RAAS to the Rescue: Angiotensin II for the Treatment of Vasodilatory Shock

Kyle Savio, Mercer University College of Pharmacy

Vasodilatory shock is characterized as hypotension resulting from peripheral vasodilatation and poor response to vasopressor therapy. Sepsis is considered the main cause for vasodilatory shock by reducing the body’s ability to constrict blood vessels and maintain hemodynamics. Therapy is claimed to be reliant on adrenergic vasopressors such as norepinephrine, but these may fail in refractory vasodilatory shock. The renin-angiotensin-aldosterone system (RAAS) is noted to play an important role in preserving the vasculature to prevent vasodilatory shock. [1]

In vasodilatory shock, RAAS failure may present without a known mechanism. It is believed that the endothelial cells are blocked or hyperpolarized, preventing a response to angiotensin II. The lungs have shown production and storage of angiotensin converting enzyme I and II which can limit effectiveness of RAAS in septic patients. Supplementing the body with angiotensin II may serve as therapy to reverse these vasodilatory effects. [2]

Angiotensin II for the Treatment of Vasodilatory Shock [3]
Design International, randomized, double-blind, placebo-controlled; N= 321
Objective To determine if addition of angiotensin II to background vasopressors would improve blood pressure in patients with catecholamine-resistant vasodilatory shock
Study Groups Angiotensin II (n= 163); placebo (n= 158)
Methods Adult patients were included if they had vasodilatory shock refractory to fluid resuscitation, indwelling bladder and arterial catheters, and received high dose vasopressors greater than or equivalent to 0.2 mcg/kg/min of norepinephrine. Excluded patients had burns covering greater than or equal to 20% of total body-surface area, acute coronary syndrome, bronchospasm, liver failure, mesenteric ischemia, active bleeding, abdominal aortic aneurysm, absolute neutrophil count of less than 1000/mm3, and received venoarterial extracorporeal membrane oxygenation or high-dose glucocorticoids. Synthetic human angiotensin II was used with doses adjusted using a protocol based off mean arterial pressure (MAP) values.

Vasodilatory shock was considered when the cardiac index was greater than 2.3 liters per minute per square meter or central venous oxygen saturation of greater than 70% coupled with central venous pressure of more than 8 mmHg and MAP between 55 and 70 mmHg. Sepsis-related organ failure assessment score (SOFA) was used to assess extent of organ failure, patient improvement, and secondary outcomes of therapy. Total SOFA scores were the total of six organ system assessments including respiratory, cardiovascular, hepatic, coagulation, renal and neurological. Each organ system SOFA score was assigned a point value (0-4) and focused on lab values or conditions specific to that area. Cardiovascular SOFA (CV-SOFA) score focused on use of vasopressors and MAP values. Higher SOFA scores were indicative of increased mortality.

Duration Treatment: 48 hours; follow up period: 28 days
Primary Outcome Measure Sufficient MAP response (≥75 mmHg or increase of 10 mmHg from baseline) at hour 3 without increase of background vasopressor
Secondary Outcome Measures Mean change in cardiovascular SOFA (CV-SOFA) score and total SOFA score
Baseline Characteristics  

Angiotensin II Placebo
Median age, years (interquartile range [IQR]) 63 (52-75) 65 (53-75)
Male, n (%) 92 (56.4) 103 (65.2)
Mean median MAP, mmHg (IQR) 66.3 (63.7-69.0) 66.3 (63.0-68.3)
Median central venous pressure, mmHg (IQR) 13 (10-15) 12 (10-16)
Median cardiac index, L/min/m2 (IQR) 3.0 (2.6-3.8) 3.2 (2.7-3.9)
Shock caused by sepsis, n (%) 127 (77.9) 132 (83.5)
Median vasopressor dose, mcg/kg/min (IQR) 0.33 (0.23-0.56) 0.34 (0.23-0.56)



Angiotensin II Placebo Odds ratio (95% CI) p value
MAP response at hour 3, n (%) 114 (69.9) 37 (23.4) 7.95 (4.76-13.3) <0.001
Mean increase in MAP at 3 hours, mmHg (SD) 12.5 2.9 <0.001
Mean change in CV-SOFA score at hour 48, (SD) -1.75 (1.77) -1.28 (1.65) 0.01
Change in Total SOFA score at hour 48, mean (SD) 1.05 (5.50) 1.04 (5.34) 0.49


Adverse Events Common Adverse Events (greater than 5% incidence in both groups): atrial fibrillation, hypokalemia, septic shock, hypotension, hypertension, pleural effusion, respiratory failure, anemia, thrombocytopenia, skin/soft tissue disorders, and organ failure
Serious Adverse Events: angiotensin II (60.7%); placebo (67.1%) — included: septic shock, multiorgan failure, cardiogenic shock, cardiac arrest, infection, respiratory failure, and hypotension
Percentage that Discontinued due to Adverse Events: angiotensin II (14.1%); placebo (21.5%)
Study Author Conclusions Angiotensin II increased blood pressure in patients with vasodilatory shock who were receiving high-dose vasopressors.

Maintaining the blinding of physicians was an issue since MAP increases indicated that angiotensin II  was administered, and could have lead to a decrease in background vasopressor doses and CV-SOFA scores. The overall potential of angiotensin II was not addressed as the study was not powered to assess mortality. Long term effects of angiotensin II can not be concluded in this study due to the short length of follow up. By using the RAAS, synthetic angiotensin II shows promise as a potential vasopressor for use in vasodilatory shock.



[1] Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. 2001;345(8):588-95.

[2]Corrêa TD, Takala J, Jakob SM. Angiotensin II in septic shock. Crit Care. 2015;19:98.

[3] Khanna A, English SW, Wang XS, et al. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017.


Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s