Angiotensin II in Vasodilatory Shock a,b c a,d,e, Brett J. Wakefield, MD , Laurence W. Busse, MD , Ashish K. Khanna, MD * KEYWORDS Vasodilatory shock Septic shock Angiotensin II Vasopressor Blood pressure KEY POINTS Vasodilatory shock, also known as distributive shock, is characterized by decreased sys- temic vascular resistance with impaired oxygen extraction leading to profound vasodilation. The Angiotensin II for the Treatment of Vasodilatory Shock (ATHOS-3) trial demonstrated the vasopressor and catecholamine-sparing effect of angiotensin II in patients with vaso- dilatory shock. Further studies suggest Angiotensin II may offer a benefit in patients with increased severity of illness, acute kidney injury requiring renal replacement therapy, severe acute respiratory distress syndrome and in brisk responders to minimal doses of therapy. INTRODUCTION Shock is common in the intensive care unit (ICU), and up to one-third of critically ill pa- tients are admitted to the ICU with some form of shock.1 Shock is defined as a path- ologic condition of acute and life-threatening circulatory failure resulting in inadequate tissue oxygen utilization.2 The tenets of management include treatment of the under- lying cause and blood pressure support with fluid resuscitation and vasopressor Conflict of Interest: Drs A.K. Khanna and L.W. Busse have received support from the La Jolla Pharmaceutical Company as consultants and speakers. Funding: No funding was procured for this work. a Department of General Anesthesiology, Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA; b Department of Anesthesiology, Division of Critical Care Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8054, St Louis, MO 63110, USA; c Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Emory University School of Medicine, Emory St. Joseph’s Hospital, 5665 Peachtree Dunwoody Road, Atlanta, GA 30342, USA; d Center for Critical Care, Department of Outcomes Research, Cleveland Clinic, 9500 Euclid Avenue - G58, Cleveland, OH 44195, USA; e Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA * Corresponding author. Cleveland Clinic Foundation, 9500 Euclid Avenue - G58, Cleveland, OH 44195. E-mail address: [email protected] Crit Care Clin 35 (2019) 229–245 https://doi.org/10.1016/j.ccc.2018.11.003 criticalcare.theclinics.com 0749-0704/19/ª 2018 Elsevier Inc. All rights reserved. 230 Wakefield et al administration when required.3 Previously, vasopressor options were limited to 2 broad classes of vasopressors: catecholamines (norepinephrine, epinephrine, and dopamine) and vasopressin. Recently, however, angiotensin II, a component of the renin–angiotensin–aldosterone system (RAAS), has been approved by the Food and Drug Administration (FDA) as the third class of vasopressor. Angiotensin II may play an important role in the treatment of difficult-to-manage vasodilatory shock. VASODILATORY SHOCK Vasodilatory shock, also known as distributive shock, is characterized by decreased systemic vascular resistance with impaired oxygen extraction leading to profound vasodilation.4 The most common type of vasodilatory shock is septic shock, which represents 50% to 80% of all cases.5,6 Other nonseptic causes of vasodilatory shock include postoperative vasoplegia, anaphylaxis, severe metabolic acidosis, pancrea- titis, and chronic angiotensin-converting enzyme (ACE) inhibitor overdose.5,7–10 The term “refractory” has been used in cases of vasodilatory shock in which there is a fail- ure to maintain mean arterial pressure (MAP) despite volume resuscitation and the use of vasopressors.11 A consensus definition for refractory vasodilatory shock has not been established; however, high-dose vasopressors defined at various thresholds are associated with substantial mortality.12,13 The recently published Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3) trial defined refractory vasodila- tory shock as shock that required the use of greater than 0.2 mcg/kg/min of norepi- nephrine equivalent vasopressor doses in order to maintain an MAP of 65 mm Hg, a threshold that was used as enrollment criteria into this study.14 This threshold is twice the threshold used in estimating a mortality of nearly 50% as part of the calculation of the Sequential Organ Failure Assessment (SOFA) score.15 A threshold of 0.5 mcg/kg/ min of norepinephrine or epinephrine has also been frequently used in clinical trials to define the threshold for refractory shock.16–18 Benbenishty and colleagues16 reported a sensitivity of 96% and specificity of 76% for prediction of mortality in patients receiving greater than 0.5 mcg/kg/min of norepinephrine, which has been confirmed in other analyses.19 Furthermore, norepinephrine-equivalent vasopressor doses of greater than 1 mcg/kg/min are associated with a mortality of 80% or higher at 90 days.12 Considering these observations, refractory vasodilatory shock may be pre- sent when (1) vasopressors fail to result in an adequate MAP response, (2) patients require additional or adjunctive therapies to support blood pressure, or (3) current levels of therapy are associated with a dose-dependent increase in mortality.16–20 HEMODYNAMIC TARGETS FOR MANAGEMENT OF VASODILATORY SHOCK Ample evidence suggests that low blood pressure is associated with increased morbidity and mortality. An MAP less than 55 mm Hg for as little as 1 minute during the intraoperative period was found to be associated with acute kidney injury (AKI) and myocardial injury.21 Similar analyses have found that as the time-weighted average of intraoperative MAP decreased from 80 to 50 mm Hg, the 30-day mor- tality more than tripled.22 Khanna and colleagues23 reported an almost 50% in- crease in mortality and myocardial injury with every 10 mm Hg difference (compared between patients) in the lowest MAP on any given day in critically ill postoperative patients. This relationship was seen at any MAP less than a threshold of 90 mm Hg.24 Blood pressure goals in septic shock are delineated in the Surviving Sepsis Campaign guidelines and describe a target MAP of at least 65 mm Hg as an initial resuscitative strategy.25 This recommendation is supported in part by a large Angiotensin II in Vasodilatory Shock 231 multicenter randomized controlled trial, which found no difference in mortality when comparing MAP targets of 80 to 85 mm Hg and 65 to 70 mm Hg in patients with septic shock.26 This study and many other smaller studies have associated higher MAP tar- gets with more cardiac arrhythmias and vasopressor use, but a similar serum lactate, regional blood flow, and mortality compared with lower blood pressure targets.27–30 Despite guideline recommendations, an MAP target of 65 mm Hg is often chal- lenging to achieve consistently, and recent data has now questioned the sufficiency of this target in the ICU.23,24,28,31 Nielsen and colleagues32 found that among patients with septic shock who are on vasopressors, 62%, 37%, and 18% had MAP values below 65, 60, and 55 mm Hg, respectively, for greater than 2 hours and up to 4 hours. In addition, increased duration at these low MAP values was associated with increased mortality. A multivariable logistic regression analysis of nearly 9000 septic patients across 110 ICUs in the United States found the risks for mortality, AKI, and myocardial injury first developed at an MAP of 85 mm Hg, and the risk of mortality and AKI progressively worsened as MAP decreased from 85 to 55 mm Hg.31 The maintenance of a minimally acceptable MAP goal during resuscitation of septic shock needs to be understood in the context of the currently available vasopressor options. The surviving sepsis campaign guidelines recommend the use of norepineph- rine as the first-line vasopressor, with the addition of epinephrine or vasopressin as adjunctive therapies.25 However, the use of catecholamines and vasopressin at high doses are associated with poor outcomes and even risk of injury. By one estimate, only 17% of patients with septic shock requiring vasopressor therapy of greater than or equal to 1 mcg/kg/min of norepinephrine-equivalent dosing survive to 90 days.12 In addition, high-dose catecholamine therapy has been shown to be inde- pendently predictive of mortality after controlling for many factors, including severity of illness.33 Catecholamine monotherapy is also associated with significant cardiac side effects, morbidity, and mortality, an effect that is correlated with the cumulative dose of catecholamines, the number of different catecholamines used, and the duration of therapy.34 Vasopressin has been shown to reduce the need for catecholamine therapy (a phenomenon commonly referred to as catecholamine-sparing) and is frequently deployed as a second-line agent in septic shock.25,35 Although superiority of vaso- pressin has yet to be demonstrated, patients with less severe shock (lactate <1.4 mmol/L or norepinephrine dose <15 mcg/min) treated with vasopressin had better survival when compared with norepinephrine.36 In addition, vasopressin has been associated with a reduced requirement for renal replacement therapy (RRT) in patients with septic shock.37 However, vasopressin at high doses has also been associated with adverse outcomes including hyperbilirubinemia, increased liver enzymes, reduced platelet count, ischemic skin lesions, and mesenteric ischemia.19,38,39 Moreover, less than half of patients with septic shock respond to vasopressin, highlighting the need for additional options.40 Angiotensin II, recently approved by the FDA, is a novel vasopressor agent that has been shown to increase blood pressure with a catecholamine-sparing effect in pa- tients with vasodilatory shock.14 ANGIOTENSIN II PHYSIOLOGY Angiotensin II is an essential component of the RAAS and is synthesized in the liver as angiotensinogen before being cleaved by renin into angiotensin I (Fig. 1). Renin is a carboxypeptidase released from the juxtaglomerular cells in response to reduced renal afferent arteriole pressure, increased sympathetic stimulation, and decreased sodium or chloride concentrations in the distal tubule.41,42 Angiotensin I undergoes 232 Wakefield et al Fig.