Article, Critical Care

Angiotensin II in septic shock

a b s t r a c t

Septic shock is a life threatening condition and a medical emergency. It is associated with organ dysfunction and hypotension despite optimal volume resuscitation. Refractory septic shock carries a very high rate of mortality and is associated with ischemic and arrhythmogenic complications from high dose vasopressors. Angiotensin II (AT-II) is a product of the Renin-angiotensin-aldosterone system. It is a vasopressor agent that has been recently approved by FDA to be used in conjunction with other vasopressors (catecholamines) in refractory shock and to reduce catecholamine requirements. We have reviewed the physiology and current literature on AT-II in refrac- tory septic/vasodilatory shock. Larger trials with longer duration of follow-up are warranted to address the ques- tions which are unanswered by the ATHOS-3 trial, especially pertaining to its effects on lungs, brain, microcirculation, inflammation, and venous thromboembolism risk.

(C) 2019

Introduction

Sepsis is a condition where life-threatening organ dysfunction is caused by a dysregulated host response to infection [1-3]. Septic shock is defined as a subset of sepsis in which profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mor- tality than with sepsis alone. Patients with septic shock can be clinically identified by a Vasopressor requirement to maintain a mean arterial pressure (MAP) of 65 mm Hg or greater and have Serum lactate level N2 mmol/L (N18 mg/dL) in the absence of hypovolemia. When fluid re- suscitation fails to improve arterial blood pressure, vasopressors are necessary. Sepsis with septic shock is associated with a high mortality rate upto 40% [1]. Refractory septic shock is the persistence of circula- tory failure despite optimized therapy (fluid resuscitation, vasopressors, inotropes) [4].The pathophysiology of septic shock is marked by an im- balance between vasodilators like nitric oxide, tumor necrosis factor (TNF)-alpha, histamine, kinins and prostaglandins, angiotensin II (AT- II) and catecholamines (epinephrine and norepinephrine) [4].Norepi- nephrine (NE) is the standard vasopressor used in hypotension due to septic shock [5].Excessive use of cathecholamines is associated with several risks like splanchnic ischemia, arrhythmias, hyperglyce- mia and peripheral ischemia and is an independent risk factor for ICU mortality [6].Use of an additional vasopressor which acts via a differ- ent mechanism of action will help achieve desired mean arterial

? None of the authors have financial or ethical conflicts of interest regarding the contents.

* Corresponding author.

E-mail address: ajadhav@soundphysicians.com (A.P. Jadhav).

pressure goal in septic shock and will help reduce complications from excessive catecholamines. AT-II has various effects from poten- tiating Sympathetic activity, direct vasoconstriction and fluid reten- tion via the release of aldosterone and vasopressin/anti diuretic hormone.

Overview of renin-angiotensin – aldosterone system (RAAS)

AT-II is an endogenous vasopressor that is produced by the body in response to shock through the RAAS. It is synthesized in the interstitial space. The tissue RAAS utilizes enzymes such as cathepsins and chymase to synthesize AT-II and acts locally [7-9]. AT II is also synthe- sized inside the cell in secretory vescicles [7].Intracellular RAAS is local- ized in the cytoplasm, mitochondria and nuclei [9]. intravascular volume depletion and decreased mean arterial pressure (MAP) leads to release of renin from the juxtaglomerular cells in the afferent arteri- ole in the kidney [10]. Angiotensinogen which is produced by the liver is converted by renin to angiotensin I (AT-I) in the plasma. AT-I is con- verted to AT-II by angiotensin converting enzyme (ACE). ACE is found in the pulmonary microcirculation and endothelium of systemic circula- tion [11].

Angiotensin converting enzyme II (ACE-2) breaks down AT I to angiotensin 1-9 (AT 1-9) and AT II to angiotensin 1-7 (AT 1-7) [11-13]. AT1-7 interacts with the bradykinin -nitric oxide prosta- glandin system and produces vasodilatation [13]. AT 1-9 inhibits AT II induced vascular smooth muscle cell migration and prolifera- tion and reduces the neointimal formation via AT2 receptor [14]. This effect helps in cardiac remodeling. The balance between ACE and ACE-2 plays an important role in hemodynamics by controlling

https://doi.org/10.1016/j.ajem.2019.03.026

0735-6757/(C) 2019

AT- II concentrations. AT-II regulates the renin angiotensin system by the negative feedback on renin production by the juxtaglomerular cells in the kidney [15].

Effects of angiotensin II (AT-2) receptors

AT-II binds to G-protein coupled receptors. Human cells express AT- 1a receptors (AT-R1a) which are located in vascular smooth muscle, heart, brain, kidneys, adrenals, pituitary gland, liver and other tissues [16]. The majority of AT-II actions are mediated through AT-R1 which stimulates aldosterone release from the adrenal cortex, causing sodium and water reabsorption along with stimulation of vasopressin release and thus subsequently increasing the blood pressure (Fig. 1) [11]. The function of the AT-2 receptor has not been completely understood and it is believed that their stimulation may counteract the effects of AT-1 on cell growth, blood pressure and inflammation [16]. AT-II binding to AT-II receptors causes vasodilatation and decreased vascular resistance [15]. Through AT-I receptors, AT-II stimulates the production of endo- thelial adhesion molecules like P-selectin, E-selectin, vascular cell adhe- sion molecule 1 (VCAM-1) which induces pro-Inflammatory mediators like vascular endothelial growth factor (VEGF) resulting in an increased vascular permeability through expression of PV-1 on Endothelial cells [17]. While AT-II exerts it pro-inflammatory effects through AT-1 recep- tors, it also binds to AT-II receptors producing vasodilatation and de- creased systemic vascular resistance. In addition, AT-II binds to AT-IV receptors and stimulates vasodilatatory, pro-inflammatory and procoagulant effects [11].

RAAS in septic shock

Clinical studies have shown activation of RAAS during sepsis [18-20]. Septic shock is a type of distributive shock characterized by reduced pe- ripheral vascular resistance, increased capillary permeability, relative hy- povolemia, increased cardiac output, and microcirculatory dysfunction leading to increased mixed venous oxygen saturations [4]. Nitric oxide causes vasodilatation resulting in reduced preload and afterload. Inflam- matory markers like alpha-TNF, interleukin-1, interleukin- 6 causes myo- cardial depression in sepsis [4]. To counteract this, different physiological processes try to restore circulating volume, vascular resistance, mean ar- terial pressure by activation of sympathetic nervous system, vasopressin release, inhibition of atrial and cerebral natriuretric peptide; increased renin secretion results in RAAS activation and elevation AT-II levels [21]. As a result of reduced effective circulating volume and reduced mean ar- terial pressure in septic shock, activation of RAAS is increased due to renal hypoperfusion. Decreased stretch of the afferent arteriole and decreased delivery of chloride to distal tubules stimulates renin release from juxtaglomerular cells [22]. Hypovolemia also stimulates sympatho-adre- nal and hypothalamo-pituitary-adrenal axis resulting in AT-II and renin release [22]. Angiotensin acts on the efferent renal arteriole causing vaso- constriction, thus preserving mean arterial pressure during hypotension and increasing glomerular filtration pressure.

Angiotensin II and shock

In vitro Experimental models of sepsis have shown downregulation of AT-R1 and AT-R2 receptors in many organs like lung, liver, heart and

Decreased intravascular volume/ decreased MAP

Juxta glomerular cells secrete renin

Angiotensinogen (Liver)

Angiotensin I

ACE-2

Angiotensin 1-9

Angiotensin converting enzyme

Vascular smooth muscle

Neo-intimal formation

AT2

Receptor

Angiotensin II

ACE-2

Angiotensin 1-7

Inhibits

Vasoconstriction Aldosterone secretion Pro-inflammatory Vasopressin release

Na and water re- absorption

Procoagulant

Angiotensin I receptor

Vasodilatation

Nitric oxide release

Decreased inflammation

Inhibition of cell growth

Angiotensin II receptor

Mas Receptor

Vasodilation Antithrombotic

Fig. 1. Flowchart showing mechanism of activation of Angiotensin II and its effects on different receptors.

brain induced by Nitric oxide and pro-inflammatory markers like IL-1B, TNF-alpha and INF-gamma [23,24]. Ikedia et al. and Sasamura et al. revealed that NO and pro-inflammatory cytokines down regulate AT-R1 expression in in-vitro models of vascular smooth muscle cells [25,26]. Mederle et al. showed that ARAP-1 (AT-R1 associated protein) could increase the expression of AT-R1 on the cell surface. Elevated AT-II levels could induce a marked down regulation of ARAP-1, thus in an auto regulatory fashion reducing the vasculature’s sensitivity to AT- II as found in sepsis [27]. Mederle et al. confirmed this hypothesis in vivo as well in an experimental sepsis model. After lipopolysaccharide injection, they found a significant down-regulation of ARAP-1 expres- sion in wild type mice and Hemodynamic compromise in ARAP-1 knockout mice. ARAP-1 expression is dependent not only on AT-II levels but also on exposure to cytokines as noted in vascular smooth muscle cells [26,27]. In an animal model, Corre^a et al. found that AT-II can be used as a safe vasopressor without adverse effects on renal perfusion or mitochondrial respiration [28]. They randomized 21 pigs to a septic or control group. The septic group was further randomized to fluid resuscitation with NE or AT-II infusion. In the control group, the au- thors tested the effects of AT-II infusion in non-septic animals. In the septic group AT-II reversed sepsis-induced hypotension, while renal blood flow did not differ between AT-II and NE. In another study, ex- ogenous AT-II did not worsen mitochondrial respiration, but was re- vealed to be having negative effects on mitochondrial function elsewhere [29].

Effect of angiotensin II on organs

AT II has a different effect on the lungs, brain, heart and the liver. Imai et al. reported that angiotensin converting enzyme- 2 (ACE-2) and the AT-R 2 protected mice from severe acute lung injury induced by acid aspiration or sepsis [30]. However ACE, AT-II and AT-R1a pro- mote disease pathogenesis inducing lung edema thereby impairing lung function. Animal studies by Zambelli et al. and Supe et al. have re- vealed an increased amount and concentration of AT-II as compared to angiotensin 1-7 (AT 1-7) in broncho-alveolar fluid in ARDS [31,32]. Zambelli et al. found that high doses of angiotensin 1-7 reduced inflam- matory cell numbers in bronchoalveolar lavage and reduced lung fibro- sis [31]. Supe et al. found that infusion of angiotensin 1-7 protected against experimental lung injury [32]. A finding from these two studies suggests that lungs benefit from angiotensin 1-7 rather than AT-II. In the kidneys, AT-II produces efferent arteriolar constriction thus increas- ing filtration fraction [33]. In septic shock where kidneys are hypo-per- fused due to distributive shock, AT-II produces efferent arteriolar constriction thus maintaining tubular perfusion and could potentially prevent renal ischemia and may even help improve renal functions. The liver plays an important role in the activation of the RAAS. Angiotensinogen is produced in the liver and its levels are reduced in Cirrhotic patients [34]. In septic shock, cirrhotic livers are limited in being able to release angiotensinogen to activate the RAAS pathway. Hence patients with liver cirrhosis in septic shock could potentially ben- efit with exogenous administration of AT-II. RAAS may be implicated in neurodegenerative disorders like Alzheimer’s disease [35], neuronal in- jury and cognitive disorder [36]. AT-R1 activation could promote reac- tive oxygen species and neuro-inflammation [37]. Villapol et al. tested AT-R2 antagonists (candisartan and telmisartan) on cognition and motor performance in traumatic brain injury patients. Both drugs im- proved cerebral blood flow and reduced neuronal injury, apoptosis and pro-inflammatory signaling [38]. These findings suggest a delete- rious effect of AT-II on brain function. In a study reviewing clinical use of AT II, 31,281 participants have been exposed to IV ATII in the studies reviewed including healthy normotensive subjects, normo- tensive and preeclamptic pregnant women, subjects with hyperten- sion, congestive heart failure, diabetes, solid tumors, and other co morbidities, critically ill patients, and children. This review was lim- ited by the heterogeneity of study design, which precluded formal

meta-analysis, reviewed studies differed in objectives; inclusion/ex- clusion criteria, co morbidities, and baseline characteristics, and only small proportion of patients had shock. This review concluded that adverse events associated with AT II were infrequent; exacerbation of asthma and congestive heart failure and one fatal cerebral hemor- rhage were reported [39].

Angiotensin II in vasodilatory shock and renal replacement therapy

Sepsis is responsible for approximately 50% of Acute Renal Failure (AKI) cases in critically ill patients [40-42]. Patients who survive AKI are at risk for long term mortality that appears to be related to its sever- ity [42,43]. Prognosis tends to be worse in patients requiring renal re- placement therapy who have concurrent vasodilatory shock and AKI [44]. These patients have a mortality rate between 40 and 55% [45,46]. AKI in vasodilatory shock occurs due to hypotension which causes re- duced renal perfusion. This vasodilatation and decreased blood flow po- tentiated by vasopressors leads to worsening AKI [47-49]. Lankedwa et al. revealed intra renal vasodilatation and shunting to be an important mechanism of AKI in sepsis [50]. In a prospective 6-month observational study in critically ill patients (n = 180), du Cheyron et al. found that pa- tients with AKI had significantly higher mortality rates in the ICU and hospital overall compared with those without AKI [51]. In a post hoc analysis of the AT-II for the Treatment of High-Output Shock 3 trial (ATHOS-3 trial), Tumlin et al. showed that in patients with AKI requiring Renal replacement therapy at the beginning of the study drug, 28 day survival and MAP response were higher in the AT-II group v/s the placebo group [42]. The authors also found that the rate of RRT libera- tion was greater in the AT-II group than the placebo group. They con- cluded that patients with vasodilatory shock and AKI-RRT may benefit from AT-II. The potential beneficial effect of AT-II on AKI-RRT could be in part to the fact that the kidneys may be particular susceptible to the effects of perfusion pressure to maintain blood flow [40]. Vasodilatory shock caused by inflammation leads to increased capillary endothelial injury and increased leakiness, reduced organ perfusion and coagula- tion defects. Endothelial cell injury may also cause loss of ACE as it is a membrane bound endothelial enzyme [40,52]. ACE burden may be esti- mated by measuring the ratio of angiotensin I and angiotensin II levels with ratio. Healthy individuals have an angiotensin I to angiotensin II level ratio of 0.5. In the ATHOS-3 trial, patients had a median angioten- sin I/angiotensin II ratio of 1.63 [53].This suggests angiotensin converting enzyme levels are reduced in vasodilatory shock likely due to endothelial dysfunction. Hence AT-II infusion will compensate for this reduction in levels and thus improve hypotension. Septic patients with less effective ACE activity as measured by increased angiotensin I/angiotensin II ratios were more likely to die compared to those with normal ACE activity [54]. Calzavacca et al. found that the use of catecholeamines is associated with unfavorable microcirculatory oxy- genation profile (increased renal oxygen consumption with catechol- amines as compared to AT-II) in an experimental sheep study model [55]. Data in vasodilatory shock models reveals that intravenous infu- sion of AT-II can restore GFR, increase urine output without decreasing renal oxygenation [40,50,53,56,57]. Unlike catecholamines, AT-II causes vasoconstriction of efferent arterioles [50,56,57]. This increases GFR by increasing glomerular capillary pressure [59]. Studies have demon- strated that septic shock creates a form of acute renal failure that is re- sponsive to infusion of AT-II [50,56,58,60].

Angiotensin II in high output shock (ATHOS trial)

Patients with distributive shock who require high dose vasopressors have a high mortality. Chawla et al. [61] in 2014 first published the ef- fects of AT-II in high output shock (ATHOS trial). This was a pilot study involving the use of AT-II. It was a prospective randomized double blind study in which 20 patients with distributive shock and a

cardiovascular Sequential Organ Failure Assessment score of 4 were randomized to either AT-II infusion (N = 10) or placebo plus stan- dard of care (N = 10). AT-II was titrated for a goal MAP of 65 mmHg. The infusion (either AT-II or placebo) was continued for 6 h then ti- trated off. The primary endpoint was the effect of the AT-II infusion on the standing dose of NE that was required to maintain a MAP of 65 mmHg. The secondary endpoints evaluated the effect of the ATII infusion on urine output, serum lactate, cardiac output, and 30-day mortality. In this study, AT-II resulted in marked reduction in NE dos- ing in all patients. There was no statistically significant difference in 30 day mortality between AT-II group and placebo group. (50% ver- sus 60% respectively, p = 1.00). Hypertension was the most common side effect noted in the AT-II group. The authors concluded the initial Dose range of AT-II that appears to be appropriate for patients with distributive shock was 2 to 10 ng/kg/min.

Limitations of ATHOS

There were several limitations of the ATHOS trial. The study had a small sample size (N = 20). The study was inadequately powered to establish a difference in mortality between AT-II and placebo groups. The placebo group had younger but sicker patients. This may have potentially influenced a difference in response to AT-II between the two populations. Based on the pressor titration protocol used specif- ically in this study, results may not be applicable for lesser sick pa- tients. The authors were unable to make a conclusion about effects of AT-II on urine output and renal functions due to the high incidence of oliguria and renal replacement therapy in both AT-II group and placebo group. The authors concluded the need for further larger randomized placebo controlled trials to more completely elucidate the role of AT-II as a pressor in the treatment of shock. This study laid the foundation for the ATHOS-3 trial.

Angiotensin II in vasodilatory shock/ATHOS-3 trial

Khanna et al. in the ATHOS-3 trial revealed AT-II effectively in- creased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors [62]. This was a multinational, double blind, randomized, controlled trial. The authors randomly assigned patients with vasodilatory shock who were receiv- ing N0.2 micrograms/kg/min of NE or the equivalent dose of another va- sopressor to receive either angiotensin II or placebo. The primary end point was a response in MAP at hour 3 after the start of infusion. Re- sponse 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. In this study 344 patients underwent ran- domization. 163 patients received AT-II and 158 received placebo (321 received a study intervention). At 48 h, the mean improvement in the cardiovascular Sequential Organ Failure Assessment score (SOFA) was greater in the AT-II group than the placebo group. Pa- tient who received AT-II had a lower requirement for catecholamine use. Also the MAP at 3 h was significantly greater in the AT-II group than the placebo group. There was no statistically significant differ- ence in mortality between the two groups. This is the first and only large study of AT-II in humans.

Critique of ATHOS 3 trial

ATHOS 3 had several issues that need to be addressed. Pertinent data such as central venous pressure, Central venous oxygen saturation, and cardiac index were missing in 72 of 321 patients (22%), 84 of 321 (26%), and 179 of 321 (56%), respectively. fluid balance difference between the two groups was not reported. Since AT-II may have deleterious effects on microcirculation, lactate and central venous oxygen saturation (which are frequently used as indirect measures of tissue perfusion and microcirculatory health) were not compared between the two

groups. In addition, cardiovascular SOFA improved in the study group which is an expected finding since AT-II Elevated blood pressure, but total SOFA was not different between the two groups. Does that mean that other organs included in total SOFA got worse in the study group compared to the control group? AT-II could have detrimental effects on lungs and brain. These two organs were not addressed specifically in ATHOS 3. The definition of refractory vasodilatory shock is arbitrary in the study and is different from other studies on septic shock and MAP N75 exceeds current recommendations. The authors acknowl- edged the study was not powered to detect Mortality benefit. They also acknowledge that follow-up was limited to 28 days, thus the possi- bility of either beneficial or harmful long term effects of AT-II therapy could not be excluded. Though the study did not show significant differ- ence in DVT between the 2 groups (1.8% group vs 0% in placebo group), the FDA package inserts report an increase in the combination of venous and arterial thrombotic events (13% vs 5%, p = 0.02). FDA recommends DVT chemoprophylaxis when using AT-II which is a standard of care while treating critically ill patients unless there is an active contra-indi- cation to do so.

In a recent literature review on the effect of angiotensin II on blood pressure in patients with circulatory shock, 24 studies includ- ing 353 patients were identified that include ATHOS III trial. Shock was distributive (n = 225), cardiogenic (n = 38), or from other causes (n = 90). Patients with cardiogenic, septic, and other types of shock exhibited similar increases in BP. Only two of 24 studies an- alyzed were RCTs, with other studies being case-control and case- study formats. Of the 353 patients included in the analysis, 163 were from ATHOS III, however, this was a well-designed RCT, lending credibility to the results [63].

Conclusion

AT-II has been shown to increase the mean arterial pressure in vasodilatory shock refractory to catecholamines. AT – II is a molecule in- nate to human physiology and, along with catecholamines and vasopres- sin, helps maintain BP throughout a variety of conditions. Its widely described effects include direct vasoconstriction of Peripheral vessels, po- tentiation of water reabsorption as part of the renin-angiotensin-aldoste- rone system, and interaction with other endogenous pressors (catecholamines and vasopressin). It also helps regulate and maintain glomerular filtration, especially during periods of reduced renal perfusion. AT-II is an available option approved by the FDA for its use in shock refrac- tory to catecholamines provided patients have been adequately volume resuscitated. Larger trials with longer duration of follow-up are warranted to address the questions which are unanswered by the ATHOS-3 trial, es- pecially pertaining to its effects on lungs, brain, microcirculation, inflam- mation, and venous thromboembolism risk.

Abbreviations

AT-I Angiotensin I

AT-II Angiotensin II AT 1-7 Angiotensin 1-7

AT 1-9 Angiotensin 1-9

ACE Angiotensin converting enzyme ACE-2 Angiotensin converting enzyme -2 AT-R1 Angiotensin receptor 1

AT-R2 Angiotensin receptor 2

RAAS Renin Angiotensin Aldosterone System AKI Acute kidney injury

RRT Renal replacement therapy NE Norepinephrine

VCAM vascular cell adhesion molecule VEGF Vascular endothelial growth factor IL-1B Interleukin-1B

TNF-alpha Tumor necrosis factor- alpha

INF-gamma Interferron-gamma

Arap Angiotensin receptor associated protein ATHOS Angiotensin II in high output shock GFR Glomerular filtration rate

SOFA Sequential Organ Failure Assessment

MAP Mean arterial pressure

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