Intravenous AII for the Treatment of Severe Hypotension in High Output Shock: A Pilot Study

Study Overview
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Brief Summary
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The investigators propose a dose finding study to determine the feasibility of Angiotensin II (AII) to increase mean arterial pressure in high-output shock. If AII can be shown to increase mean arterial pressure, this could lead to future pharmacologic development based on the AII hormonal pathway. The investigators propose a 20 patient, randomized, placebo-controlled, blinded study in the treatment of high-output shock. Patients with high-output shock and a cardiovascular SOFA (sequential organ failure score) score of > 4 will be eligible. In addition, patients must already be receiving cardiac output monitoring and have a cardiac index > 2.4 L/min/ 1.73 m2. Patients will be randomized to intravenous AII or saline in a blinded fashion. There will be 10 patients in each arm. This is a safety and dose finding feasibility study. The investigators are starting with a small cohort consistent with similar types of studies. The investigators estimate that ten patients in each arm will generate a basis for determining if there is sufficient signal for AII to improve blood pressure at the doses outlined. The primary endpoint in the study will be the effect of AII on the standing dose of norepinephrine which is required to maintain a MAP of 65 mmHg. Secondary endpoints will be the effect of AII on urine output, serum lactate, and creatinine clearance. 30 day post dose mortality will also be assessed. Subjects discharged prior to day 30 will be contacted by telephone for this assessment.

Official Title
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Intravenous AII for the Treatment of Severe Hypotension in High Output Shock: A Pilot Study

Conditions
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Septic Shock

Intervention / Treatment
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* Drug: Angiotensin II


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: High-output shock Cardiovascular SOFA score of > 4 Cardiac Index > 2.4 liters/min/BSA 1.73m2 Indwelling arterial line already present as part of standard care Age > 21 years of age Signed consent form Use of indwelling urinary catheter as standard care expected at least for 12 hours during the study interventions Exclusion Criteria: Patients with acute coronary syndrome Patients with a known history of vasospasm Patients with a history of asthma Patients currently experiencing bronchospasm Patients with active bleeding with an anticipated need for > 4 units of PRBC or Hemoglobin < 7g/dL or any other condition that would contraindicate drawing serial blood samples

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Angiotensin<br>The angiotensin arm will receive angiotensin II acetate at an initial dose of 20ng/kg/min, titratable during the study (6 hours) for MAP goals as outlined in the protocol. | Drug: Angiotensin II<br>* All patients will have their vasopressors titrated to a mean arterial pressure (MAP) of 65 mm of Hg (standard MAP goal in the ICU for patients suffering from shock). Patients will then be randomized to control or IV AII. In the interventional arm, AII will start at a dose of 20ng/kg/min; the dose can then be titrated up to 30ng/kg/min, and then to 40ng/kg/min. The intervention will last for 6 hours. Each patient will start with the assigned starting dose indicated above. After the first hour, if the patient is still requiring standing norepinephrine (the standard vasopressor for the treatment of shock in the GW ICU), the dose of the control/interventional drug can be increased 50%. After the second hour, if the patient is still requiring a standing dose of norepinephrine, the control/interventional can be increased again to twice the initial dose. At the end of 6 hours, the study drug will be titrated off.<br>|
| Placebo Comparator: Control<br>Control patients will receive placebo intravenously equal in duration, color and volume to the intervention arm's angiotensin II. | Drug: Angiotensin II<br>* All patients will have their vasopressors titrated to a mean arterial pressure (MAP) of 65 mm of Hg (standard MAP goal in the ICU for patients suffering from shock). Patients will then be randomized to control or IV AII. In the interventional arm, AII will start at a dose of 20ng/kg/min; the dose can then be titrated up to 30ng/kg/min, and then to 40ng/kg/min. The intervention will last for 6 hours. Each patient will start with the assigned starting dose indicated above. After the first hour, if the patient is still requiring standing norepinephrine (the standard vasopressor for the treatment of shock in the GW ICU), the dose of the control/interventional drug can be increased 50%. After the second hour, if the patient is still requiring a standing dose of norepinephrine, the control/interventional can be increased again to twice the initial dose. At the end of 6 hours, the study drug will be titrated off.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy | The primary endpoint in the study will be the effect of AII on the standing dose of norepinephrine which is required to maintain a MAP of 65 mmHg. | 6 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biomarkers | Secondary endpoints will be the effect of AII on urine output, serum lactate, and creatinine clearance. | 6 hours | 
| Mortality | 30 day post dose mortality will be assessed. Subjects discharged prior to day 30 will be contacted by telephone for this assessment. | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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high output shock, distributive shock, warm shock, septic shock, pressor, angiotensin, ATII, vasopressor