Vasodilatory Shock in the ICU and the Role of Angiotensin II

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

[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 vasopressor, 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 manage patients with refractory septic shock, nonresponsive 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

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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 management strategies once patients are deemed nonresponsive or refractory to the afore- Phenylephrine 1 mg/kg/min 0.1 mg/kg/min mentioned adjunct agents (i.e., MAP below goal on Vasopressin 0.04 unit/min 0.1 mg/kg/min two or more vasoactive agents, worsening lactate in

&& Put together from [26 ]. Derived from the Sequential Organ Failure (SOFA) a patient with normal cardiac function at a MAP of score and data from the VASST trial. 65 mmHg, etc.). In these scenarios, utilizing alternative vasoactive agents may be warranted. The US tachyarrhythmias on norepinephrine or epineph- food and drug administration (FDA) recently rine, understanding that the actual vasopressor approved angiotensin II as a means to increase blood action of phenylephrine is the weakest in the group. pressure (BP) in adults with septic or other distribu- A dose conversion of vasoactive agents to norepi- tive shock [31]. This vasopressor may be of signifi- nephrine equivalent doses is shown in Table 1. cant benefit both as a primary and adjunct therapy Optimal MAP for targeting vasopressor therapy is and warrants further discussion. also an area that deserves further investigation. The SSC guidelines recommend titrating vasoactive agents to a MAP of more than 65 mmHg. This is based on a Angiotensin II moderate level of evidence and is mostly supported Three major pathways mediate vasoconstriction: the by trials that have shown fewer cardiac arrhythmias, sympathetic nervous system and catecholamines, less vasopressor use, and similar mortality at higher the vasopressin pathway, and the renin–angioten- and lower MAP targets [27–29]. A recent large database sin–aldosterone system (Fig. 1). Renin is a serine analysis in a surgical critical care population has protease which mediates the conversion of angioten- shown that moderate amounts of hypotension were sinogen to angiotensin I. Angiotensin I is converted strongly associated with myocardial and renal injury to the octapeptide angiotensin II by the activity of in postoperative critical care patients, hence implicat- angiotensin-converting enzyme (ACE) [32]. Angio- ing that ignoring even moderate amounts of hypoten- tensin II acts on angiotensin type 1 receptors to sion is unwise in the critically ill [30&]. produce vasoconstriction via a G-protein-mediated

Vasodilatory Shock Adrenal medulla Decreased MAP Hypothalamus Volume Depleon Liver Phenylephrine* Norepinephrine Epinephrine Posterior Pituitary Angiotensinogen

Renin Vasopressin Selepressin* Angiotensin I α1 receptor α2 receptor β1 receptor β2 receptor

ACE/Chymase V2 receptor V1B receptor V1A receptor

Tachycardia Vasoconstricon Inhibit Vasodilaon Angiotensin II norepinephrine Increased inotropy Mydriasis Bronchodilaon Renin release release Aquaporin inseron Vasoconstricon vWF/factor VIII release ACTH release Platelet aggregaon Vasodilaon AT-1 receptor AT-2 receptor

Vasoconstricon Vasodilaon Aldosterone secreon Nitric oxide release + Na H2O Reabsorpon Natriuresis Vasopressin release Inhibion of cell Cell Growth growth

* Phenylephrine and selepressin are exogenous vasopressors

FIGURE 1. Pathways for blood pressure homeostasis during vasodilatory shock. Phenylephrine and selepressin are exogenous vasopressors. Created by Brett Wakefield.

1070-5295 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-criticalcare.com 279 Cardiovascular system pathway involving phospholipase C, inositol-1,4,5- and accelerate approval in the setting of a positive triphosphtate, and diacylglycerol [33]. During sepsis, result [39]. In ATHOS-3, volume replete (25 ml/kg) endothelial dysfunction can decrease ACE activity, patients with vasodilatory shock requiring vasopres- subsequently reducing angiotensin II levels [34]. In sor therapy with norepinephrine (or equivalents, addition, low ACE expression and angiotensin II Table 1) of greater than 0.2 mg/kg/min to maintain levels have been shown to be predictors of mortality MAPs between 55 and 70 mmHg for a minimum of 6 in patients with severe sepsis [35]. As a result of the and a maximum of 48 h were randomly assigned to reduced angiotensin II levels in sepsis as well as the receive either angiotensin II or placebo. Vasodila- octapeptide’s vasoconstrictive effects, angiotensin II tory shock was defined as a cardiac index (CI) greater appears to be an attractive option that makes physi- than 2.3 lt/min/m2 or a combination of a central ological sense for use in patients with septic shock. venous oxygen saturation greater than 70% and In 1957, two independent teams successfully central venous pressure greater than 8 mmHg. The synthesized a peptide identical to naturally occur- initial 3 h of the study protocol required gradual ring angiotensin II [36,37]. Following the surge of titration of the study drug from an initial dose of angiotensin II research performed after the peptides 20 ng/kg/min to a maximum dose of 200 ng/kg/min. synthesis, there has been a paucity of literature The primary endpoint was a response to MAP at 3 h describing its use in vasodilatory shock. Recently, following the start of the infusion (Table 2) and was however, this topic has been reevaluated. defined as an increase from baseline of 10 mmHg or In 2014, the Angiotensin II for the Treatment of an increase to at least 75 mmHg without a concomi- High-Output Shock (ATHOS) pilot study evaluated the tant increase in background vasopressors. This use of intravenous ATHOS [38]. This study included 20 phase of the trial assessed the potency and safety patients with distributive shock and a cardiovascular of the medication. From hour 3 to 48, the study drug sequential organ failure assessment (SOFA) score of 4 and background vasopressors were titrated to main- and randomized them to receive either angiotensin II tain MAP targets between 65 and 70 mm Hg. Sec- or placebo. Angiotensin II was initiated at a dose of ondary endpoints included the change between 20 ng/kg/min and titrated to maintain a MAP more baseline and 48-h cardiovascular SOFA score and than 65 mmHg. The infusion was continued for 6 h total SOFA score. A safety assessment was included and then discontinued. The primary objective of the which evaluated all adverse events, drug discontin- ATHOS pilot study was to evaluate the effect of angio- uations, and an exploratory endpoint of all-cause tensin II on the dose of norepinephrine required to mortality at 7 and 28 days. maintain a MAP of 65 mmHg. Four hundred and four patients were assessed for This trial demonstrated a reduction in norepi- eligibility across 75 ICUs in North America, Europe, nephrine dosing for all patients treated with angio- and Australasia. Of these, 344 patients were random- tensin II. Following 1 h of angiotensin II infusion, ized – and the final modified intention to treat the mean norepinephrine dose was 27.6 29.3 mg/ population included 163 who received angiotensin min in the placebo group compared with II and 158 who received placebo for a final number 7.4 12.4 mg/min in the angiotensin II group. of 321. As expected, septic shock was the over- Thirty-day mortality was similar in both groups whelming majority diagnosis in most patients. Base- and the only adverse event demonstrated in the line demographic characteristics were comparable experimental arm was hypertension, experienced in the two groups. Importantly, this was a very sick in 20% of patients. The ATHOS trial was a proof patient population, with at least two-thirds of the of concept study demonstrating the catecholamine patients requiring vasopressin 6 h prior to randomi- sparing effect of human synthetic angiotensin II, zation and a median APACHE II score of 28 (22–33). whereas maintaining a MAP more than 65 mmHg in In addition, patients had a very high vasopressor patients with high output shock. requirement at randomization, with a median norepinephrine equivalent dose being 0.34 ug/kg/min (interquartile range: 0.23–0.56 ug/kg/min). The pri- Angiotensin II in vasodilatory shock mary endpoint at hour 3 was achieved in 69.9% of Following the successful pilot study, a multicenter patients in the angiotensin II group as compared randomized controlled trial, ATHOS-3, was devel- with 23.4% of the control group [P < 0.001, Table 2 oped under a special protocol assessment agreement and Fig. 2 (A)]. Although there was no difference in (SPA) with the US FDA [26&&]. A SPA is a rare agree- overall SOFA scores, there was a significant improvement in which the FDA expresses full concurrency ment in mean cardiovascular SOFA scores in the with the phase III trial’s study protocol. This implies angiotensin II group at hour 48 (1.75 vs. 1.28, the scientific merit of the protocol and the suggested P ¼ 0.01 Table 2). In addition, patients on angioten- end points meet the FDA’s criteria of a phase III trial sin II had a more significantly decreased background

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Table 2. Primary and secondary end points from the Angiotensin II for the Treatment of High-Output Shock 3 trial

Angiotensin II, Placebo, Odds or hazard End point N ¼ 163 N ¼ 158 ratio (95% CI) P value

Primary efficacy end point: MAP response at hour 3, n (%)a 114 (69.9) 37 (23.4) Odds ratio 7.95 (4.76–13.3) <0.001 Secondary efficacy end points Mean change in cardiovascular SOFA score at hour 48 1.75 1.77 1.28 1.65 0.01 Mean change in total SOFA score at hour 48 1.05 5.50 1.04 5.34 0.49 Additional end points Mean change in NE-equivalent dose from baseline to hour 3b 0.03 0.10 0.03 0.23 <0.001 All-cause mortality at day 7, n (%) 47 (29) 55 (35) Hazard ratio 0.78 (0.53–1.16) 0.22 All-cause mortality at day 28, n (%) 75 (46) 85 (54) Hazard ratio 0.78 (0.57–1.07) 0.12

Values are means SD unless otherwise noted. MAP, mean arterial pressure; NE, norepinephrine; SOFA, sequential organ failure assessment. Reproduced with && permission [26 ]. aResponse with respect to MAP at hour 3 after the start of infusion was defined as an increase from baseline of at least 10 mmHg or an increase to at least 75 mmHg, without an increase in the dose of background vasopressors. bData were missing for three patients in the angiotensin II group and for one patient in the placebo group. vasopressors dose requirement from hour 0 to 3 The current review also evaluated the physiologic [0.03 vs. þ0.03, P < 0.001 Table 2 and Fig. 2 (B)] changes on major organ systems induced by angio- and this catecholamine sparing effect likely tensin II administration [40&&]. The primary cardio- explained the benefit of improvement in cardiovas- vascular response to angiotensin II is increased BP. cular SOFA scores. Mortality at 28 days was similar in During the ATHOS-3 trial, patients treated with both treatment groups (46% in angiotensin II group, angiotensin II also experienced an increase in heart 54% in control group, P ¼ 0.12). Furthermore, a rate, which was largely attributed to a well described multivariate analysis of factors across both groups synergistic effect with catecholamine usage [43]. The (angiotensin II and placebo) associated with achiev- most common endocrine effects included increased ing a MAP of 75 mmHg at hour 3, showed an odds aldosterone and decreased renin. Vasopressor doses significantly in favor of a treatment assignment to of angiotensin II have shown a corresponding angiotensin II, and to the presence of a diagnosis of increase in pulmonary pressures. In addition, angio- acute respiratory distress syndrome (ARDS). The tensin II administration has been associated with presence of low albumin, the use of AT1 blockers asthma exacerbation and bronchoconstriction. In (ARBs), and most importantly a high vasopressor the ATHOS pilot study, wheezing was reported in requirement (norepinephrine dose >0.5 ug/kg/min) one in 10 patients receiving angiotensin II for distrib- at the point of randomization was associated with a utive shock [38]. Decreased glomerular filtration rate, significantly reduced odds of reaching the primary decreased renal plasma flow, and impaired natriuresis endpoint. Overall, the ATHOS-3 trial clearly dem- have been associated with angiotensin II use. onstrated the safety, efficacy, and catecholamine sparing effect of angiotensin II in the treatment of vasodilatory shock. Other research with angiotensin II Recently, Busse et al. [40&&] reviewed the safety of Szerlip et al. evaluated a subgroup of the ATHOS-3 angiotensin administration in a systematic review of patient population. Patients with increased severity 1124 studies with 31 281 human participants of illness metrics (APACHE II score >30, n 123 and involving the use angiotensin II. Of these studies, MAP < 65 mmHg, n ¼ 102) were analyzed for 28-day 13 evaluated use during shock states. Only two all-cause mortality [44&&]. The subgroup (APACHE II deaths were attributed to angiotensin II. One score >30) receiving angiotensin II demonstrated a healthy patient developed a cerebral hemorrhage significant mortality benefit when compared with after 6 days of continuous infusion and another patients on placebo within the ATHOS-3 population patient with acute heart failure experienced fulmi- [51.9 vs. 70.8%, hazard ratio (HR): 0.62; 95% confi- nant ventricular failure [41,42]. Of note, neither of dence interval (CI): 0.39–0.98; P ¼ 0.0370]. Patients these deaths were in the setting of vasodilatory with MAP less than 65 mmHg at randomization had shock. Less than 300 adverse events were reported; a 28-day mortality of 54% compared with 70% for the most common of which were transient head- those that received placebo, a difference which ache, abnormal chest sensations, and orthostatic trended toward significance (HR: 0.66; 95% CI: symptoms following discontinuation. 0.4–1.1; P ¼ 0.1003). These findings suggest that

FIGURE 2. Treatment responses from the Angiotensin II for the Treatment of High-Output Shock 3 Trial. Efficacy outcomes are shown according to study group. (a) Shows the mean arterial pressure from initiation of angiotensin II or placebo through 48 h. The gray shading indicates the initial 3 h during which the goal was to increase the mean arterial pressure to 75 mmHg or higher; thereafter, the target mean arterial pressure was determined by the treating team. (b) Shows the changes from baseline in mean doses of vasopressors, denoted in norepinephrine-equivalents, from initiation of angiotensin II or placebo through 48 h. In both parts (a) and (b), I bars indicate standard errors. At each time point, the number at risk and the mean value includes only patients who were receiving at least one vasopressor. Reproduced with permission [26&&].

282 www.co-criticalcare.com Volume 24 Number 4 August 2018 Vasodilatory shock in the ICU and the role of angiotensin II Wakefield et al. angiotensin II administration may be beneficial in including norepinephrine, epinephrine, and vaso- patients with a high severity of illness. pressin, as all four hormones are secreted in response In patients with increasing degrees of ARDS sever- to shock. However, an important question remains ity, angiotensin II administration significantly – who should receive and who will best benefit from improved BP in each ARDS subgroup [MAP responses angiotensin II? Certainly, angiotensin II may not be achieved by 67% (OR ¼ 6.7, P < 0.001), 69% the appropriate vasopressor for every patient with (OR ¼ 6.6, P < 0.001), and 61% (OR ¼ 8.4, P ¼ 0.005) distributive shock. The ATHOS-3 trial excluded for mild, moderate, and severe ARDS, respectively] patients with a CI less than 2.3 [26&&]. As previously and demonstrated a trend toward a reduction in 28- mentioned, angiotensin II has been noted to induce day mortality [45]. Further, an attempt was recently ventricular failure in a patient with poor cardiac made to delineate which patients respond to angio- function [42]. Although chronic exposure to angiotensin II. A subset of 163 patients were examined for tensin II promotes ventricular dysfunction and response to angiotensin II at doses 5 ng/kg/min or less induces ventricular remodeling, acute exposure (super responders), doses more than 5 ng/kg/min, or may contribute to reduced ventricular performance placebo at 30 min after drug initiation. Angiotensin II through angiotensin II induced increases in after- super-responders, had significantly reduced all-cause load [50]. Pure increases in systemic vascular resis- mortality at day 28 compared with patients receiving tance in the setting of sepsis can increase mortality placebo [HR: 0.50 (95% CI 0.32–0.78), P ¼ 0.0018] or particularly in patients with reduced cardiac func- higher doses [0.45 (95% CI 0.28–0.72), P ¼ 0.0007]. tion as previously demonstrated with the use of the As this dose of 5 ng/kg/min or less represents a phys- nitric oxide synthase inhibitor 546C88 [51]. Angio- iological level of angiotensin II, a response here may tensin II is likely most useful in patients with normal reflect a novel and effective means of achieving nor- or hyperdynamic cardiac function. It is important to mal homeostatic mechanisms to correct vasodilatory keep in perspective that all initially high output shock in an exquisitely responsive population [46]. ‘warm shock’ may eventually morph into low out- Considering the renal effects of angiotensin II, put shock, a change that is not always detectable. researchers in Melbourne, Australia evaluated the Our current best practices use norepinephrine and vasoconstrictive effect of angiotensin II on renal vasopressin in escalating doses, and this may not be oxygenation during septic acute kidney injury the best answer for low output shock in a (AKI) [47&]. Current evidence indicates AKI during septic patient. sepsis may result from renal medullary hypoxia [48]. ACE inhibitor and ARB use prior to surgery has Sepsis was induced in merino ewes with a resultant become an important cause of intraoperative and decrease in medullary and urinary PO2. Angiotensin postoperative vasoplegia and refractory hypoten- II was initiated at 24 h resulting in improvement in sion [52]. Considering these medications create an BP and a transient increase in creatinine clearance iatrogenic angiotensin II deficiency and end-organ without a reduction in medullary PO2. Tumlin et al. resistance administration of angiotensin II may cor- performed a post-hoc analysis on the ATHOS-3 pop- rect the relative imbalance. Further research is ulation looking at the effect of angiotensin II on required to evaluate whether angiotensin II should outcomes of AKI requiring renal replacement ther- be the first line vasopressor agent for patients with apy. The patient population was limited to those ACE inhibitor induced vasoplegia. ACE resides in having AKI and receiving renal replacement at the the pulmonary capillary endothelium, and a lack of initiation of angiotensin II or placebo. Results ACE activity can also result from prolonged exclu- showed a significant benefit with hemodynamic sion or injury of the pulmonary capillary endo- stability (P ¼ 0.001), liberation from renal replace- thelium as in ARDS/acute lung injury, severe ment (P ¼ 0.007), and mortality (P ¼ 0.012) in pneumonia, and prolonged exposure to cardiopul- patients on angiotensin II with AKI on renal replace- monary bypass. Hence, hypotensive states in these ment [49]. These data suggest angiotensin II admin- patients may be exquisitely responsive to exogenous istration may be safe and efficacious in the setting of angiotensin II. septic AKI. Can laboratory tests identify the patients who will have the greatest benefit from angiotensin II? Zhang et al. [35] described increased mortality in Future of angiotensin II in vasodilatory shock septic patients with reduced levels of angiotensin II Based on the findings of the ATHOS-3 trial, the US and ACE. Wunderink et al. [53&&] evaluated whether FDA recently granted approval to angiotensin II the angiotensin I to II ratio predicts outcomes in after a priority review of the new drug application. distributive shock. They found a relatively low It would seem appropriate and logical to add angio- angiotensin II state with a ratio greater than 1.63 tensin II to our armamentarium of vasopressors (as defined by a population median derived from

ATHOS-3 data) was associated with higher mortal- Conflicts of interest ity. In addition, there was a survival benefit in A.K.K. has received support from the La Jolla pharma- patients with a high ATI/ATII receiving angiotensin ceutical company as a consultant and speaker. II compared with placebo (HR: 0.64, 95% CI 0.41– 1.00, P ¼ 0.047). These data suggest the importance of ACE, and the utility of ATI/ATII as biomarkers REFERENCES AND RECOMMENDED that may suggest benefit and define the need and READING use for angiotensin II in septic hypotensive patients. Papers of particular interest, published within the annual period of review, have been highlighted as: The ATHOS-3 trial was designed to answer spe- & of special interest cific questions of human synthetic Angiotensin II. && of outstanding interest

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