Continuing Education Activity

Angiotensin is a peptide endocrine hormone and an important part of the renin-angiotensin-aldosterone system, an inter-related endocrine system important in volume and blood pressure control. Angiotensinogen, an alpha-globulin, and the peptide prohormone is synthesized primarily by the liver and circulates in plasma. Angiotensin II (AT-II) has recently received FDA approval for use in patients in shock. This activity reviews the indications, contraindications, activity, adverse events, and other key elements of AT-II therapy in the clinical setting as relates to the essential points needed by members of an interprofessional team managing the care of patients presenting with shock.

Objectives:

• Identify the indications approved for II in the therapeutic setting.
• Review the dose forms and dosing parameters for angiotensin II.
• Summarize monitoring, contraindications, and toxicity for angiotensin II.
• Outline interprofessional team strategies for improving care coordination and communication to advance appropriate clinical outcomes with angiotensin II therapy to treat shock and drive optimal patient results.

Indications

Angiotensin is a peptide endocrine hormone and an important part of the renin-angiotensin-aldosterone system, an inter-related endocrine system important in volume and blood pressure control. Angiotensinogen, an alpha-globulin, and the peptide prohormone is synthesized primarily by the liver and circulates in plasma. When blood pressure drops, or when sympathetic signals reach the kidney, renin, a peptide produced primarily by the renal juxtaglomerular cells, is released and enzymatically cleaves off two amino acids forming angiotensin I (ATI), a decapeptide. ATI is further cleaved into an octapeptide, angiotensin II (ATII) by the action of angiotensin-converting enzyme (ACE), primarily in the pulmonary endothelium, though this enzyme is present in the endothelium of other organs including the heart.[1][2][3]

ATII has recently received FDA approval for use in patients in shock. ATII is the active hormone and acts at ATII receptors. Animal studies suggested that ATII was safe and effective in increasing blood pressure in shock. Furthermore, after a small human trial showed success, the direct use of angiotensin II as a vasopressor was studied in critically ill patients. The results of the ATHOS-3 trial results were published in the August 2017 New England Journal of Medicine. Researchers studied the drug in a placebo-controlled, double-blinded protocol with 321 subjects in the intensive care unit setting. Multiple hospitals in nine countries recruited severely ill patients with septic and vasodilatory shock who were not adequately responding to fluid and high-dose norepinephrine or equivalent standard of care pressors. Treatment with synthetic human angiotensin II resulted in statistically significant improvements in mean arterial pressure in the treatment group. The primary endpoints included achieving mean arterial pressure greater than or equal to 75 mm Hg in the first 3 hours of infusion and blood pressure maintenance with decreased use of vasopressors, including epinephrine, norepinephrine, and dopamine at 48 hours. While the originally published analysis of the data did not show a statistically significant mortality benefit, additional analysis has shown a statistically significant reduction in mortality at 28 days in a subgroup of treated patients.

In December of 2017, after a priority review, intravenous (IV) synthetic human angiotensin II was approved by the FDA for the treatment of septic and other distributive, vasodilatory shock in adults. The timing of initiation of this medication as used in ATHOS 3 trial was when the norepinephrine dose was 0.2 mcg/kg/min dosing, or cumulative catecholamine dosing was 0.2 mcg/kg/min within first 48 hrs of patients presentation. The patient in the trial was adequately resuscitated with 25 ml/kg of crystalloid before initiation of this medication. 

Clinical trials for the use of this drug in pediatric patients with refractory shock are currently recruiting patients.[4][5][6]

Mechanism of Action

ATII is a potent vasopressor, acting on vascular endothelial receptors. The two types of ATII receptors present in the heart and vasculature smooth muscle that are responsible for signal transduction in mediating the vasoconstrictive action of ATII are the AT1 and AT2 receptors. Their signaling leads to calcium-dependent phosphorylation of myosin, which leads to contraction of the vascular smooth muscle. This arterial smooth muscle contraction is responsible for raising blood pressure.[7][8]

Also, ATII interacts with AT receptors at various sites in the nephron to stimulate sodium reabsorption. ATII also acts on the zona glomerulosa of the adrenal cortex to stimulate the release of aldosterone, a steroid hormone that acts on the kidney to promote sodium and water retention.

Angiotensin-converting enzyme inhibitors (ACEI) may increase the effect of IV angiotensin II, and the use of angiotensin receptor blockers (ARB) may reduce the effect of IV angiotensin II. The mechanism for the interaction with ACEIs is not specified. The interaction with ARBs is by pharmacodynamic antagonism of the drug at the receptor site.

Administration

Angiotensin II is only available in an intravenous form for IV administration through a central venous line. The drug is available in vials of 2.5 mg/mL and 5 mg/2mL. One vial of the medication gets diluted in 0.9% sodium chloride solution to a concentration of either 5000 ng/mL or 10000 ng/mL before infusion. The higher concentration is for patients who are fluid restricted.

It is started at an infusion of 20 ng/kg per minute and titrated up as needed to a maximum dose of 200 ng/kg/min during the first 3 hours of use and a maximum maintenance dose of 40 ng/kg/min.

Adverse Effects

Most Common Adverse Events During Clinical Trials

• Thromboembolic events (12.9%) including DVT (4.3%)
• Thrombocytopenia (9.8%)
• Tachycardia (8.6%)

Other adverse reactions occurring at greater than 4%

• Fungal infection
• Delirium
• Acidosis
• Hyperglycemia
• Peripheral ischemia

The safety of the active drug was similar to placebo. Compared with placebo, fewer patients receiving angiotensin II required discontinuation of the drug due to serious adverse events. The rates of anticipated adverse events such as tachyarrhythmias, ventricular tachycardia, atrial tachycardia, and distal ischemia were similar between the two groups.  

Contraindications

No contraindications are in the prescribing information. However, patients with acute coronary syndrome, mesenteric ischemia, and ischemic limb should not get angiotensin II as vasoconstriction may potentially worsen these conditions. Nearly half of the study population was over 65, and safety data was no different for patients under versus over that age. No data exists for the use of angiotensin II in pediatric patients at this time, though clinical trials have begun. The potential for mutagenicity, carcinogenicity, or adverse effects on fertility have not been studied. Patients with burns, acute coronary syndrome, bronchospasm, liver failure, mesenteric ischemia, active bleeding, abdominal aortic aneurysm, patients with a neutrophil count of less than 1000, and patient on high dose glucocorticoids were excluded from the ATHOS 3 trial. Thus the efficacy of this medication in these conditions is unproven and requires caution.

Monitoring

Patients on this drug are receiving treatment in an intensive care setting with concomitant intensive hemodynamic monitoring, including mean arterial pressure. Blood pressure monitoring is especially crucial since hypertension is a potential direct adverse effect of the drug. Angiotensin II has a plasma half-life of less than a minute, so with careful monitoring, hypertension can be quickly reversed.

The drug should be carefully titrated based on blood pressure response to a mean arterial pressure of 75 or greater. 

Because of the potential for both arterial and venous thromboembolic events, all treated patients should receive concurrent deep vein thrombosis (DVT) prophylaxis.

Because of the effects of angiotensin II on the kidneys and other parts of the renin-angiotensin-aldosterone system, it is prudent to monitor kidney function with BUN and serum creatinine. Serum potassium requires monitoring, as well. The potential for thrombocytopenia suggests monitoring of complete blood count (CBC), including platelet counts.

Toxicity

The pharmacologic effect of this drug is to raise blood pressure. An overdose of the drug could result in hypertension. Careful monitoring and titration of the drug should prevent this effect, but in the even that it occurs, the short plasma half-life of angiotensin II means that this toxicity is easily reversible, and no antidote or further treatment should be required. The potential for thromboembolic events in patients treated with angiotensin II dictates the need for DVT prophylaxis during treatment.

Enhancing Healthcare Team Outcomes

Angiotensin II is often useful in the management of unresponsive shock vs. the traditional inotropic agents. However, healthcare workers, including the ICU nurse, intensivist, cardiologist, infectious disease specialist, pharmacist, and internist, need to be fully aware of the drug's potential toxicity. The patient requires monitoring in an ICU setting with an interprofessional team. The drug should be infused in large veins, preferably central veins, as it has the potential to cause severe vasoconstriction of the peripheral vessels; this is the responsibility of the nursing staff. Because of the potential for both arterial and venous thromboembolic events, all treated patients should receive concurrent deep vein thrombosis (DVT) prophylaxis, which the pharmacist can help drive appropriate agent selections and verify dosing and medication reconciliation. All patients need to have their renal function monitored while the patient is on angiotensin II. One significant caveat to the use of this agent is the lack of mortality benefit with this agent. The ATHOS 3 trial did not report any mortality improvement; this study was not powered to prove the mortality benefit. Small case studies indicate that angiotensin II can raise blood pressure, but it often does not improve survival in patients with shock. The argument for the use of this agent is that clinicians wait till it is very late in the clinical process before initiating this agent, leading to mortality. The hypothesis of angiotensin II deficiency states that the condition, as reflected by elevated renin levels, can be used to identify patients where this agent may potentially be more effective, justifying its early use in the vasoplegic shock state. However, renin testing is not done in routine labs and is a send-out test for most hospitals, with results delayed for days. The cost of angiotensin II is another concern in its widespread adoption. Daily therapy with this agent is approximately three thousand dollars, which, when compared to norepinephrine, is many times more expensive. Use of this medication requires complex decision making requiring an interprofessional team, including clinicians, specialists, nursing, and pharmacy, necessary for successful treatment with angiotensin II. [Level V]