Unexpected refractory hypotension under general anesthesia is an increasingly recognized perioperative issue. One cause for this type of hypotension is vasoplegic syndrome (VS). It is most commonly seen during cardiac surgery, but can occur during any anesthetic. It is characterized by severe hypotension refractory to catecholamine therapy in the absence of other identifiable causes for hypotension. While there is no standardized definition for VS, some researchers have defined it as a mean arterial pressure <50mmHg with a cardiac index >2.5 L/min x m² and a low systemic vascular resistance despite adrenergic vasopressor administration.¹ The incidence of VS in cardiac surgical patients is 8% to 10 %, but may increase to upwards of 50% of patients taking renin-angiotensin system (RAS) antagonists.² In cardiac surgical patients with persistent hypotension into the postoperative period, the associated mortality approaches 25%.³ While RAS antagonists and their causal association with VS will be the focus of this review, many other risk factors exist. They include intravenous heparin, beta-blockers, calcium channel blockers, protamine use, myocardial dysfunction, diabetes mellitus, heart transplant, a higher added EuroSCORE, presence of pre-cardiopulmonary bypass (CPB) hemodynamic instability, valvular and heart failure surgery, increased duration of CPB, or ventricular assist device insertion.^4,5 Some authors suggest holding RAS antagonists preoperatively in order to prevent VS. A lack of evidence has precluded clear guidelines surrounding the perioperative use of RAS antagonists thus far. To recognize and treat VS, a thorough understanding of the proposed mechanisms of this syndrome and current state of the science is needed to guide best-practice decisions.

Under normal physiologic circumstances, blood pressure is maintained via three separate but redundant systems: the sympathetic system, the renin-angiotensin system and the vasopressinergic system. Most anesthetic drugs reduce the influence of the sympathetic system on cardiovascular tone. Therefore, under general anesthesia there is believed to be an increased reliance on the RAS and the vasopressinergic system to maintain blood pressure.⁶ RAS antagonists such as angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) block the RAS response to hypotension. Therefore, patients taking these agents have an increased risk of refractory hypotension under general anesthesia.² Other proposed mechanisms for developing VS include: cytokine and nitric oxide-mediated smooth muscle relaxation, catecholamine receptor down regulation, cell hyperpolarization, and endothelial injury.⁴

ACEIs and ARBs are commonly utilized in patients with hypertension, congestive heart failure and diabetic neuropathy. ACEIs prevent the conversion of angiotensin I (ATI) to angiotensin II (ATII), which results in lower arterial resistance, increased vascular capacitance, increased cardiac output, and stroke work. ACEI promote natriuresis and a reduction in left ventricular hypertrophy. ARBs act along the same RAS pathway. These agents block the ATII receptor for a more complete RAS blockade. Multiple drugs exist within both classes, each with different pharmacokinetic properties that may alter the timing of RAS recovery after cessation of the drug. Observational and randomized trials have demonstrated that stopping the RAS antagonist the day before surgery may attenuate VS.⁶ However, when longer acting agents are stopped 24 hours prior to surgery, RAS antagonism may still persist into the operative period.⁶

The treatment of VS can be challenging. Endogenous release of vasopressin (AVP) occurs to compensate for the blockage of both the RAS and the sympathetic nervous system, but this may not resolve the hypotension. 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. Ischemic skin necrosis has been reported after peripheral intravenous administration through an infiltrated intravenous line.⁸

Methylene blue (MB) or tetramethylthionine chloride is a well described alternative treatment for VS.1 It is believed to interfere with the nitric oxide (NO)-cyclic guanylate monophosphate (cGMP) pathway, inhibiting its vasorelaxant effect on smooth muscle.4 Case series and reports have suggested that MB may be effective in raising mean arterial pressure while minimizing the use of vasopressors in a variety of patient populations with VS such as; patients with severe burns, septic shock, liver transplant, and pheochromocytoma surgery.⁴ However, the literature is most robust regarding the use of MB in patients undergoing cardiac surgery. 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 Further studies are warranted to investigate if other patient populations are susceptible to MB induced neurotoxicity at these lower doses.

While both vasopressin and MB are effective second line therapies for VS, many questions still exist concerning how best to manage this syndrome perioperatively. Further investigation into the proper timing and dose of V1 agonists and MB is needed.

With regards to prevention, retrospective trials have suggested stopping ACEIs/ARBs in advance of anesthesia to reduce the incidence of hypotension.¹⁶ A recent large retrospective trial from the Cleveland Clinic suggested that the preoperative use of ACEIs (withholding ACEIs on the morning of surgery only) was not associated with an increase in perioperative vasopressor use, in-hospital complications or 30-day mortality.¹⁷ However, questions still remain regarding the timing for discontinuing these medications.¹⁸ Given the pharmacologic differences of each ACEI/ARB, the appropriate timing for cessation is likely to be different for each medication. In addition, research to determine the possible harm of stopping these medications perioperatively is lacking. Lastly, outcomes regarding placing patients on appropriate alternative agents for perioperative blood pressure control should be investigated.

While many questions remain, it is clear that refractory hypotension under general anesthesia is a recognized problem correlating with the increased use of RAS antagonists. It may be reasonable to discontinue these medications perioperatively, but evidence to support a “best-practice” guideline is lacking. Should VS occur, conventional therapies remain first line with vasopressin/terlipressin and methylene blue as reasonable second line options. Further research is needed to help elucidate the definition, causes, and best prevention and treatment strategies for vasoplegic syndrome.

Dr. Shear is a Clinical Assistant Professor, Department of Anesthesiology, NorthShore University HealthSystem, University of Chicago. Dr. Greenberg, MD is Director of Critical Care Services, Evanston Hospital and a Clinical Assistant Professor, Department of Anesthesiology NorthShore University HealthSystem, University of Chicago.

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