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Pharmacist Continuing Education: Overview of Vasopressors and Current Place in Therapy of Angiotensin II

18 Mar 2019 1:02 PM | Deleted user

Authors: Brandon Reynolds, PharmD, PGY1 Pharmacy Practice Resident
Dalena Vo, PharmD, PGY2 Critical Care Pharmacy Resident
Mentor:  Erin Pender, PharmD, BCPS, BCCCP
Truman Medical Centers - Kansas City, MO

Program Number: 2019-03-01
Approval Dates: April 1, 2019 - October 1, 2019
Approved Contact Hours: One (1) CE(s) per LIVE session.

Learning Objectives:

  1. Define the four types of shock and their most common etiologies.
  2. Explain pharmacology of clinically relevant vasopressors and their receptor binding capabilities.
  3. Summarize the available literature supporting the use of angiotensin-II in distributive shock.
  4. Discuss current place in therapy for vasopressors.


Shock is a broad term encompassing a disease state characterized by systemic hypoperfusion and organ dysfunction with multiple underlying etiologies. It is a particularly dangerous condition, carrying a mortality rate of at least 25%.1 Well understood shock modalities include cardiogenic, distributive, hypovolemic, and obstructive, with distributive being the most common. 2 Table 1 outlines common causes for each shock subset. Although the term shock has been in the literature for decades, diagnosis and treatment of the condition, especially septic shock, has undergone several revisions. 

In distributive (vasodilatory) shock, a leaky vasculature leads to low systemic vascular resistance and hypotension in the presence of preserved cardiac function. Treatment consists of fluid resuscitation with the addition of vasopressors for fluid-refractory shock. The goal of vasopressors in this situation is to cause vasoconstriction and thereby increase systemic vascular resistance. In contrast, cardiogenic shock involves decreased cardiac output due to diminished work of the heart. Positive inotropes can be utilized in this setting to increase contractility of the heart and subsequently improve blood pressure. Obstructive and hypovolemic shock rarely require vasopressors as the underlying mechanism should be identified and treated accordingly. 

In order to better understand why certain vasopressors are preferred in the guidelines, it is essential that pharmacists stay up-to-date on current literature. Therefore, this article will focus on mechanisms of action and place in therapy for vasopressors, as well as current evidence and role of the new vasopressor, angiotensin II.

Table 1: Shock Causes

Adrenergic Receptors and Vasopressors

The five main receptor targets for vasoactive agents include alpha1, beta1, beta2, dopamine, and vasopressin. Alpha1 receptors are mostly located on vascular smooth muscle with stimulation producing vasoconstriction. Beta1 receptors can be found on myocardial cells and activation of these receptors causes increased chronotropy (heart rate) and inotropy (contractility) of the heart. Beta2 stimulation on vascular smooth muscle causes vasodilation. Activation of dopaminergic receptors on the kidneys, heart, and splanchnic vasculature results in vasodilation of renal and mesenteric beds. Lastly, two different subtypes of vasopressin receptors can produce either vasoconstriction of vascular smooth muscle or increased water reabsorption through agonism of V1 or V2 receptors, respectively.3

Norepinephrine is an endogenous catecholamine with potent alpha adrenergic agonist activity and mild beta adrenergic activity. Therefore, most of the effects of norepinephrine are on mean arterial pressure with less pronounced increases in cardiac output and stroke volume.4 Epinephrine is another endogenous catecholamine with affinity for both alpha and beta receptors. However, stimulation of these receptors are dose dependent. At lower doses, beta adrenergic effects are more pronounced, but as infusion rates increase (>0.1 mcg/kg/min), alpha adrenergic effects become predominant.3,5 Similar to epinephrine, pharmacologic effects of dopamine are dose dependent. Low doses of dopamine (<5 mcg/kg/min) are considered “renal protective” as activation of dopaminergic receptors produce splanchnic and renal vasodilation with subsequent increase in urine output and renal blood flow.5 However, studies have failed to show any clinical benefit in preventing renal failure and current sepsis guidelines recommend against initiating low dose dopamine for this purpose.6 Moderate doses of dopamine (5-10 mcg/kg/min) have inotropic effects and high doses of dopamine (>10 mcg/kg/min) have more vasoconstriction.

Vasopressin’s ability to increase blood pressure stems from inhibition of nitric oxide production and direct constriction of vascular smooth muscle.  Vasopressin-modulated increase in vascular sensitivity to catecholamines may further potentiate its pressor activity.3 Next, phenylephrine is the only vasopressor that selectively stimulates alpha1 receptors. Although it has no effect on beta receptors and heart rate, reflex tachycardia can develop with rapid changes in blood pressure.3 It should be noted that initiating phenylephrine in patients with already diminished myocardial function may have deleterious effects on cardiac output due to increasing systemic vascular resistance and further increasing demand of the heart. Lastly, the newest vasopressor, angiotensin II, acts on a completely different pathway from the adrenergic and vasopressin systems. Activation of this third system, the renin-angiotensin-aldosterone system (RAAS), through administration of angiotensin II produces potent vasoconstriction of arterioles and increases in blood pressure. Table 2 summarizes mechanisms of action for each vasopressor.

Table 2: Summary of adrenergic receptors and vasopressors

Angiotensin II hasn’t had a strong evidence base for inclusion in practice guidelines due to a lack of clinical data. As such, many clinicians have chosen not to consider angiotensin II as a therapeutic option, instead favoring treatments with well-documented data such as the other agents listed in Table 2. Considering the high mortality burden of vasodilatory shock and the adverse effects that are associated with the commonly used vasopressors, the use of angiotensin II has increased in popularity. In an effort to further explore the use of angiotensin II as a treatment option, researchers prepared a high-quality trial known as Angiotensin-II for the Treatment of Vasodilatory Shock (ATHOS-3).

Primary Literature for Angiotensin II (ATHOS-3) 

The Angiotensin-II for the Treatment of Vasodilatory Shock (ATHOS-3) trial was published in the New England Journal of Medicine in 2017. This trial was a prospective, multi-center, double-blind, randomized controlled study which enrolled 321 patients with vasodilatory shock. Vasodilatory shock was defined as a cardiac index of >2.3 L/min/m2 or a central venous oxygen saturation of >70% with a central venous pressure of >8 mmHg, and a mean arterial pressure (MAP) between 55 and 70 mmHg. To be included, patients had to be ≥18 years of age with vasodilatory shock despite at least 25 mL/kg of fluid resuscitation and receiving at least 0.2 mcg of norepinephrine/kg/min or the equivalent dose of another vasopressor for at least 6 hours but less than 48 hours. Patients were excluded if they had burns covering >20% of their body surface area, acute coronary syndrome, bronchospasm, liver failure, mesenteric ischemia, active bleeding, abdominal aortic aneurysm, or an absolute neutrophil count <1000/mm3 or who were receiving venoarterial extracorporeal membrane oxygenation or treatment with high-dose glucocorticoids. Included patients were randomized to receive either angiotensin II or placebo in addition to the standard of care vasopressor. There were no significant differences between groups at randomization. The primary outcome measure of this trial was MAP response by the 3rd hour after initiation of treatment or placebo. Patients were considered to have met the primary outcome measure if by hour 3 their MAP was 75 mmHg or greater or their MAP increased by at least 10 mmHg. Secondary outcome measures included the mean change in cardiovascular Sequential Organ Failure Assessment (SOFA) score at hour 48 and the overall change in SOFA score at hour 48. Alpha was predefined as 0.05, and power was set and met at 90% for the primary outcome measure. A sample size of 150 patients was required in each group to determine superiority of angiotensin II over placebo.7

The study group initiated treatment at a rate equivalent to 20 ng of angiotensin II/kg/min which was titratable up to 200 ng/kg/min for the first 3 hours. During this time, standard-of-care vasopressors could not be adjusted unless for safety reasons.  Between 3 hours 15 minutes and 48 hours, angioteninsin II or placebo and other vasopressors could both be adjusted to maintain a target MAP between 65 and 75 mm Hg.  The study drug or placebo was then discontinued at hour 48 after completion of a tapering protocol. If the background vasopressor required an increase of 0.1 mcg of norepinephrine/kg/min or the equivalent or if the patient decompensated, the study drug could be restarted for up to 7 days so long as it had not been off for >3 hours prior.7

At hour 3, there were statistically more patients in the angiotensin II group that met the primary outcome measure (69.9% vs 23.4%, p<0.001; odds ratio [OR] 7.95; 95% confidence interval [CI] 4.76 to 13.3). Cardiovascular SOFA scores were statistically lower in the angiotensin II group than in placebo (-1.75 vs -1.28 respectively, p=0.01). The mean change in SOFA score between groups was not statistically significant (p=0.49). Mean change in norepinephrine-equivalent dosage from baseline to hour 3 was statistically significant (-0.03 ± 0.1 vs. 0.03 ± 0.23, p <0.001). Angiotensin II did not improve all-cause mortality over placebo at day 7 (29% vs 35% respectively; hazard ratio [HR] 0.78; 95% CI 0.53-1.16) or at day 28 (46% vs. 54% respectively; HR 0.78; 95% CI 0.57-1.07).7 There were no significant differences in adverse events between groups reported in the study, however, FDA labeling for angiotensin II warns of increased incidence of arterial and venous thromboembolic events compared to placebo-treated patients (13% vs. 5% respectively).8 Results of the study are summarized in Table 3.

Table 3: ATHOS-3 Trial Endpoints

ATHOS-3 Summary

Overall, for patients in vasodilatory (distributive) shock refractory to ≥25 mL/kg of fluid resuscitation and ≥0.2 mcg/kg/minute of norepinephrine or the equivalent dose of another vasopressor, addition of angiotensin II significantly increased MAP and decreased vasopressor requirements within 3 hours of initiation. In patients that received angiotensin II, the cardiovascular subsection of their SOFA score also decreased by hour 48, driven by the aforementioned decrease in vasopressor requirements. Angiotensin II did not decrease all-cause mortality at day 7 or day 28, although these mortality results were not powered to detect a difference.7

Places in Therapy

There are several published studies comparing norepinephrine to dopamine or epinephrine. One such study (SOAP-II) found no difference in 28-day mortality, but a higher incidence of arrhythmias in the dopamine group.9 Similar results have been demonstrated with trials comparing norepinephrine to epinephrine.10,11 Therefore,  norepinephrine is currently recommended as the first line vasopressor in septic shock refractory to fluid resuscitation and epinephrine can be initiated in addition to norepinephrine to further increase MAP.6 Dopamine or vasopressin may also be used in septic shock. However, dopamine should only be initiated in patients at low risk of tachyarrhythmias due to the results from the SOAP-II trial. Furthermore, guidelines recommend initiating vasopressin in addition to norepinephrine to further increase MAP or to decrease norepinephrine dosage.9 In contrast to vasopressin, phenylephrine has limited use in septic shock and is not recommended in the guidelines. However, one advantage of phenylephrine is that it comes manufactured as a “push dose” and is often utilized in operating rooms for transient hypotension to avoid running a vasopressor infusion. Lastly, current data does not support the use of angiotensin II as first line therapy for septic shock. Based on the ATHOS-3 study, angiotensin II may be used in addition to norepinephrine in refractory shock similar to epinephrine or vasopressin.


There are three main systems that current vasopressors act on: the adrenergic, vasopressin, and renin-angiotensin-aldosterone system. Norepinephrine, epinephrine, phenylephrine, dopamine, and vasopressin have all been extensively studied. Common reasons for initiating these vasopressors include septic shock, anaphylactic reactions, or during advanced cardiac life support (ACLS). Angiotensin II is a novel vasopressor that acts on the renin-angiotensin-aldosterone system, a mechanism not previously utilized by the aforementioned vasopressors. The ATHOS-3 study supports the use of angiotensin II as an addition to norepinephrine for vasodilatory shock to reduce vasopressor requirements, increase MAP, and reduce the cardiovascular SOFA score, making angiotensin II a strong consideration for this subset of patients.

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  1. Angus D, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29(7):1303-1310
  2. Vincent J and Backer D. Circulatory shock. N Engl J Med 2013; 369(18):1726-1734
  3. Overgaard C and Dzavik V. Inotropes and vasopressors. AHA 2008; 118:1047-1056
  4. Hollenburg S. Vasoactive drugs in circulatory shock. Am J Respir Crit Care Med 2011; 183(7):847-855
  5. Jentzer J, et al. Pharmacotherapy update on the use of vasopressors and inotropes in the intensive care unit. J Cardiovasc Pharmacol Ther 2015; 20(3):249-260
  6. Rhodes, et al. Surviving sepsis campaign: International guidelines for the management of sepsis and septic shock: 2016. Crit Care Med 2017; 43(3):304-377
  7. Khanna A, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med 2017; 377:419-430
  8. La Jolla Pharmaceutical Company. Giapreza™ (angiotensin II) [package insert]. San Diego, CA. 2017
  9. De Backer, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010; 362(9):779-789
  10. Myburgh J, et al. A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med 2008; 34:2226–2234
  11. Avni T, et al. Vasopressors for the treatment of septic shock: Systematic review and meta-analysis. PLoS One 2015; 10:e0129305

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