Mechanistic Assessment of Norepinephrine TheRapy vs. Angiotensin-II in Septic Shock (MANTRA) Grant Submission- Dysfunctional Renin-Angiotensin System in Septic Shock
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 入组人数
- 78
- 试验地点
- 2
- 主要终点
- Mean Renin Level - Hour 24
研究概览
简要总结
Despite best therapy efforts, sepsis and septic shock are associated with mortality rates of up to 40%. This clinical trial will determine the benefit of exogenous Angiotensin II versus norepinephrine (conventional care) treatment in septic shock patients. This trial will determine whether there are better predictors of septic shock severity. This approach may inform more appropriate treatment regimens and improve outcomes for these patients.
详细描述
This study will determine whether normalization of renin-angiotensin-aldosterone system (RAAS) signaling in sepsis occurs more rapidly with treatment with Angiotensin II compared with conventional vasopressors. Trial samples will be used to identify the best RAAS biomarker predictor of treatment response via in-depth longitudinal analysis of RAAS component and to determine the extent and mechanisms of Angiotensin II impact on innate immune function during sepsis. Successful accomplishment of our aims will provide the capability to improve endotyping of septic patients by establishing the most precise and robust measurement of renin (and RAAS dysfunction). This work will improve staging and clinical precision and will facilitate the criteria for therapeutic development of targets in septic shock.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •- The presence of septic shock, defined by sepsis-3 criteria: 1-adult patients (18 years or older) with septic shock, defined by SEPSIS-3 criteria: a) suspected or known infection, b) hypotension requiring vasopressors, and c) lactate >2mmol/L 2-receiving either norepinephrine or phenylephrine with or without additional vasopressor support 3- total norepinephrine equivalent dose (NED) ≥0.1 mcg/kg/min and ≤0.5 mcg/kg/min, to maintain a MAP of at least 65 mmHg, is required for randomization 4-ability to consent and randomize within 24 hrs of first reaching NED threshold and within 48 hrs of hospital arrival
排除标准
- •Age <18 years
- •Prisoners
- •Pregnant women
- •Patients for whom urgent surgery is anticipated
- •Leukocyte count <1,000 cells/μL
- •Absolute monocyte count <200 cells/μL
- •Bone marrow transplant within the past 30 days
- •Patients that will be withdrawing aggressive resuscitation, including withdraw of vasopressor support
- •transfer from outside ICU
- •history of liver cirrhosis with Child-Pugh score ≥6
研究组 & 干预措施
Angiotensin II
Continuous infusion of Angiotensin II for up to 48 hours
干预措施: Angiotensin II (Drug)
Norepinephrine
Continuous infusion of Norepinephrine for up to 48 hours
干预措施: Norepinephrine (Drug)
结局指标
主要结局
Mean Renin Level - Hour 24
时间窗: Hour 24
Mean plasma renin level (PRA) as a measure of renin-angiotensin-aldosterone system restoration. Normal levels of active renin \<1.1 pM (40 pg/mL). A level higher than normal can indicate level of shock.
次要结局
- Troponin I Level(Baseline, Hour 24, Hour 48)
- Number of Days Without Renal Replacement Therapy(Day 28)
- Number of Days of Vasopressor Use(Day 28)
- Number of Days Without Mechanical Ventilation(Day 28)
- Number of Hours Vasopressor Free(Hour 72)
- Number of Hours Alive(Hour 72)
- Number of Days Alive(Day 28)
- Sequential Organ Failure Assessment (SOFA) Score(Baseline, Hour 24, Hour 48)
- APACHE-II Score(Baseline, Hour 24, Hour 48)
- Kidney Disease Improving Global Outcomes (KDIGO) Stage(Baseline, Hour 24, Hour 48)
- Creatinine Level(Baseline, Hour 24, Hour 48)
- BUN Level(Baseline, Hour 24, Hour 48)
- Bicarbonate Level(Baseline, Hour 24, Hour 48)
- Number of Participants with Acute Respiratory Distress Syndrome (ARDS)(Baseline, Hour 24, Hour 48)
- SpO2/FiO2 Ratio Level(Baseline, Hour 24, Hour 48)
- PaO2/FiO2 Ratio Level(Baseline, Hour 24, Hour 48)
- Serum Aspartate Aminotransferases Level(Baseline, Hour 24, Hour 48)
- Alanine Aminotransferases Level(Baseline, Hour 24, Hour 48)
- Alkaline Phosphatase Level(Baseline, Hour 24, Hour 48)
- Bilirubin Level(Baseline, Hour 24, Hour 48)
- Albumin Level(Baseline, Hour 24, Hour 48)
- Troponin T Level(Baseline, Hour 24, Hour 48)
- Neutrophil Gelatinase-Associated Lipocalin Serum Level(Baseline, Hour 24, Hour 48)
- Neutrophil Gelatinase-Associated Lipocalin Urine Level(Baseline, Hour 24, Hour 48)
- Kidney Injury Molecule-I Urine Level(Baseline, Hour 24, Hour 48)
- Kidney Injury Molecule-I Blood Level(Baseline, Hour 24, Hour 48)
- Soluble Receptor for Advanced Glycation End Product Level(Baseline, Hour 24, Hour 48)
- Syndecan-1 Level(Baseline, Hour 24, Hour 48)
- Protein C Level(Baseline, Hour 24, Hour 48)
- Neuron-Specific Enolase Level(Baseline, Hour 24, Hour 48)
- S-100β Level(Baseline, Hour 24, Hour 48)
- TNFα Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- sTNFR1 Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- IL-6 Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- sIL-6R Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- IL-8 Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- IL-1β Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- Interferon Gamma Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- IL12p70 Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- IL-17 Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- MIP1-alpha Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- MIP1-beta Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- IP-10 Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- IL-10 Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- IL-1RA Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- IL-12p40 Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- C reactive protein (CRP) Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- Procalcitonin Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- Platelet Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- Absolute Neutrophil Count Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- Absolute Granulocyte Count Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- Absolute Lymphocytes Count Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- Neutrophil-Lymphocyte Ratio Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48)
- Norepinephrine Equivalent Dose Requirement (NEE)(Baseline, Hour 3, Hour 12, Hour 24, Hour 48, Hour 72)
- Mean Renin Level(Baseline, Hour 3, Hour 12, Hour 48, Hour 72)
- Angiopoietin-2 Level(Baseline, Hour 24, Hour 48, Hour 72)
- Lactate Level(Baseline, Hour 3, Hour 12, Hour 24, Hour 48, Hour 72)
- Angiotensin (1-7)(Baseline, Hour 3, Hour 12, Hour 24, Hour 48, Hour 72)
- Plasma renin activity(baseline, hour 3, hour 12, hour 24, hour 48)
- Prorenin(baseline, hour 3, hour 12, hour 24, hour 48)
- Soluble prorenin receptor (sPRR)(baseline, hour 24, hour 48)
- Aldosterone(baseline, hour 3, hour 12, hour 24, hour 48)
- Intact Aogen(baseline, hour 24, hour 48)
- ANG II(baseline, hour 3, hour 12, hour 24, hour 48, hour 72)
- Angiotensin-converting enzyme (ACE)(baseline, hour 24, hour 48)
- Angiotensin-converting enzyme-2 (ACE2)(baseline, hour 24, hour 48)
- Dipeptidyl peptidase 3 (DPP3)(baseline, hour 24, hour 48)
- RNA Paxgene Bulk (Bulk RNA sequencing)(baseline, hour 24, hour 48)
- Whole blood cryopreserved (scRNAsesq)(baseline, hour 24, hour 48)