Septic Shock, Vasodilatory Shock
Conditions
Keywords
septic shock, vasopressor, angiotensin II, renin, dipeptidyl peptidase 3 (DPP3), randomized controlled trial
Brief summary
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.
Detailed description
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.
Interventions
DRUGAngiotensin II
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.
Sponsors
University of New Mexico
La Jolla Pharmaceutical Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients ≥18 years-old with persistent vasodilatory shock despite moderate-dose norepinephrine monotherapy, defined as those who require ≥0.1 mcg/kg/min for at least 30 minutes to maintain a MAP between 65-70 mmHg. * 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. * 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. * 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. * 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. * Approval from the attending physician and clinical pharmacist conducting the study.
Exclusion criteria
* Patients who are \< 18 years of age. * Patients diagnosed with acute occlusive coronary syndrome requiring intervention and/or cardiogenic shock. * Patients with or suspected to have abdominal aortic aneurysm or aortic dissection. * Acute stroke. * Patients with acute mesenteric ischemia or those with a history of mesenteric ischemia. * Patients with known Raynaud's phenomenon, systemic sclerosis, or vasospastic disease. * Patients on venoarterial extracorporeal membrane oxygenation (VA-ECMO). * Patients with liver failure with a Model for End-Stage Liver Disease (MELD) score of =/\>30. * Patients with burns covering \>20% of total body surface area. * Patients with a history of asthma or chronic obstructive pulmonary disease (COPD) with active acute bronchospasm or (if not mechanically ventilated) with an acute exacerbation of their asthma/COPD requiring the use of inhaled bronchodilators. * Patients requiring more than 500 mg daily of hydrocortisone or equivalent glucocorticoid medication as a standing dose. * Patients with an absolute neutrophil count (ANC) of \< 1,000/mm3 * 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. * Patients with active bleeding AND hemoglobin \< 7g/dL or any other condition that would contraindicate serial blood sampling. * Untreated venous thromboembolism (VTE) or inability to tolerate pharmacologic VTE prophylaxis. * Patients with a known allergy to mannitol. * Patients with an expected survival of \<24 hours, SOFA score ≥ 16, or death deemed to be imminent or inevitable during the admission. * Either the attending physician or patient and/or substitute decisionmaker are not committed to all active treatment, e.g., do-not-resuscitate (DNR) status. * 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. * Prisoner status * Patients who are currently participating in another interventional clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ability of Baseline Active Renin to Predict Norepinephrine Equivalent Dose (NED) at 3 Hours | 3 hours post drug initiation or SOC equivalent | 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. |
| Ability of Baseline DPP3 to Predict NED at 3 Hours | 3 hours post drug initiation or SOC equivalent | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hospital Mortality | Until hospital discharge or 28 days post-randomization. | Death before hospital discharge. Specified as a key secondary outcome. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJoao P Teixeira, MD
University of New Mexico
PRINCIPAL_INVESTIGATORNathan D Nielsen, MD MSc
University of New Mexico
Participant flow
Pre-assignment details
Two subjects were excluded after consent and randomization but before study start. See below for details.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 68.5 years |
| Baseline SOFA score | 8.5 units on a scale |
| Race and Ethnicity Not Collected | 0 Participants |
| Sex: Female, Male Female | 25 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 20 | 5 / 20 |
| other Total, other adverse events | 18 / 20 | 18 / 20 |
| serious Total, serious adverse events | 2 / 20 | 1 / 20 |
Outcome results
None listed