Septic Shock
Conditions
Keywords
high output shock, distributive shock, warm shock, septic shock, pressor, angiotensin, ATII, vasopressor
Brief summary
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.
Interventions
DRUGAngiotensin II
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.
Sponsors
George Washington University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. High-output shock 2. Cardiovascular SOFA score of \> 4 3. Cardiac Index \> 2.4 liters/min/BSA 1.73m2 4. Indwelling arterial line already present as part of standard care 5. Age \> 21 years of age 6. Signed consent form 7. Use of indwelling urinary catheter as standard care expected at least for 12 hours during the study interventions
Exclusion criteria
1. Patients with acute coronary syndrome 2. Patients with a known history of vasospasm 3. Patients with a history of asthma 4. Patients currently experiencing bronchospasm 5. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Standing Dose of Norepinephrine Which is Required to Maintain a Mean Arterial Pressure (MAP) of 65 mmHg - Hour 1 | 1 hour after initiation of angiotensin II (ATII) | 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. |
| Standing Dose of Norepinephrine Which is Required to Maintain a MAP of 65 mmHg - Hour 2 | 2 hours after initiation of ATII | 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
| Measure | Time frame | Description |
|---|---|---|
| Mortality | 30 days | 30 day post dose mortality will be assessed. Subjects discharged prior to day 30 will be contacted by telephone for this assessment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 10 |
| Control Control patients will receive placebo intravenously equal in duration, color and volume to the intervention arm's angiotensin II. | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | Angiotensin | Control | Total |
|---|---|---|---|
| Acute kidney injury | 9 Participants | 8 Participants | 17 Participants |
| Acute physiology and chronic health evaluation (APACHE) score, continous | 27.2 Scores on a scale 0-71 (higher is worse) STANDARD_DEVIATION 9.7 | 34 Scores on a scale 0-71 (higher is worse) STANDARD_DEVIATION 6.8 | 30.6 Scores on a scale 0-71 (higher is worse) STANDARD_DEVIATION 8.9 |
| Age, Continuous | 68.4 years STANDARD_DEVIATION 17.5 | 57.3 years STANDARD_DEVIATION 12.4 | 62.9 years STANDARD_DEVIATION 15.8 |
| Baseline Norepinephrine dose | 19.8 mcg/min STANDARD_DEVIATION 11.7 | 30.3 mcg/min STANDARD_DEVIATION 20.4 | 25.1 mcg/min STANDARD_DEVIATION 17 |
| Baseline Sequential Organ Failure Assessment (SOFA) score, Continous | 14.9 Scores on a scale 0-24 (higher is worse) STANDARD_DEVIATION 2.8 | 16.9 Scores on a scale 0-24 (higher is worse) STANDARD_DEVIATION 2.9 | 15.9 Scores on a scale 0-24 (higher is worse) STANDARD_DEVIATION 3 |
| Baseline Vasopressin dose | 0.03 units/min STANDARD_DEVIATION 0.02 | 0.05 units/min STANDARD_DEVIATION 0.02 | 0.04 units/min STANDARD_DEVIATION 0.02 |
| Cancer | 1 Participants | 5 Participants | 6 Participants |
| Cerebrovascular accident | 4 Participants | 1 Participants | 5 Participants |
| Chronic kidney disease | 3 Participants | 4 Participants | 7 Participants |
| Chronic obstructive pulmonary disease | 2 Participants | 0 Participants | 2 Participants |
| Congestive heart failure | 2 Participants | 0 Participants | 2 Participants |
| Diabetes | 4 Participants | 3 Participants | 7 Participants |
| Hemodialysis | 0 Participants | 1 Participants | 1 Participants |
| Hypertension | 4 Participants | 5 Participants | 9 Participants |
| Immunocompromised state (as defined by steroid therapy or history of immunocompromise disease) | 1 Participants | 5 Participants | 6 Participants |
| Ischemic heart disease | 1 Participants | 1 Participants | 2 Participants |
| Liver disease | 5 Participants | 4 Participants | 9 Participants |
| Race/Ethnicity, Customized Black | 3 Participants | 5 Participants | 8 Participants |
| Race/Ethnicity, Customized Caucasian | 6 Participants | 3 Participants | 9 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Male | 6 Participants | 9 Participants | 15 Participants |
| Steroids | 1 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 10 | 6 / 10 |
| other Total, other adverse events | 2 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
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.
Time frame: 2 hours after initiation of ATII
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Angiotensin | Standing Dose of Norepinephrine Which is Required to Maintain a MAP of 65 mmHg - Hour 2 | 7.3 mcg/min | Standard Deviation 11.9 |
| Control | Standing Dose of Norepinephrine Which is Required to Maintain a MAP of 65 mmHg - Hour 2 | 28.6 mcg/min | Standard Deviation 30.2 |
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.
Time frame: 1 hour after initiation of angiotensin II (ATII)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Angiotensin | Standing Dose of Norepinephrine Which is Required to Maintain a Mean Arterial Pressure (MAP) of 65 mmHg - Hour 1 | 7.4 mcg/min | Standard Deviation 12.4 |
| Control | Standing Dose of Norepinephrine Which is Required to Maintain a Mean Arterial Pressure (MAP) of 65 mmHg - Hour 1 | 27.6 mcg/min | Standard Deviation 29.3 |
Secondary
Mortality
30 day post dose mortality will be assessed. Subjects discharged prior to day 30 will be contacted by telephone for this assessment.
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Angiotensin | Mortality | 5 Participants |
| Control | Mortality | 6 Participants |