Russian Clinical Trial of Mesenchymal Cells in Patients With Septic Shock and Severe Neutropenia

Russian Single-center Open Randomized Clinical Trial of the Impact of Mesenchymal Stromal Cells Therapy on Organ Dysfunction and 28-day Mortality in Patients With Septic Shock and Severe Neutropenia.

Septic shock remains a significant clinical problem associated with high rates of mortality among neutropenic patient despite antimicrobial therapy and supportive care. Recently, mesenchymal stromal cells (MSC) have demonstrated remarkable potential effect in sepsis. MSC treatment significantly reduced mortality in septic mice receiving appropriate antimicrobial therapy. MSCs reduced systemic inflammatory cytokine levels in mice, down-regulated of inflammation and inflammation-related genes (such as interleukin-10, interleukin-6). Bacterial clearance was greater in MSC-treated mice. Thus, MSCs have beneficial effects on experimental sepsis and suggest that MSСs-therapy may be an effective adjunctive treatment to reduce sepsis-related mortality. The safety of MSCs is proved by Graft-versus-host disease treatment MSCs in patients after bone marrow transplantation. This study hypothesis is that MSCs reduce organ dysfunction/injury, systemic inflammation and mortality in patients with septic shock and severe neutropenia. The main goal of the study is to evaluate the impact of MSCs therapy on organ dysfunction/injury, systemic inflammation and 28-day mortality in patients with septic shock and severe neutropenia. All patients will be randomized in two groups: control group (standard treatment of septic shock) and MSCs-group (standard treatment of septic shock + MSCs infusion of 1-2 millions/kg/ day).

All activities related to this human subjects research have been guided by ethical principles and have been reviewed and approved Federalwide Assurance National Ctr for Hematology, FWA00006482. The goal of the trial is to evaluate plasma concentration of proinflammatory cytokine interleukin-6 and the antiinflammatory cytokine interleukin-10, plasma levels of blood creatinine, bilirubin, procalcitonin, C-reactive protein. Then we will evaluate requirement for renal replacement therapy, requirement for mechanical ventilation or non-invasive mechanical ventilation, pulmonary function-coefficient, partial oxygen pressure arterial blood level, electrocardiograms, Kaplan - Meier curve,28-days mortality.

Septic Shock, Nonchemotherapy Drug-induced Neutropenia, Neutropenia After Chemotherapy in Oncohematological Patients, Neutropenia in Patients With Aplastic Anemia

Mesenchymal Stromal Cells, Septic Shock, Neutropenia, Procalcitonin, Interleukin-6, Interleukin-10, C-reactive protein, Survival, Organ dysfunction

according to Surviving Sepsis Campaign 2012 Antibiotic therapy Fluid therapy Vasopressors Inotropic therapy Steroids

MSCs intravenous infusion of 1-2 millions/kg/day will be performed not more than 10 hs after onset of septic shock in patients with severe neutropenia(≤ 1x10^9/l). according to Surviving Sepsis Campaign 2012: Antibiotic therapy Fluid therapy Vasopressors Inotropic therapy Steroids

MSCs intravenous infusion of 1-2 millions/kg/day will be performed not more than 10 hs after onset of septic shock in patients with severe neutropenia(≤ 1x10^9/l).

Liver: levels of serum total bilirubin, transaminases, lactate dehydrogenase, plasma protrombin level Pancreas: amylase level Renal: number of hemodialysis/ hemodiafiltration, blood urea and creatinine levels Pulmonary: requirement for mechanical ventilation or non-invasive mechanical ventilation, pulmonary function-coefficient, partial oxygen pressure arterial blood level Cardiac: requirement for vasopressors, main parameters obtained from Transpulmonary Thermodilution- Systemic Vascular Resistance Index ( SVRI ), Cardiac Output (CO)

plasma concentration of proinflammatory cytokine IL-6 and the antiinflammatory cytokine IL-10, concentration of procalcitonin, C-reactive protein Fibrinogen level, lactate level , the factor XII-dependent fibrinolytic activity blood routine examination

Inclusion Criteria: septic shock ≤10 hs after onset of septic shock severe neutropenia(≤ 1 10^9/l) Patients ≥17 years Signed Informed Consent to treatment Exclusion Criteria: oncohematological patients with resistance to chemotherapy Unsigned Informed Consent to treatment Age >75 years; Pregnancy

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Mei SH, Haitsma JJ, Dos Santos CC, Deng Y, Lai PF, Slutsky AS, Liles WC, Stewart DJ. Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med. 2010 Oct 15;182(8):1047-57. doi: 10.1164/rccm.201001-0010OC. Epub 2010 Jun 17.

Kebriaei P, Robinson S. Treatment of graft-versus-host-disease with mesenchymal stromal cells. Cytotherapy. 2011 Mar;13(3):262-8. doi: 10.3109/14653249.2010.549688. Epub 2011 Jan 13.