Funding and protocol changes. Replaced with new pilot trial.

This will be a randomized controlled unblinded pragmatic single-center pilot trial of the use of vasopressin vs. angiotensin II as a second-line vasopressor in patients with septic shock and persistent hypotension despite moderate-to-high doses of norepinephrine.

Sepsis affects >1 million Americans yearly and, when septic shock ensues, is associated with high morbidity and mortality. Though first-line norepinephrine is standard of care, there are limited prospective data to guide the choice of additional vasopressors in septic shock. While more studies are needed, preliminary data suggest that the vasopressor angiotensin II (AngII) may improve outcomes in septic shock.

This study is a pilot randomized controlled trial (RCT) comparing AngII (intervention) and vasopressin (standard of care) as second-line vasopressors in septic shock. The goal is to demonstrate feasibility of a large multicenter RCT and eventually to demonstrate that AngII use improves important endpoints (e.g., mortality, need for organ support) in all or certain subsets of patients with septic shock.

Furthermore, there are no biomarkers currently available and validated to guide the choice of vasopressor therapy in septic shock. In this study the investigators will investigate serum renin as such a biomarker. Renin has been shown in preliminary studies to accurately predict mortality in septic shock, outperforming lactate, and to predict beneficial response to AngII. The investigators aim to validate the use of renin as a biomarker in septic shock and prove its utility in guiding vasopressor selection, with the goal of incorporating renin levels at specified time points and/or change in renin levels into an algorithm used to select patients for AngII therapy in the subsequent large multicenter RCT.

Inclusion Criteria:

• 1. Adult patients ≥18 years-old with vasodilatory shock refractory to norepinephrine monotherapy, defined as those who require ≥0.2 mcg/kg/min to maintain a MAP between 65-70 mmHg. Patients will be screened once they require ≥0.1 mcg/kg/min of norepinephrine and, if eligible, may be consented at this point. Study drug (angiotensin II or vasopressin) will be initiated once norepinephrine dose reaches ≥0.2 mcg/kg/min for at least 30 minutes.
• 2. Patients are required to have central venous and arterial catheters present, and they are expected to remain in place for at least the initial 72 hours of study.
• 3. Patients are required to have an indwelling urinary catheter present, and it is expected to remain in place for at least the 72 hours of study.
• 4. Patients must have received 20-30 mL/kg of crystalloid over the previous 24-hour period, as clinically appropriate, and no longer be fluid responsive as per UNMH protocol. By UNMH protocol, lack of fluid responsiveness is considered a failure to increase stroke volume, stroke volume index, cardiac output, or cardiac index (typically measured by non-calibrated pulse contour analysis using a FloTrac device) by at least 10% after a 500-mL crystalloid bolus or a passive leg raise. Patients for whom the treating physicians feel that 20 mL/kg of crystalloid may be clinically inappropriate can qualify for the study if the reason for withholding further IV fluids is documented.
• 5. Patient or (in patients unable to consent) legal authorized representative (LAR) is willing and able to provide written informed consent and comply with all protocol requirements.
• 6. Approval from the attending physician and clinical pharmacist conducting the study.

Exclusion Criteria:

• 1. Patients who are < 18 years of age.
• 2. Patients diagnosed with acute occlusive coronary syndrome requiring intervention and/or cardiogenic shock.
• 3. Patients with or suspected to have abdominal aortic aneurysm or aortic dissection.
• 4. Acute stroke.
• 5. Patients with acute mesenteric ischemia or those with a history of mesenteric ischemia.
• 6. Patients with known Raynaud's phenomenon, systemic sclerosis, or vasospastic disease.
• 7. Patients on veno-arterial (VA) ECMO.
• 8. Patients with liver failure with a Model for End-Stage Liver Disease (MELD) score of ≥30.
• 9. Patients with burns covering >20% of total body surface area.
• 10. Patients with a history of asthma or COPD with active acute bronchospasm or (if not mechanically ventilated) with an acute exacerbation of their asthma/COPD requiring the use of inhaled bronchodilators.
• 11. Patients requiring more than 500 mg daily of hydrocortisone or equivalent glucocorticoid medication as a standing dose.
• 12 Patients with an absolute neutrophil count (ANC) of < 1,000/mm3.
• 13. Patients with hemorrhagic shock OR active bleeding AND an anticipated need (within 48 hours of initiation of the study) for transfusion of >4 units of packed red blood cells.
• 14. Patients with active bleeding AND hemoglobin < 7g/dL or any other condition that would contraindicate serial blood sampling.
• 15. Untreated venous thromboembolism (VTE) or inability to tolerate pharmacologic VTE prophylaxis.
• 16. Patients with a known allergy to mannitol.
• 17. Patients with an expected survival of <24 hours, SOFA score ≥ 16, or death deemed to be imminent or inevitable during the admission
• 18. Either the attending physician or patient and/or substitute decision-maker are not committed to all active treatment (e.g., DNR status).
• 19. Patients who are known to be pregnant at the time of screening. [All women ≤50 years-old will need a negative serum pregnancy test (serum quantitative beta-hCG) to enroll.]
• 20. Prisoner status
• 21. Patients who are current participating in another interventional clinical trial.