Dysfunctional Renin-Angiotensin System in Septic Shock

Phase 4

Not yet recruiting

• Conditions: Septic Shock
• Interventions: Drug: Angiotensin II; Drug: Norepinephrine

• Registration Number: NCT06746753
• Lead Sponsor: Wake Forest University Health Sciences

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Status Verified: 2024-12
• Study First Submitted: 2024-12-18
• Study First Submitted QC: 2024-12-18
• Study First Posted: 2024-12-24
• Last Update Submitted: 2025-03-24
• Last Update Posted: 2025-03-25
• Study Start: 2025-07
• Primary Completion: 2026-12
• Study Completion: 2026-12

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 78

Inclusion Criteria

• The presence of septic shock, defined by sepsis-3 criteria
• The requirement for Norepinephrine of at least 10 micrograms/minute up to 35 micrograms/minute for at least 1 hour, with or without Vasopressin, to maintain a mean arterial pressure of 65 mmHg
• Clinical suspicion or proven evidence of infection

Exclusion Criteria

• 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Angiotensin II	Angiotensin II	Continuous infusion of Angiotensin II for up to 48 hours
Norepinephrine	Norepinephrine	Continuous infusion of Norepinephrine for up to 48 hours

Primary Outcome Measures

Name	Time	Method
Mean Renin Level - Hour 24	Hour 24	Mean renin level 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.

Secondary Outcome Measures

Name	Time	Method
Norepinephrine Equivalent Dose Requirement (NEE)	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	NEE indicates severity of shock and need for vasopressors to support blood pressure. Normal range is 0.0-1.0 mcg/kg/min. Levels above normal indicate shock and need for vasopressors. The higher the level the more severe.
Number of Days Without Renal Replacement Therapy	Day 28	Number of days without renal replacement therapy
Number of Days of Vasopressor Use	Day 28	Number of days without vasopressor use
Number of Days Without Mechanical Ventilation	Day 28	Number of days without invasive mechanical ventilation
Number of Hours Vasopressor Free	Hour 72	Number of hours without requiring vasopressors during first 72 hours after randomization
Number of Hours Alive	Hour 72	Number of hours alive during first 72 hours after randomization
Number of Days Alive	Day 28	Number of days alive
Mean Renin Level	Baseline, Hour 3, Hour 12, Hour 48	Mean renin level 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.
Sequential Organ Failure Assessment (SOFA) Score	Baseline, Hour 24, Hour 48	SOFA score indicates the number and severity of failed organs and provides prognostic information on in-hospital survival in patients with severe sepsis and septic shock. Score above 0 indicates organ failure. The higher the score the more failed organs and degree of organ failure.
APACHE-II Score	Baseline, Hour 24, Hour 48	APACHE-II score assesses severity of illness in critically ill patients and indicates risk of mortality. Score range 0-10 low risk of mortality, 11-20 moderate risk, 21-30 high risk, 31 or above very high risk.
Lactate Level	Baseline, Hour 3, Hour 12, Hour 48	Lactate is an indicator of sepsis severity. Levels 2.3-20 mmol/L indicate sepsis. The higher the score the more severe.
Kidney Disease Improving Global Outcomes (KDIGO) Stage	Baseline, Hour 24, Hour 48	Participant stage of acute kidney injury will be determined as follows Stage 1: Increase in serum creatinine ≥ 0.3 mg/dL in 48 hours or 1.5 to 1.9 multiplied by baseline (in 7 days); Stage 2: 2.0 to 2.9 multiplied by baseline serum creatinine; Stage 3: 3.0 or more multiplied by baseline; increase in serum creatinine ≥ 4.0 mg/dL; or beginning of renal replacement therapy regardless of a previous KDIGO stage. Higher stage indicates higher severity of renal failure.
Creatinine Level	Baseline, Hour 24, Hour 48	Creatinine level is an indicator of renal disease severity. Normal range for women 0.7-1.3 mg/dL, men 0.6-1.1 mg/dL. Levels higher than normal indicate renal disease. The higher the level the more severe.
BUN Level	Baseline, Hour 24, Hour 48	BUN level is an indicator of renal disease severity. Levels above 24 mg/dL indicate renal disease. The higher the level the more severe.
Bicarbonate Level	Baseline, Hour 24, Hour 48	Bicarbonate level is an indicator of acid base disturbance severity. Normal range is 22-29 mEq/L. Levels above or below the normal range indicate acid base disturbance. The higher the score the more severe.
Number of Participants with Acute Respiratory Distress Syndrome (ARDS)	Baseline, Hour 24, Hour 48	Number of participants with ARDS
SpO2/FiO2 Ratio Level	Baseline, Hour 24, Hour 48	SpO2/FiO2 ratio level is an indicator of lung injury severity. Mild severity 315-235, moderate severity 148-235, severe \<148.
PaO2/FiO2 Ratio Level	Baseline, Hour 24, Hour 48	PaO2/FiO2 ratio level is an indicator of lung injury severity. Mild severity 201-300 mmHg; moderate severity 101-200 mmHg, severe ≤ 100 mmHg.
Serum Aspartate Aminotransferases Level	Baseline, Hour 24, Hour 48	Serum aspartate aminotransferases level is an indicator of liver injury severity. Normal range 8-48 U/L. Levels above normal indicate livery injury. The higher the level the more severe.
Alanine Aminotransferases Level	Baseline, Hour 24, Hour 48	Alanine aminotransferases level is indicator of liver injury severity. Normal range 7-55 U/L. Levels higher than normal indicate liver injury. The higher the level the more severe.
Alkaline Phosphatase Level	Baseline, Hour 24, Hour 48	Alkaline phosphatase level is an indicator of liver injury severity. Normal range 40-129 U/L. Levels higher than normal indicate liver injury. The higher the level the more severe.
Bilirubin Level	Baseline, Hour 24, Hour 48	Bilirubin level is an indicator of liver injury severity. Normal range 0.1-1.2 mg/dL. Levels higher than normal indicate liver injury. The higher the liver the more severe.
Albumin Level	Baseline, Hour 24, Hour 48	Albumin level is an indicator of liver injury severity. Normal range 3.5-5.0 g/dL. Levels higher than normal indicate liver injury. The higher the level the more severe.
Troponin I Level	Baseline, Hour 24, Hour 48	Troponin I level is an indicator of cardiac myocyte injury. Normal range 0-0.04 ng/mL. Levels higher than normal indicate cardiac myocyte injury. The higher the level the more severe.
Troponin T Level	Baseline, Hour 24, Hour 48	Troponin T level is an indicator of cardiac myocyte injury. Normal range 0-0.01 ng/mL. Levels higher than normal indicate cardiac myocyte injury. The higher the level the more severe.
Neutrophil Gelatinase-Associated Lipocalin Serum Level	Baseline, Hour 24, Hour 48	Neutrophil gelatinase-associated lipocalin serum level indicates risk of kidney injury. Normal serum level is \<10 mcg/L. Levels higher than normal indicate risk of kidney injury.
Neutrophil Gelatinase-Associated Lipocalin Urine Level	Baseline, Hour 24, Hour 48	Neutrophil gelatinase-associated lipocalin urine level indicates risk of kidney injury. Normal urine level is ≤50 ng/ml. Risk of kidney disease: Low risk 51-149 ng/ml, moderate risk 150-299 ng/ml, and high risk ≥300 ng/ml.
Kidney Injury Molecule-I Urine Level	Baseline, Hour 24, Hour 48	Kidney injury molecule-I urine level is used to detect kidney injury. Normal level is \<1 ng/ml. Levels higher than normal indicate ischemic kidney injury.
Kidney Injury Molecule-I Blood Level	Baseline, Hour 24, Hour 48	Kidney injury molecule-I blood level is used to detect kidney injury. Normal levels 0.42-2.0 ng/ml. Levels higher than normal indicate kidney injury. The higher the level the more severe.
Soluble Receptor for Advanced Glycation End Product Level	Baseline, Hour 24, Hour 48	Soluble receptor for advanced glycation end product level is a marker of aging, hypertension and diabetes. Normal range is 647-1248 pg/ml. Levels higher than normal indicate risk for hypertension and diabetes.
Angiopoietin-2 Level	Baseline, Hour 24, Hour 48	Angiopoietin-2 level is a marker of inflammation. Normal range is 1434-4141 pg/mL. Levels higher than normal indicate inflammation.
Syndecan-1 Level	Baseline, Hour 24, Hour 48	Syndecan-1 level is a marker of disease severity in critically ill patients. Levels \>20ng/ml indicate severe disease. The higher the level the more severe.
Protein C Level	Baseline, Hour 24, Hour 48	Protein C level is an indicator of inflammation and thrombotic state. Normal level is \<8 mg/L. Levels higher than normal indicate inflammation and thrombotic state. The higher the level the more severe.
Neuron-Specific Enolase Level	Baseline, Hour 24, Hour 48	Neuron-specific enolase level is an indicator of brain injury. Normal range is 16-17 ug/L. Levels higher than normal indicate brain injury. The higher the level the more severe.
S-100β Level	Baseline, Hour 24, Hour 48	S-100β level is indicator of brain injury. Normal range is 0.02-0.05 μg/dL. Levels higher than normal indicate brain injury. The higher the number the more severe.
TNFα Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	TNFα level is an indicator of systemic inflammation. Normal levels are 75 +/- 15 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.
sTNFR1 Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	sTNFR1 level is an indicator of systemic inflammation. Normal levels are \<2.4 ng/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.
IL-6 Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	IL-6 level is an indicator of systemic inflammation. Normal range is 0-43.5 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.
sIL-6R Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	sIL-6R level is an indicator of systemic inflammation. Normal range is 14-46 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.
IL-8 Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	IL-8 level is an indicator of systemic inflammation. Normal range is 0-66.1 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.
IL-1β Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	IL-1β level is an indicator of systemic inflammation. Normal range is 0.5-12 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.
Interferon Gamma Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	IFN-ɣ level is an indicator of systemic inflammation. Normal range is 0-8.6 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.
IL12p70 Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	IL12p70 level is an indicator of systemic inflammation. Normal range is 0-1.9 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.
IL-17 Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	IL-17 level is an indicator of systemic inflammation. Normal range is 0-1.4 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.
MIP1-alpha Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	MIP1-αlpha level is an indicator of systemic inflammation. Normal range is 0-208 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.
MIP1-beta Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	MIP1-beta level is an indicator of systemic inflammation. Normal range is 59-647 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.
IP-10 Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	IP-10 level is an indicator of systemic inflammation. Normal range is 4.8-9.8 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.
IL-10 Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	IL-10 level is an indicator of systemic inflammation. Normal range is 4.8-9.8 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.
IL-1RA Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	IL-1RA level is an indicator of systemic inflammation. Normal range is 100-300 ng/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.
IL-12p40 Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	IL-12p40 level is an indicator of systemic inflammation. Normal range is 0.064-1000 pg/ml. Levels higher than normal indicate inflammation. The higher the score the more severe.
C reactive protein (CRP) Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	CRP level is an indicator of systemic inflammation. Normal range is 0-10 mg/dl. Levels higher than normal indicate inflammation. The higher the score the more severe.
Procalcitonin Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	Procalcitonin level is an indicator of systemic inflammation. Levels \>0.25 mg/ml indicate inflammation and infection. The higher the score the more severe.
Platelet Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	Platelet level is an indicator of systemic inflammation and thrombocytosis. Normal range is 150000-450000 platelets per microliter. Levels higher than normal indicate inflammation and thrombocytosis. The higher the score the more severe.
Absolute Neutrophil Count Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	Absolute neutrophil count level is an indicator of inflammation and infection/sepsis. Normal range is 2500-7000 neutrophils per microliter. Levels higher than normal indicate inflammation, infection/sepsis. The higher the score the more severe.
Absolute Granulocyte Count Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	Absolute granulocyte count level is an indicator of inflammation and infection/sepsis. Normal range is 1500-8500 granulocytes per microliter. Levels higher than normal indicate inflammation, infection/sepsis. The higher the score the more severe.
Absolute Lymphocytes Count Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	Absolute lymphocyte count level is an indicator of inflammation and infection/sepsis. Normal range is 1000-4800 granulocytes per microliter. Levels higher than normal indicate inflammation, infection/sepsis. The higher the score the more severe.
Neutrophil-Lymphocyte Ratio Level	Baseline, Hour 3, Hour 12, Hour 24, Hour 48	Neutrophil-lymphocyte ratio level is an indicator of inflammation and infection/sepsis or marrow malignancy. Normal range is 1-2. Levels higher than normal indicate inflammation, infection/sepsis, marrow malignancy. The higher the score the more severe.

Trial Locations

Locations (1)

Atrium Health Wake Forest Baptist; 🇺🇸 Winston-Salem, North Carolina, United States