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
40
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 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, using treatment arm (AngII vs. SOC) and baseline Sequential Organ Failure Assessment (SOFA) scores as covariables.
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 to predict total NED at 3 hours, using treatment arm (AngII vs. SOC) and baseline SOFA scores as covariables.
Time frame: 3 hours post drug initiation or SOC equivalent
Ability of pre-baseline renin to predict NED at 3 hours
The primary outcome analysis will be repeated, but instead using the ability of pre-baseline renin levels (obtained at randomization, approximately 2 hours before drug initiation or equivalent SOC timepoint) to predict total NED at 3 hours, using treatment arm (AngII vs. SOC) and baseline SOFA scores as covariables.
Time frame: 3 hours post drug initiation or SOC equivalent
Ability of pre-baseline DPP3 to predict NED at 3 hours
The primary outcome analysis will be repeated, but instead using the ability of pre-baseline DPP3 levels (obtained at randomization, approximately 2 hours before drug initiation or equivalent SOC timepoint) to predict total NED at 3 hours, using treatment arm (AngII vs. SOC) and baseline SOFA scores as covariables.
Time frame: 3 hours post drug initiation or SOC equivalent
Ability of changes in renin level to predict NED at 3 hours
The primary outcome analysis will be repeated, but instead evaluating the ability of changes in renin level (from pre-baseline to baseline) to predict total NED at 3 hours, using treatment arm (AngII vs. SOC) and baseline SOFA scores as covariables.
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Time frame: 3 hours post drug initiation or SOC equivalent
Ability of changes in DPP3 level to predict NED at 3 hours
The primary outcome analysis will be repeated, but instead evaluating the ability of changes in DPP3 level (from pre-baseline to baseline) to predict total NED at 3 hours, using treatment arm (AngII vs. SOC) and baseline SOFA scores as covariables.
Time frame: 3 hours post drug initiation or SOC equivalent
Background NED at 1 hour
Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints.
Time frame: 1 hour post drug initiation or SOC equivalent
Background NED at 6 hours
Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints.
Time frame: 6 hours post drug initiation or SOC equivalent
Background NED at 12 hours
Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints.
Time frame: 12 hours post drug initiation or SOC equivalent
Background NED at 24 hours
Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints.
Time frame: 24 hours post drug initiation or SOC equivalent
Background NED at 48 hours
Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints.
Time frame: 48 hours post drug initiation or SOC equivalent
Background NED at 72 hours
Comparison of background NED in AngII arm and SOC arm will be compared at multiple timepoints.
Time frame: 72 hours post drug initiation or SOC equivalent
Time to shock reversal
Time (in hours) to sustained vasopressor independence will be compared in two arms.
Time frame: 72 hours post drug initiation or SOC equivalent
Change in Sequential Organ Failure Assessment (SOFA) score at 24 hours
Change in SOFA score from baseline to 24 hours. (SOFA score ranges from 0 to 24, with higher score indicating worse organ function.)
Time frame: 24 hours post drug initiation or SOC equivalent
Change in Sequential Organ Failure Assessment (SOFA) score at 48 hours
Change in SOFA score from baseline to 24 hours. (SOFA score ranges from 0 to 24, with higher score indicating worse organ function.)
Time frame: 48 hours post drug initiation or SOC equivalent
Change in Sequential Organ Failure Assessment (SOFA) score at 72 hours
Change in SOFA score from baseline to 24 hours. (SOFA score ranges from 0 to 24, with higher score indicating worse organ function.)
Time frame: 72 hours post drug initiation or SOC equivalent
Acute Kidney Injury (AKI)
Rate of AKI during first 28 days as defined by KDIGO (Kidney Disease: Improving Global Outcomes) criteria
Time frame: 28 days post randomization
Days free from renal replacement therapy (RRT)
Days alive and free from RRT. Freedom from RRT is considered a period without RRT of at least 72 hours. Specified as a key secondary outcome.
Time frame: 28 days post randomization
Days free from invasive mechanical ventilation (IMV)
Days alive and free from IMV. Specified as a key secondary outcome.
Time frame: 28 days post randomization
Intensive care unit (ICU) length of stay
Length of stay (in days)
Time frame: Until ICU discharge or study termination, up to 26 weeks.
Hospital length of stay
Length of stay (in days)
Time frame: Until hospital discharge or study termination, up to 26 weeks.
ICU mortality
Death before ICU discharge. Specified as a key secondary outcome.
Time frame: Until ICU discharge or 28 days post-randomization.
Hospital mortality
Death before hospital discharge. Specified as a key secondary outcome.
Time frame: Until hospital discharge or 28 days post-randomization.