ICU patients with vasodilatory shock continue to have a high mortality despite advancements in treatment. Maintaining blood pressure, and thus organ perfusion, is one key in management. Decreases in mean arterial pressure (MAP) can have serious complications including damage to the kidneys, heart, and brain. The human body has 3 sources of natural vasopressors – the sympathetic nervous system, vasopressin, and the renin-angiotensin system. There is data which suggests that all 3 of these systems work synergistically. However, we currently only possess two categories of exogenous vasopressor agents at our disposal – catecholamines and vasopressin. There are a limited number of options for catecholamine resistant vasodilatory shock. In a previous pilot study, this group has shown a potential usefulness of angiotensin II as a vasopressor.
Does the addition of angiotensin II to patients already receiving vasopressors improve MAP when compared to placebo?
Adults >18 years of age with vasodilatory shock defined as cardiac index > 2.3 L/min/m2 or ScvO2 > 70% and central venous pressure > 8mmHg despite receiving at least 25 cc/kg IV fluids over previous 24 hours and high dose vasopressors defined as > 0.2ug/kg/min of norepinephrine or equivalent for 6-48 hours to maintain MAP 55-70mmHg. Patients also had a central venous line, an arterial line, and a bladder catheter.
Angiotensin II infusion started at rate of 20 ng/kg/min and adjusted to maximum 200 ng/kg/min as needed for goal MAP 75 mm Hg
Normal saline infusion
Primary: MAP response at 3 hours. Response defined as MAP 75 mm Hg or increase in MAP from baseline of 10 mm Hg without increase in other vasopressors
Change in cardiac SOFA score
Change in total SOFA score
Change in norepinephrine dose from baseline to 3 hours
All cause mortality at 7 days
All cause mortality at 28 days
Multi center, prospective, randomized, double-blind, placebo-controlled
Patients who are <18 years of age, any patient with burns covering >20% of total body surface area, patients with a Cardiovascular SOFA score ≤3, patients diagnosed with acute occlusive coronary syndrome requiring intervention, patients on VA ECMO, patients who have been on ECMO for less than 12 hours, patients in liver failure with a MELD score of ≥30, patients with a history of asthma or who are currently experiencing bronchospasm requiring the use of inhaled bronchodilators, patients with acute mesenteric ischemia or a history of mesenteric ischemic, patients with a history of, presence of, or highly-suspected of having an aortic dissection or abdominal aortic aneurysm, patients requiring more than 500 mg daily of hydrocortisone or equivalent glucocorticoid medication as a standing dose, patients with Raynaud’s phenomenon, systemic sclerosis or vasospastic disease, patients with an expected lifespan of <12 hours, patients with 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, patients with an absolute neutrophil count of <1000 cells/mm3, patients with a known allergy to mannitol, patients who are current participating in another interventional clinical trial, patients who are known to be pregnant at the time of screening.
- 404 patients screened for enrollment
- 344 patients were randomized
- 321 patients initiated into study
- 221 patients completed study (99 patients died, 1 withdrew consent)
- 160 patients completed follow up at day 28
- 80.7% of patients enrolled were determined to have shock due to sepsis
- No significant difference in baseline demographic characteristics between the two groups
- Map response at 3 hours (primary)
- 69.9% in treatment group vs 23.4% in placebo group
- OR 7.95. 95% CI 4.76-13.3
- Secondary Endpoints
- Mean change in NE equivalent dose from baseline to 3 hours
- -0.03 +/- 0.10 in treatment group vs 0.03 +/- 0.23 in placebo group
- Mean change in cardiovascular SOFA score at 48 hours
- -1.75 +/- 1.77 in treatment group vs -1.28 +/- 1.65 in placebo group
- Mean change in NE equivalent dose from baseline to 3 hours
- All other secondary outcomes not statistically significant
- Largest study looking at effectiveness of angiotensin II as a vasopressor
- Randomization and blinding were appropriately performed
- Placebo controlled
- Significant industry conflicts of interest – sponsor representatives were involved in drafting the manuscript and creating the protocol. A professional medical writer was employed by the sponsor for revisions
- Primary outcome was not patient centered
- Small sample size – not powered to detect mortality benefits or clinically significant side effects
- Vast majority of patients with septic shock – decreases applicability of drug to other forms of shock
- Cannot exclude beneficial or harmful long term effects of angiotensin II beyond 28 days
- Possible inadvertent unblinding by providers with observable MAP response to angiotensin II
“ Angiotensin II effectively increased blood pressure in patients with vasodilatory shock
that did not respond to high doses of conventional vasopressors.”
In this small, multi-centered trial, addition of angiotensin II to patients with high vasopressor needs led to increase rate of achieving goal MAP at 3 hours and allowed for decrease in other vasopressors. However, the study was not powered to detect changes in morbidity or mortality and did not show any improvement in any patient centered outcome.
Potential Impact To Current Practice
Angiotensin II is now FDA approved and intensivists will likely begin to use this medication for the treatment of septic shock. The available data is not applicable to the ED population and more research should be done before ED docs consider including it in their armamentarium.
The addition of angiotensin II to the treatment regimen of patients in vasodilatory shock receiving high doses of other vasopressors improved MAP and decreased required doses of other vasopressors. Further studies should be performed to investigate the potential morbidity and mortality effects of angiotensin II as well as it’s use in the ED.