jafron, China)
* If no appropriate vascular access available, a double lumen catheter is placed by treating physicians, under ultrasonographic guidance. * Two sessions of hemoperfusion using HA-330 Disposable Hemoperfusion Cartridge are performed 24 hours apart. * Hemoperfusion is performed using either hemoperfusion or continuous renal replacement therapy machine. The optimal blood flow rate is 150-200 mL/min. The duration for each session in 2 hours. No systemic anticoagulant is given except for priming of the cartridge according to manufacturer recommendations. * The first hemoperfusion session is recommended to be initiated within 12 hours after randomization.
Sponsors
Siriraj Hospital
Mahidol University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Septic shock patients, according to The Third International Consensus Definitions for Sepsis and Septic Shock and * Is receiving intravenous norepinephrine 0.2 mcg/kg/min or more, or equivalent dose of other vasoactive agents
Exclusion criteria
One who has * acute coronary syndrome * life-threatening arrhythmias * acute ischemic stroke * life-threatening, uncontrolled bleeding * underlying conditions judged to have with limited life expectancy (less than 6 months) by primary physicians One who is * judged by treating physicians as in moribund state and expected not to survive to 24 hours regardless of treatment given * known to be pregnant at enrollment * not in the competent state to give informed consent and not having relatives to do so * not willing to pursue intensive medical therapy considered standard of care for patients with septic shock
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 28-day mortality | 28 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hospital mortality | up to 24 weeks | — |
| ICU-free day | 28 days | Number of days that patient is alive and not admitted in the ICU in the first 28 days, with the day of randomization defined as Day 0 In case of ICU readmission, the days from the final ICU discharge within 28 days are counted. All 28-day non-survivors are counted 0, irrespective of their place of care at the time of death, and censored observations after 28 days |
| Vasopressor-free day | 28 days | Number of days that patient is alive after successful discontinuation of vasoactive agents in the first 28 days, with the day of randomization defined as Day 0 Successful discontinuation of vasoactive agents is defined as discontinuation of vasoactive agents without resumption until Day 28 or until hospital discharge, whichever is first. In case of multiple periods of vasoactive agents use, the days from the final discontinuation of vasoactive agents are counted. All 28-day non-survivors are counted 0, irrespective of their use of vasoactive agents at the time of death, and censored observations after 28 days |
| Ventilator-free day | 28 days | Number of days that patient is alive after successful liberation of mechanical ventilation in the first 28 days, with the day of randomization defined as Day 0 Successful liberation of mechanical ventilation is defined as discontinuation mechanical ventilation (either via orotracheal or tracheostomy tube) for 48 hours or more. Non-invasive positive pressure ventilation is not regarded as mechanical ventilation. In case of multiple periods of mechanical ventilation, the days from the final successful liberation of mechanical ventilation within 28 days are counted. All 28-day non-survivors are counted 0, irrespective of their ventilation status at the time of death, and censored observations after 28 days |
| Renal replacement therapy (RRT) -free day | 28 days | Number of days that patient is alive after successful discontinuation of renal-replacement therapy in the first 28 days, with the day of randomization defined as Day 0 Successful discontinuation of renal-replacement therapy is defined as discontinuation of all modes of renal-replacement therapy without resumption for at least 7 days and until Day 28 or until hospital discharge, whichever is first. Hemoperfusion according to treatment protocol in 'Standard of care and hemoperfusion with HA-330' arm is not counted as renal-replacement therapy. All 28-day non-survivors are counted 0, irrespective of their use of renal-replacement therapy at the time of death, and censored observations after 28 days |
| Vasoactive inotropic score at Hour 24, Hour 48 and Day 7 | 7 days | — |
| ICU mortality | up to 24 weeks | — |
| Arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) at Hour 24, Hour 48 and Day 7 | 7 days | — |
| Acute Physiology and Chronic Health Evaluation score (APACHE II) at Hour 24, Hour 48 and Day 7 | 7 days | — |
| Sequential Organ Failure Assessment score (SOFA) at Hour 24, Hour 48 and Day 7 | 7 days | — |
| Serum C-reactive protein level at Hour 24 and Hour 48 | 48 hours | — |
| Plasma Interleukin-6 level at Hour 24 and Hour 48 | 48 hours | — |
| Adverse events | 28 days | — |
| Shock reversal at Hour 6 | 6 hours | Shock reversal is defined as mean arterial pressure at or more than 65 mmHg with one of the following: * Reduction of serum lactate level of 20% or more * Hourly urine output of 0.5 mL/kg or more |
Countries
Thailand
Contacts
Primary ContactRanistha Ratanarat, MD
Backup ContactNattapat Wongtirawit, MD
Outcome results
None listed