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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 mean arterial pressure (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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Angiotensin | Active Comparator | The angiotensin arm will receive angiotensin II acetate at an initial dose of 20ng/kg/min, titratable during the study (6 hours) for mean arterial pressure (MAP) goals as outlined in the protocol. |
|
| Control | Placebo Comparator | Control patients will receive placebo intravenously equal in duration, color and volume to the intervention arm's angiotensin II. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Angiotensin II | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Standing Dose of Norepinephrine Which is Required to Maintain a Mean Arterial Pressure (MAP) of 65 mmHg - Hour 1 | The primary endpoint in the study will be the effect of AII on the standing dose of norepinephrine which is required to maintain a mean arterial pressure (MAP) of 65 mmHg. | 1 hour after initiation of angiotensin II (ATII) |
| Standing Dose of Norepinephrine Which is Required to Maintain a MAP of 65 mmHg - Hour 2 | 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. | 2 hours after initiation of ATII |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Lakhmir Chawla, MD | GW University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| GW University | Washington D.C. | District of Columbia | 20037 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25286986 | Derived | Chawla LS, Busse L, Brasha-Mitchell E, Davison D, Honiq J, Alotaibi Z, Seneff MG. Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study. Crit Care. 2014 Oct 6;18(5):534. doi: 10.1186/s13054-014-0534-9. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Angiotensin | 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. |
| FG001 | Control | Control patients will receive placebo intravenously equal in duration, color and volume to the intervention arm's angiotensin II. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Angiotensin | 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. |
| BG001 | Control |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Standing Dose of Norepinephrine Which is Required to Maintain a Mean Arterial Pressure (MAP) of 65 mmHg - Hour 1 | The primary endpoint in the study will be the effect of AII on the standing dose of norepinephrine which is required to maintain a mean arterial pressure (MAP) of 65 mmHg. | Posted | Mean | Standard Deviation | mcg/min | 1 hour after initiation of angiotensin II (ATII) |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Angiotensin | 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypertension | Cardiac disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Trials Unit, Department of Anesthesiology and Critical Care Medicine | George Washington University Medical Faculty Associates | 202-715-4750 | mseneff@mfa.gwu.edu |
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| ID | Term |
|---|---|
| D012772 | Shock, Septic |
| ID | Term |
|---|---|
| D018805 | Sepsis |
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
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| ID | Term |
|---|---|
| D000804 | Angiotensin II |
| ID | Term |
|---|---|
| D000809 | Angiotensins |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
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|
Control patients will receive placebo intravenously equal in duration, color and volume to the intervention arm's angiotensin II.
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Baseline Sequential Organ Failure Assessment (SOFA) score, Continous | Mean | Standard Deviation | Scores on a scale 0-24 (higher is worse) |
|
| Acute physiology and chronic health evaluation (APACHE) score, continous | Mean | Standard Deviation | Scores on a scale 0-71 (higher is worse) |
|
| Ischemic heart disease | Count of Participants | Participants |
|
| Congestive heart failure | Count of Participants | Participants |
|
| Chronic obstructive pulmonary disease | Count of Participants | Participants |
|
| Diabetes | Count of Participants | Participants |
|
| Chronic kidney disease | Count of Participants | Participants |
|
| Hemodialysis | Count of Participants | Participants |
|
| Liver disease | Count of Participants | Participants |
|
| Cancer | Count of Participants | Participants |
|
| Immunocompromised state (as defined by steroid therapy or history of immunocompromise disease) | Count of Participants | Participants |
|
| Steroids | Count of Participants | Participants |
|
| Hypertension | Count of Participants | Participants |
|
| Cerebrovascular accident | Count of Participants | Participants |
|
| Acute kidney injury | Count of Participants | Participants |
|
| Baseline Norepinephrine dose | Mean | Standard Deviation | mcg/min |
|
| Baseline Vasopressin dose | Mean | Standard Deviation | units/min |
|
|
|
| Primary | Standing Dose of Norepinephrine Which is Required to Maintain a MAP of 65 mmHg - Hour 2 | 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. | Posted | Mean | Standard Deviation | mcg/min | 2 hours after initiation of ATII |
|
|
|
| Secondary | Mortality | 30 day post dose mortality will be assessed. Subjects discharged prior to day 30 will be contacted by telephone for this assessment. | Posted | Count of Participants | Participants | 30 days |
|
|
|
| 5 |
| 10 |
| 0 |
| 10 |
| 2 |
| 10 |
| EG001 | Control | Control patients will receive placebo intravenously equal in duration, color and volume to the intervention arm's angiotensin II. | 6 | 10 | 0 | 10 | 0 | 10 |
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| D010335 |
| Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012769 | Shock |
| D009479 | Neuropeptides |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D009842 | Oligopeptides |
| D009419 | Nerve Tissue Proteins |
| D011506 | Proteins |
| D012898 | Autacoids |
| D018836 | Inflammation Mediators |
| D001685 | Biological Factors |