This trial will be a randomized controlled single-center pilot trial comparing the use of angiotensin II versus standard-of-care (SOC) vasopressor therapy in adult patients with persistent vasodilatory shock despite moderate-dose norepinephrine, with a primary outcome of the ability of novel biomarkers (renin and DPP3) to predict blood pressure response to angiotensin II. Given our angiotensin II will be compared to SOC, this will be an unblinded study.
Sepsis affects \>1 million Americans yearly and, when septic shock ensues, it 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, especially in certain subsets of patients, such as those with acute kidney injury (AKI) requiring renal replacement therapy (RRT), acute respiratory distress syndrome (ARDS), or high severity of illness. Furthermore, there are no validated biomarkers currently available to guide the choice of vasopressor therapy in septic shock. In this study the investigators will evaluate two potential biomarkers, renin and dipeptidyl peptidase 3 (DPP3). Renin has been shown in preliminary studies to accurately predict mortality in septic shock, outperforming lactate, and to predict beneficial response to AngII. A less well-known candidate biomarker is DPP3, which is an aminopeptidase that cleaves a variety of biologically active oligopeptides including angiotensin II. Similar to renin, preliminary observational data show that elevated DPP3 levels in patients with sepsis are associated with organ dysfunction and short-term mortality, outperforming lactate as a predictor of death. This study is an unblinded pilot randomized controlled trial (RCT) comparing AngII (intervention) to standard-of-care (SOC) vasopressor therapy in adult patients with persistent vasodilatory shock requiring moderate dose norepinephrine. The primary outcome will be the ability of renin and DPP3 to predict blood pressure (BP) response to AngII. As both renin and DPP3 are associated with overall short-term prognosis in sepsis, the SOC arm will allow us to determine if the predictive value of renin and DPP3 is specific to AngII therapy. A variety of secondary clinical outcomes will also be tracked, but the primary purpose of this pilot study is to inform the future design of a large multicenter RCT evaluating the biomarker-guided use of angiotensin II as a second-line vasopressor in septic shock.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
42
Angiotensin II (Giapreza) is a pharmacologic version of a naturally occurring peptide hormone of the same name which is a component of the renin-angiotensin-aldosterone system (RAAS). Angiotensin II (Giapreza) was FDA-approved in 2017 as a vasoconstrictive agent in the treatment of vasodilatory shock.
University of New Mexico Health Sciences Center
Albuquerque, New Mexico, United States
Ability of Baseline Active Renin to Predict Norepinephrine Equivalent Dose (NED) at 3 Hours
BP response will be assessed at 3 hours in both groups and measured using NED. The primary outcome will be ability of baseline renin (obtained at drug initiation or equivalent SOC timepoint) to predict total NED at 3 hours, stratified by treatment arm (AngII vs. SOC) and adjusted for baseline Sequential Organ Failure Assessment (SOFA) scores. Shown are beta-coefficients from linear regression analyses between baseline levels of each biomarker and change in NED at 3 hours, adjusted for baseline SOFA score. NED shown is as defined by Goradia et al. J Crit Care. 2021;61:233-240 and See et al. J Crit Care. 2024;79:154453.
Time frame: 3 hours post drug initiation or SOC equivalent
Ability of Baseline DPP3 to Predict NED at 3 Hours
BP response will be assessed at 3 hours in both groups and measured using NED. The primary outcome will be ability of baseline DPP3 (obtained at drug initiation or equivalent SOC timepoint) to predict total NED at 3 hours, stratified by treatment arm (AngII vs. SOC) and adjusted for baseline Sequential Organ Failure Assessment (SOFA) scores. Shown are beta-coefficients from linear regression analyses between baseline levels of each biomarker and change in NED at 3 hours, adjusted for baseline SOFA score. NED shown is as defined by Goradia et al. J Crit Care. 2021;61:233-240 and See et al. J Crit Care. 2024;79:154453.
Time frame: 3 hours post drug initiation or SOC equivalent
Hospital Mortality
Death before hospital discharge. Specified as a key secondary outcome.
Time frame: Until hospital discharge or 28 days post-randomization.
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