REVIEW CURRENT OPINION Vasodilatory shock in the ICU and the role of angiotensin II Brett J. Wakefielda, Gretchen L. Sachab, and Ashish K. Khannaa,c Purpose of review There are limited vasoactive options to utilize for patients presenting with vasodilatory shock. This review discusses vasoactive agents in vasodilatory, specifically, septic shock and focuses on angiotensin II as a novel, noncatecholamine agent and describes its efficacy, safety, and role in the armamentarium of vasoactive agents utilized in this patient population. Recent findings The Angiotensin II for the Treatment of High-Output Shock 3 study evaluated angiotensin II use in patients with high-output, vasodilatory shock and demonstrated reduced background catecholamine doses and improved ability to achieve blood pressure goals associated with the use of angiotensin II. A subsequent analysis showed that patients with a higher severity of illness and relative deficiency of intrinsic angiotensin II and who received angiotensin II had improved mortality rates. In addition, a systematic review showed infrequent adverse reactions with angiotensin II demonstrating its safety for use in patients with vasodilatory shock. Summary With the approval and release of angiotensin II, a new vasoactive agent is now available to utilize in these patients. Overall, the treatment for vasodilatory shock should not be a one-size fits all approach and should be individualized to each patient. A multimodal approach, integrating angiotensin II as a noncatecholamine option should be considered for patients presenting with this disease state. Keywords angiotensin II, catecholamines, septic shock, vasodilatory shock, vasopressors INTRODUCTION vasoactive agents, if needed, to augment hemody- Vasodilatory shock is the most common form of namics [6]. There are several vasoactive agents that circulatory shock and is characterized by reduced can be utilized, both catecholamine and noncate- systemic vascular resistance and hypoperfusion. cholamine derived; however, there are little data to Septic shock is the most common cause of vaso- guide the practitioner to the appropriate choice of dilatory shock [1] and other, less common, non- agent. Historically, catecholamine agents such as, septic causes of vasodilatory shock include disease norepinephrine, dopamine, epinephrine, and phen- processes such as severe acute pancreatitis, anaphy- ylephrine have been utilized; however, noncate- laxis, and anaphylactoid-like reactions, neurogenic cholamine agents such as vasopressin, and more shock, adrenal insufficiency, and vasoplegia post- recently, angiotensin II, have been studied with cardiac surgery. Septic shock, as defined by the promising results. This review will focus on the Sepsis-3 guidelines is described as a subset of sepsis utilization of vasoactive agents in septic shock, in which underlying circulatory and cellular and metabolic abnormalities are profound enough to aDepartment of General Anesthesiology, Anesthesiology Institute, substantially increase mortality [2]. Overall mortal- bDepartment of Pharmacy and cDepartment of Outcomes Research, ity rates of sepsis are around 15–25% [3–5], yet, rates Center for Critical Care, Cleveland Clinic, Cleveland, OH, USA of septic shock are more than 40% [2]. Due to the Correspondence to Ashish K. Khanna, MD, FCCP, FCCM, Cleveland high mortality rates, prompt diagnosis, assessment, Clinic Foundation, 9500 Euclid Avenue – G58, Cleveland, OH 44195, and treatment of these patients are crucial and USA. Tel: +1 513 658 5866; e-mail: [email protected] center on early antibiotic administration [6–8], Curr Opin Crit Care 2018, 24:277–285 aggressive resuscitation, and the initiation of DOI:10.1097/MCC.0000000000000517 1070-5295 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-criticalcare.com Cardiovascular system [16]. These findings have led to cautious skepticism KEY POINTS in the utilization of epinephrine by clinicians. Nor- Treating patients with vasodilatory and septic shock epinephrine and vasopressin have not shown should not be a one-size fits all approach and should proven superiority of one vs. the other in rigorous use a multimodal approach integrating both randomized trials [17,18]. However, vasopressin has catecholamine, and if needed, noncatecholamine shown improved mortality in patients with ‘less vasoactive agents. severe’ forms of septic shock (those with lactate Angiotensin II has recently gained FDA approval for the concentrations <1.4 mmol/l, and those with norepi- treatment of vasodilatory shock and can be added to nephrine doses 15 mg/min) [17] and is also associ- the armamentarium of agents utilized for hemodynamic ated with less need for renal replacement therapy management in these patients. [18]. In addition, a benefit consistently shown with vasopressin is its reduction in catecholamine The Angiotensin II for the Treatment of High-Output Shock 3 trial demonstrated the efficacy, safety, and requirements in patients on norepinephrine [17– catecholamine sparing effects of angiotensin II in 20]. Furthermore, in a recent phase II study, sele- patients with high-output vasodilatory shock. pressin, a selective vasopressin V1A agonist, was able to reduce norepinephrine dosing and maintain ade- Future studies are needed and should include the effect quate MAP in patients with septic shock [21]. of angiotensin II on renal function, lung injury, tissue perfusion, and microcirculation. Despite this, the true clinical niche of vasopressin is still debated. Finally, phenylephrine, a weak vaso- pressor, has also been historically recommended as an alternative second-line option, specifically in focusing on angiotensin II as a novel, noncatechol- those who developed tachyarrhythmias to norepi- amine agent and its efficacy, safety, and role in the nephrine [22], but due to lack of efficacy, data have armamentarium of vasoactive agents utilized in this since been removed from the guidelines [6]. patient population. Overall, there is little guidance on how to man- age patients with refractory septic shock, nonre- sponsive to second or third line agents. In Vasoactive agents for septic shock addition, there has been increasing evidence in Currently, norepinephrine is the recommended favor of limiting catecholamine agents as increasing vasoactive agent of choice for patients with septic doses may be associated with an increased risk of shock [6]. Historically, dopamine was also recom- mortality [23,24] and their use may have detrimen- mended first line [9,10]. However, after these rec- tal effects including decreased splanchnic perfusion, ommendations were published, several studies and hyperglycemia, tachyarrhythmias, and an inhibi- meta-analyses have demonstrated increased mortal- tory effect on the innate and adaptive immune ity and tachyarrhythmias associated with dopamine systems [25]. Because of this, the early utilization when compared with norepinephrine, resulting in of noncatecholamine agents, especially to limit cat- the removal of dopamine’s recommendation as first echolamine dosages and using a multimodal line [11–14]. Importantly, there are few large, ran- approach may be an attractive therapeutic manage- domized, controlled trials comparing catechol- ment strategy in patients with refractory septic amine agents and evaluating the agent that is shock. In fact, as previously mentioned, vasopressin most efficacious as first line in patients with septic [17–20] and, additionally, angiotensin II [26&&] have shock. As such, the Surviving Sepsis Campaign (SSC) been shown to decrease catecholamine dose require- supports the use of norepinephrine as a first line ments which may minimize the occurrence of the vasoactive agent based on a strong recommendation detrimental effects associated with catecholamines. and moderate quality of evidence [6]. The SSC guidelines recommend epinephrine and vasopressin as second line adjuncts to raise Vasopressor management strategies mean arterial pressure (MAP) to 65 mmHg in Regardless, the overall clinical approach to utilizing patients unable to maintain goal MAP [6]. To date, vasoactive agents in patients with septic shock is to no mortality difference has been detected between initiate norepinephrine first line with vasopressin as the use of norepinephrine and epinephrine [15,16] second line. Epinephrine (or dobutamine) should be and an equipotent effect in terms of achieving a considered in patients with poor cardiac function to MAP goal more than 70 mmHg has been seen [16]. increase cardiac output and stroke volume due to However, one trial identified that 12.9% of patients higher beta-1 receptor affinity in the myocardium, receiving epinephrine experienced transient meta- weighing the risk of tachyarrhythmias. Phenyleph- bolic effects resulting in withdrawal from the study rine should be considered in patients with malignant 278 www.co-criticalcare.com Volume 24 Number 4 August 2018 Vasodilatory shock in the ICU and the role of angiotensin II Wakefield et al. Table 1. Norepinephrine equivalent conversion chart After exhausting the options detailed above, there is no further guideline driven recommenda- Vasoactive Norepinephrine tions regarding patients with refractory hypoten- agent Dose equivalent dose sion, not at goal MAP, or on increasing doses of Epinephrine 0.1 mg/kg/min 0.1 mg/kg/min norepinephrine, both areas that warrant further Norepinephrine 0.1 mg/kg/min 0.1 mg/kg/min investigation. It is not known how to adjust thera- Dopamine 15 mg/kg/min 0.1 mg/kg/min peutic