Angiotensin Receptor Blocker (ARB) Reversal

From Angiotensin Axis Blocking Drugs In the Perioperative Period. Anesthesiology News, Feb 2016

What does an angiotensin receptor blocker (ARB) do?

Angiotensin II receptor blockers (ARBs) represent a newer class of effective and well tolerated antihypertensive agents 1. Several clinical studies have indicated the beneficial effects of ARBs in hypertensive patients such as reduction of left ventricular hypertrophy, decrease in ventricular arrhythmias, and improved diastolic function 1. Inhibitors of the renin-angiotensin system (RAS), either angiotensin converting enzyme (ACE) inhibitors or ARBs, mediate vasodilation and consequently decrease blood-pressure by different mechanisms 1. ARBs specifically inhibit angiotensin II from binding to its receptor, the Angiotensin-1 (AT 1) receptor on vascular smooth muscle cells. This blockade results in increased angiotensin II and normal bradykinin plasma levels. ARBs were developed to overcome several deficiencies of ACE inhibitors, which, by comparison, lead to decreased angiotensin II, but increased bradykinin levels. Hence, the key advantage of ARBs over ACE inhibitors is their lack of adverse effects related to bradykinin potentiation. ARBs have been shown to reduce morbidity and mortality associated with hypertension, and therefore, it is not surprising that an increasing number of patients scheduled for surgery are chronically treated with ARBs 2. However, RAS blockade increases the risk of severe hypotension during and after anesthetic induction. ACE-inhibitors are well known for inducing severe circulatory side effects during anesthesia, which led to the general recommendation to withhold the drug on the day of surgery 3.

Refractory hypotension during general anesthesia despite preoperative discontinuation of an angiotensin receptor blocker. F1000Research 2013, 2:12.

Comparison of Angiotensin‐Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Management Strategies Before Cardiac Surgery: A Pilot Randomized Controlled Registry Trial. Journal of the American Heart Association. 2018;7:e009917.

Consequences of continuing renin angiotensin aldosterone system antagonists in the preoperative period: a systematic review and meta-analysis. BMC Anesthesiol. 2018 Feb 26;18(1):26.

From Angiotensin Axis Blocking Drugs In the Perioperative Period. Anesthesiology News, Feb 2016

How do I reverse an ARB in an emergency?

Chronic AT 1 blockade also reduces the vasoconstrictor response to α 1 receptors activated by norepinephrine, which explains why ARB-induced hypotension can be so resistant to phenylephrine, ephedrine and norepinephrine 2, 8 Clinical studies have shown significant vasoconstrictor effects of vasopressin and increased cardiac filling during echocardiographic measurements 2.

Vasopressin or its synthetic analogues can restore the sympathetic response and may be useful pressors in cases of refractory hypotension during anaphylaxis 9 and septic shock 10 as well as in patients on RAS inhibitors, although norepinephrine has been reported to have a more favorable effect on splanchnic perfusion and oxygen delivery 11.

Refractory hypotension during general anesthesia despite preoperative discontinuation of an angiotensin receptor blocker. F1000Research 2013, 2:12.

Angiotensin Axis Blocking Drugs In the Perioperative Period. Anesthesiology News, Feb 2016.

  • When conventional therapies such as: decreasing the anesthetic agent, volume expansion, phenylephrine, ephedrine, norepinephrine, and epinephrine are not effective, exogenous vasopressin may improve hypotension. To date, at least 5 clinical trials have demonstrated that patients on chronic ACEI/ARB undergoing general anesthesia, respond to exogenous vasopressin derivatives with an increase in blood pressure and fewer hypotensive episodes.6,7 Typically, a 0.5-1 unit bolus of AVP is administered to achieve a rise in mean arterial pressure.4 The subsequent recommended infusion dose is 0.03U/min for AVP and 1-2 mcg/kg/h for terlipressin. Caution should be used as V1 agonists have been associated with the following deleterious effects: reduction in cardiac output and systemic oxygen delivery, decreased platelet count, increased serum aminotransferases and bilirubin, hyponatremia, increased pulmonary vascular resistance, decrease in renal blood flow, increase in renal oxygen consumption, and splanchnic vasoconstriction.
  • Studies involving cardiac surgical patients suggest that MB treatment for patients with VS may reduce morbidity and mortality.5 It has also been suggested that the early use (preoperative use in patients at risk for VS) of MB in patients undergoing coronary artery bypass grafting may reduce the incidence of VS.5,9A bolus dose of 1-2mg/kg over 10-20 minutes followed by an infusion of 0.25mg/kg/hr for 48-72 hours is typically utilized in clinical practice and trials (with a maximum dose of 7 mg/kg).10 Side effects include cardiac arrhythmias (transient), coronary vasoconstriction, increased pulmonary vascular resistance, decreased cardiac output, and decreased renal and mesenteric blood flow.1 Both pulse and cerebral oximeter readings may not be reliable during MB administration due to wavelength interference.11,12 The use of MB is absolutely contraindicated in patients with severe renal impairment because it is primarily eliminated by the kidney.13 It may also cause methemoglobinemia and hemolysis.13 At high doses, neurotoxicity may occur secondary to the generation of oxygen free radicals. Neurologic dysfunction may be more severe in patients receiving serotoninergic agents such as: tramadol, ethanol, antidepressants, dopamine agonists and linezolid. Recommended doses for VS ranging from 1-3 mg/kg do not typically cause neurologic dysfunction.14 However, recent reports suggest that MB in doses even ≤ 1mg/kg in patients taking serotonin reuptake inhibitors (SSRIs) may lead to serotonin toxicity due to its monoamine oxidase (MAO) inhibitor property.15

Vasoplegic Syndrome and Renin-Angiotensin System Antagonists. APSF Newsletter, Circulation 94,429 • Volume 27, No. 1 • Summer-Spring 2012.

Vasopressin for persistent hypotension due to amlodipine and olmesartan overdose: A case report. Ann Med Surg (Lond). 2021 May; 65: 102292.

Vasoplegic syndrome following cardiothoracic surgery—review of pathophysiology and update of treatment options. Crit Care. 2020; 24: 36.

Refractory hypotension during general anesthesia despite preoperative discontinuation of an angiotensin receptor blocker. F1000Research 2013, 2:12.

Terlipressin for refractory hypotension following angiotensin-II receptor antagonist overdose. Anaesthesia, 2006,61, pages 402–414.

Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-430.

Vasopressin: physiology and clinical use in patients with vasodilatory shock: a review. Neth J Med. 2005 Jan;63(1):4-13.

Treatment of intraoperative refractory hypotension with terlipressin in patients chronically treated with an antagonist of the renin-angiotensin system. Anesth Analg. 1999 May;88(5):980-4.

Role of vasopressinergic V1 receptor agonists in the treatment of perioperative catecholamine-refractory arterial hypotension. Best Pract Res Clin Anaesthesiol. 2008 Jun;22(2):369-81.

Predicting response to methylene blue for refractory vasoplegia following cardiac surgery. Pharmacotherapy Conference: 2013 American College of Clinical Pharmacy Annual Meeting. October 2013.