Hemodynamic Response to Angiotensin-II When Used as the Second Vasopressor Agent for Septic Shock

Study Overview
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Brief Summary
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Norepinephrine is a catecholamine that is the first-line vasopressor for septic shock. The addition of non-catecholamine vasopressors, including vasopressin and angiotensin-II may be used in adults with septic shock that have inadequate mean arterial pressure while on norepinephrine. Uncertainty exists regarding the timing of initiation of these agents and there is a lack of data comparing their safety and efficacy. The current literature suggests that earlier initiation of angiotensin-II will have a more significant reduction on norepinephrine-equivalent dose compared to later initiation. In addition, approximately half of patients initiated on vasopressin do not have an early hemodynamic response 6 hours after initiation. The purpose of this study is to evaluate the efficacy of angiotensin-II when used as the second vasopressor agent for septic shock.

Detailed Description
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Objectives: Primary Objective: 1. To evaluate the efficacy of ang-II when used as the second vasopressor agent for septic shock Secondary Objectives: To assess the duration of response to ang-II To assess overall survival To assess the amount of time spent in the ICU To assess the need for renal replacement therapy To assess the overall duration of vasoactive medication use To assess toxicity and tolerability

Official Title
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An Open-label, Single-arm, Single-center Study Evaluating the Hemodynamic Response to Angiotensin-II When Used as the Second Vasopressor Agent for Septic Shock

Conditions
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Septic Shock, Shock, Sepsis, Systemic Inflammatory Response Syndrome

Intervention / Treatment
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* Drug: Angiotensin II and hydrocortisone sodium succinate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients admitted to the ICU within 12 hours of presentation to the emergency department for septic shock requiring 15-25 mcg/min of norepinephrine. Septic shock will be defined as having a known or presumed infection with two or more criteria of systemic inflammatory response syndrome, a mean arterial pressure <65 mm Hg despite fluid resuscitation requiring vasopressor support, and a serum lactate >2 mmol/L. Criteria of systemic inflammatory response syndrome include a temperature >100.4°F or <96.8°F; heart rate >90/min; respiratory rate >20/min and a white blood cell count >12,000/mm3 or <4,000/mm3. Exclusion Criteria: Age <18 years Pregnancy or lactation Known allergic reactions to angiotensin-II or hydrocortisone sodium succinate Requiring >25 mcg/min of norepinephrine or on any vasopressor other than norepinephrine at study enrollment Clinically significant bleeding precluding the use of chemical prophylaxis for venous thromboembolism Treatment with another investigational drug or other intervention during study timeframe

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>Drug: Angiotensin II Other Names: Giapreza | Drug: Angiotensin II and hydrocortisone sodium succinate<br>* Intravenous infusion angiotensin II (titrated for each individual patient by effect) and hydrocortisone 50 mg intravenous bolus every 6 hours.<br>* Other names: Giapreza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of hemodynamic response, defined as a decrease in norepinephrine-equivalent dose with a MAP ≥65 mm Hg at 1 hour after initiation of angiotensin-II | Defined as a decrease in norepinephrine-equivalent dose with a MAP ≥65 mm Hg at 1 hour after initiation of angiotensin-II. | 1 hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of hemodynamic response at 3 hours after initiation of angiotensin-II | Defined as a decrease in norepinephrine-equivalent dose with a MAP ≥65 mm Hg at 3 hours after initiation of angiotensin-II. | 3 hours | 
| The incidence of hemodynamic response at 6 hours after initiation of angiotensin-II | Defined as a decrease in norepinephrine-equivalent dose with a MAP ≥65 mm Hg at 6 hours after initiation of angiotensin-II. | 6 hours | 
| 28-day mortality | Defined as all cause mortality up to 28 days from study enrollment. | 28 days | 
| ICU length of stay | Defined as the time spent within the ICU until discharge to a step down unit. | 1 year | 
| Need for renal replacement therapy | Defined as patients started on either continuous renal replacement therapy (CRRT) or intermittent hemodialysis (IHD) during the study period. | 1 year | 
| Vasoactive medication duration overall | Defined as the duration (hours) of vasoactive medication use during the study period. | 1 year | 
| Incidence of adverse reactions | Define as an unexpected or unintended effect suspected to be caused by a medicine. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sepsis, Angiotensin II, Hydrocortisone