Journal of Translational Critical Care Medicine

: 2019  |  Volume : 1  |  Issue : 1  |  Page : 7--11

Angiotensin in Clinical Practice

Ehsan Ahmadnia, Anna Hall, Marlies Ostermann 
 Department of Critical Care, Guy's and St Thomas' Hospital, King's College London, London, UK

Correspondence Address:
Dr. Marlies Ostermann
Department of Critical Care, Guy's and St Thomas' Hospital, King's College London, London SE1 7EH


Interest in the use of angiotensin (AT) (particularly in the context of shock) had been rekindled by recent randomized trial data (notably the AT II for the Treatment of High-Output Shock-3 study). This review article outlines the renin–AT system in health and during sepsis as well as the proposed clinical uses of AT II. The potential for wider application within critical care is also considered.

How to cite this article:
Ahmadnia E, Hall A, Ostermann M. Angiotensin in Clinical Practice.J Transl Crit Care Med 2019;1:7-11

How to cite this URL:
Ahmadnia E, Hall A, Ostermann M. Angiotensin in Clinical Practice. J Transl Crit Care Med [serial online] 2019 [cited 2022 May 20 ];1:7-11
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Pharmacological management of blood pressure is a key component of contemporary critical care. In the setting of sepsis, systemic arterial hypotension requiring exogenous vasopressor support is a cardinal feature of septic shock.[1] International guidelines[2] recommend aiming for a mean arterial pressure (MAP) of at least 65 mmHg in septic shock, with the rationale that adequate organ perfusion may mitigate the progression to organ dysfunction/failure. Prompt reversal of hypotension is advised,[2] noting that intraoperative studies concluded that even short periods of hypotension (i.e. min) conferred a greater risk of acute kidney injury (AKI) and myocardial injury.[3],[4] Furthermore, it has been suggested that those with a history of chronic hypertension, aiming for a higher MAP may reduce AKI in sepsis.[5]

Hypotension in the context of sepsis can be multifactorial, with distributive (i.e. vasodilatory) and cardiogenic components. In adequately fluid-resuscitated patients, catecholamines (typically noradrenaline) and vasopressin analogs (typically vasopressin) are used to ameliorate the distributive element of sepsis-induced shock. The number of suitable vasoconstrictor drugs is limited. Apart from a greater number of adverse cardiac events with dopamine compared to noradrenaline, there is no compelling outcome data to support the use of one vasopressor over any of the others.[6],[7],[8],[9],[10]

The renin–angiotensin system (RAS) has predominantly been viewed as a target for therapeutic antagonism, particularly within acute and chronic cardiovascular care.[11],[12] However, the reemergence of angiotensin II (AT II) as an agonist of the RAS (with subsequent hypertensive effect) within a recent randomized controlled trial (RCT)[13] has prompted much interest in it as an additional therapeutic pharmacological option for vasodilatory shock. This review explores the physiology, history, and clinical experience of AT II use.

 The Physiology Of the Renin–angiotensin System

The renin–AT cascade[14],[15],[16] [Figure 1] gives rise to AT II, an octapeptide with potent vasopressor properties. Its action is terminated by rapid degradation through a number of pathways, whose products include AT (1-7)AT III, AT IV, and AT A.[16] The breakdown products of AT II are biologically active, and the complex interplay between them is still being investigated. AT II has a half-life of around 30 s in the circulation, compared with around 15–30 min in tissues.[14],[15]{Figure 1}

The existence of a wide range of RASs accounts for the difference between circulation and tissue half-life. In addition to the “classic” RAS which helps to maintain macrocirculatory homeostasis, most tissues have been shown to have “tissue” RAS and “intracellular” RAS. The tissue RAS is predominantly involved in microcirculatory regulation and inflammatory processes (including vascular permeability, apoptosis, cellular growth, migration, and cell differentiation), with the intracellular RAS participating in intracellular signaling pathways.[17]

The numerous effects of AT II are mediated through AT receptors on the cell membranes of various tissues. These receptors include AT II receptor type 1 (AT-1), AT II receptor type 2 (AT-2), AT II receptor type 4 (AT-4), and Mas receptors[18],[19],[20],[21] [Table 1]. AT-1 is responsible for the positive effects of the “classic” RAS, whereas the main biological effects of AT-2 stimulation are actions of the “tissue” RAS.{Table 1}

The renin–angiotensin system during sepsis

During the life-threatening insult of sepsis, dysregulation at the macrocirculatory, microcirculatory, and cellular level can occur.[1] As noted above, the roles of the various RASs include preservation of intravascular volume and adequate MAP (classic RAS) and protection of tissue/cellular homeostasis (tissue and intracellular RAS). Different phenotypes of RAS can be observed in sepsis, with both over- and understimulation of the RAS described in humans.[22],[23],[24]

Notwithstanding this, levels of renin, AT I, and AT II are usually elevated during sepsis.[22] Whether this is broadly adaptive or maladaptive is currently being studied, but previous work has indicated that patients with severe sepsis and low circulating levels of AT II and AT-converting enzyme (ACE) have a higher risk of 28-day mortality.[22]

Given that ACE is present in large numbers on the pulmonary capillary endothelium, conditions that affect this endothelium (such as pneumonia and acute respiratory distress syndrome) can rapidly reduce ACE activity and thus systemic levels of AT II.[25],[26] There are also data indicating that endotoxemia associated with Gram-negative sepsis deactivates ACE.[27]

Alongside altered AT II levels during sepsis, important changes occur in the domain of AT receptors. Several studies have demonstrated downregulation of AT-1 receptors in sepsis, with nitric oxide and pro-inflammatory cytokines probably responsible for this decrease.[28],[29] Furthermore, reduced activity of the AT-1 receptor-associated protein 1 (Arap 1), which is expressed by vascular smooth muscle cells, has been shown in sepsis.[30] Given that the role of Arap 1 is to help traffic the AT-1 receptor to the cell membrane, decreased Arap 1 levels will tend to result in fewer AT-1 receptors at the cell membrane, predisposing to decreased vasomotor tone and decreased MAP.

Downregulation of AT-2 receptors may also occur during sepsis.[31] This will lead to decreased catecholamine release by the adrenal medulla, promoting hypotension despite a functioning classic RAS.

 Clinical Use Of Angiotensin II


Tigerstedt and Bergman first described renin in 1898.[32],[33] The other components of the RAS were described later, with AT II being discovered in the 1930s (although under a different name).[34] A recent study identified 31,281 patients in the literature that have been exposed to exogenous intravenous AT II in various clinical settings (with the first trial in 1941 and a host of studies in the 1960s).[35]

Vasodilatory shock

Nonrandomized studies in the 1960s investigated the effect of AT II during hypotensive shock.[36],[37],[38] While the underlying etiology of shock was not always determined, sepsis was considered to be the cause in around half of the cases in one of these reports.[36] In these early clinical studies, AT II appeared to be comparable to noradrenaline in terms of blood pressure augmentation (although noradrenaline increased cardiac output to a greater degree).

The first prospective RCT of AT II in high-output shock was the AT II for the Treatment of High-Output Shock (ATHOS) trial,[39] published in 2014. This pilot study suggested that AT II was an effective vasopressor in the setting of high-output vasodilatory shock, with a noradrenaline-sparing effect.

This led to the ATHOS-3 trial,[13] which is the largest prospective RCT to date in this domain. It was a pharmaceutical company-sponsored phase 3, double-blind, placebo-controlled, multicenter RCT conducted by Khanna et al. A total of 321 patients with high-output vasodilatory shock (on at least 0.2 μg/kg/min of noradrenaline or equivalent) received either AT II infusion or placebo. The investigators found that AT II was significantly better at increasing blood pressure compared to placebo (70% vs. 23%, P < 0.001). The trial was neither powered to study mortality nor organ dysfunction differences; however, no statistically significant difference in 28-day mortality was observed. In the patients studied, the safety profile of AT II appeared acceptable, with similar rates of serious adverse events in both groups.

The ATHOS-3 trial is an important addition to the literature but does not give us the definitive answer in terms of patient-centered outcomes (including mortality and morbidity). It did not test AT II in patients with low cardiac output, and so its safety profile in those with a significant cardiogenic component to their septic shock remains to be elucidated.[40] AT II may have a positive inotropic effect[36] and has been associated with increased blood pressure in different types of shock (including cardiogenic shock).[41] As the original ATHOS trial[39] indicated, there may be a large degree of heterogeneity in terms of blood pressure response to AT II. Given that circulating AT II levels may be particularly low in certain groups (such as those with liver cirrhosis or lung disease),[42] further work to determine those phenotypes most likely to benefit from AT II would be welcome.


The use of AT II to counteract the effects of ACE-inhibitor overdose would seem an attractive and logical solution. Case reports describe the successful use of AT II in ACE-inhibitor overdose.[43],[44],[45] While there is a good physiological rationale for the use of AT II in this setting, it should be noted that AT II has generally been used as a “rescue” therapy for refractory hypotension secondary to ACE-inhibitor poisoning rather than the first-line therapy. Furthermore, selection and publication biases are frequent in the setting of poisoning.

Neuraxial anesthesia

Neuraxial anesthesia predisposes patients to hypotension. In the context of obstetric anesthesia, where uteroplacental blood flow depends on maternal blood pressure, the vasodilatory effects of neuraxial anesthesia are typically closely counteracted by exogenous vasoconstrictor administration. Ephedrine and phenylephrine are commonly used vasoconstrictors in this setting.[46] AT II has been evaluated in two small randomized trials.[47],[48] While AT II proved effective in maintaining blood pressure compared to ephedrine in these studies, a recent systematic review suggested that there was insufficient evidence to recommend their use in the setting of spinal anesthesia for cesarean section.[46]

Wider application within critical care

While underscoring the safety of AT II for high-output vasodilatory shock, the recent literature[49] has also noted its potential for other forms of shock. Particularly within the context of refractory shock,[50] having the option of an alternative biological pathway for resolution of shock is welcome. Furthermore, it would appear to allow a decatecholaminization strategy, which is being increasingly appreciated as a strategy to reduce harm.[51],[52]

AT II may confer particular benefit to those with AKI requiring renal replacement therapy (RRT). A post hoc analysis of the ATHOS-3 participants[53] noted greater 28-day survival and greater liberation from RRT by day 7. The biological rationale for this may be primarily due to microcirculatory and inflammatory cascade effects (“tissue RAS”) rather than merely the maintenance of macrocirculatory perfusion (“classic RAS”). Clearly, this post hoc analysis should be viewed as hypothesis generating but is notable given the importance of AKI within critical care.


The RASs have an integral role in maintaining homeostasis. This includes both macrocirculatory stability and microcirculatory/intracellular stability. Sepsis can give rise to profound changes in the RAS, predisposing to hypotension and shock. As such, agonism of the RAS appears to be an attractive target for therapeutic intervention. The recent ATHOS-3 trial has shed light on the potential role of AT II as a therapy for high-output vasodilatory shock. Previously published data also suggests that AT II may be of benefit in ACE-inhibitor poisoning. However, more studies are needed to determine if AT II has any impact on patient-centered outcomes and to determine which subgroups are most (and least) likely to benefit from AT II therapy. Those with AKI may be particularly likely to benefit. In the future, this may facilitate a more tailored approach to the management of shock in clinical practice and enable a decatecholaminization strategy.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016;315:801-10.
2Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017;43:304-77.
3Walsh M, Devereaux PJ, Garg AX, Kurz A, Turan A, Rodseth RN, et al. Relationship between intraoperative mean arterial pressure and clinical outcomes after noncardiac surgery: Toward an empirical definition of hypotension. Anesthesiology 2013;119:507-15.
4Salmasi V, Maheshwari K, Yang D, Mascha EJ, Singh A, Sessler DI, et al. Relationship between intraoperative hypotension, defined by either reduction from baseline or absolute thresholds, and acute kidney and myocardial injury after noncardiac surgery: A Retrospective cohort analysis. Anesthesiology 2017;126:47-65.
5Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med 2014;370:1583-93.
6Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M, et al. Effect of early vasopressin vs. Norepinephrine on kidney failure in patients with septic shock: The VANISH randomized clinical trial. JAMA 2016;316:509-18.
7Myburgh JA, Higgins A, Jovanovska A, Lipman J, Ramakrishnan N, Santamaria J, et al. Acomparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med 2008;34:2226-34.
8Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358:877-87.
9De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010;362:779-89.
10Zhou F, Mao Z, Zeng X, Kang H, Liu H, Pan L, et al. Vasopressors in septic shock: A systematic review and network meta-analysis. Ther Clin Risk Manag 2015;11:1047-59.
11Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: The task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013;34:2159-219.
12Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: The task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the heart failure association (HFA) of the ESC. Eur J Heart Fail 2016;18:891-975.
13Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med 2017;377:419-30.
14Paul M, Poyan Mehr A, Kreutz R. Physiology of local renin-angiotensin systems. Physiol Rev 2006;86:747-803.
15Corrêa TD, Takala J, Jakob SM. Angiotensin II in septic shock. Crit Care 2015;19:98.
16Pinter M, Jain RK. Targeting the renin-angiotensin system to improve cancer treatment: Implications for immunotherapy. Sci Transl Med 2017;9. pii: eaan5616.
17Fyhrquist F, Saijonmaa O. Renin-angiotensin system revisited. J Intern Med 2008;264:224-36.
18Zhuo JL, Li XC. New insights and perspectives on intrarenal renin-angiotensin system: Focus on intracrine/intracellular angiotensin II. Peptides 2011;32:1551-65.
19Bucher M, Hobbhahn J, Kurtz A. Nitric oxide-dependent down-regulation of angiotensin II type 2 receptors during experimental sepsis. Crit Care Med 2001;29:1750-5.
20Steckelings UM, Kaschina E, Unger T. The AT2 receptor – A matter of love and hate. Peptides 2005;26:1401-9.
21Carey RM, Wang ZQ, Siragy HM. Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function. Hypertension 2000;35:155-63.
22Zhang W, Chen X, Huang L, Lu N, Zhou L, Wu G, et al. Severe sepsis: Low expression of the renin-angiotensin system is associated with poor prognosis. Exp Ther Med 2014;7:1342-8.
23Wray GM, Coakley JH. Severe septic shock unresponsive to noradrenaline. Lancet 1995;346:1604.
24Salgado DR, Rocco JR, Silva E, Vincent JL. Modulation of the renin-angiotensin-aldosterone system in sepsis: A new therapeutic approach? Expert Opin Ther Targets 2010;14:11-20.
25Orfanos SE, Armaganidis A, Glynos C, Psevdi E, Kaltsas P, Sarafidou P, et al. Pulmonary capillary endothelium-bound angiotensin-converting enzyme activity in acute lung injury. Circulation 2000;102:2011-8.
26Johnson AR, Coalson JJ, Ashton J, Larumbide M, Erdös EG. Neutral endopeptidase in serum samples from patients with adult respiratory distress syndrome. Comparison with angiotensin-converting enzyme. Am Rev Respir Dis 1985;132:1262-7.
27Dunn CW, Horton JW. Role of angiotensin II in neonatal sepsis. Circ Shock 1993;40:144-50.
28Schmidt C, Höcherl K, Kurt B, Moritz S, Kurtz A, Bucher M, et al. Blockade of multiple but not single cytokines abrogates downregulation of angiotensin II type-I receptors and anticipates septic shock. Cytokine 2010;49:30-8.
29Bucher M, Ittner KP, Hobbhahn J, Taeger K, Kurtz A. Downregulation of angiotensin II type 1 receptors during sepsis. Hypertension 2001;38:177-82.
30Mederle K, Schweda F, Kattler V, Doblinger E, Miyata K, Höcherl K, et al. The angiotensin II AT1 receptor-associated protein arap1 is involved in sepsis-induced hypotension. Crit Care 2013;17:R130.
31Bucher M, Hobbhahn J, Kurtz A. Nitric oxide-dependent down-regulation of angiotensin II type 2 receptors during experimental sepsis. Crit Care Med 2001;29:1750-5.
32Tigerstedt R, Bergman P. Niere und kreislauf. Scand Arch Physiol 1898;8:223-71.
33Phillips MI, Schmidt-Ott KM. The discovery of renin 100 years ago. News Physiol Sci 1999;14:271-4.
34Basso N, Terragno NA. History about the discovery of the renin-angiotensin system. Hypertension 2001;38:1246-9.
35Busse LW, Wang XS, Chalikonda DM, Finkel KW, Khanna AK, Szerlip HM, et al. Clinical experience with IV angiotensin II administration: A Systematic review of safety. Crit Care Med 2017;45:1285-94.
36Cohn JN, Luria MH. Studies in clinical shock and hypotension. ii. Hemodynamic effects of norepinephrine and angiotensin. J Clin Invest 1965;44:1494-504.
37Belle MS, Jaffee RJ. The use of large doses of angiotensin in acute myocardial infarction with shock. J Lancet 1965;85:193-4.
38Del Greco F, Johnson DC. Clinical experience with angiotensin II in the treatment of shock. JAMA 1961;178:994-9.
39Chawla LS, Busse L, Brasha-Mitchell E, Davison D, Honiq J, Alotaibi Z, et al. Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): A pilot study. Crit Care 2014;18:534.
40Dellinger RP, Trzeciak S. Angiotensin II for the treatment of vasodilatory shock-promise and caution. N Engl J Med 2017;377:486-7.
41Busse LW, McCurdy MT, Ali O, Hall A, Chen H, Ostermann M, et al. The effect of angiotensin II on blood pressure in patients with circulatory shock: A structured review of the literature. Crit Care 2017;21:324.
42Antonucci E, Agosta S, Sakr Y. Angiotensin II in vasodilatory shock: Lights and shadows. Crit Care 2017;21:277.
43Jackson T, Corke C, Agar J. Enalapril overdose treated with angiotensin infusion. Lancet 1993;341:703.
44Newby DE, Lee MR, Gray AJ, Boon NA. Enalapril overdose and the corrective effect of intravenous angiotensin II. Br J Clin Pharmacol 1995;40:103-4.
45Trilli LE, Johnson KA. Lisinopril overdose and management with intravenous angiotensin II. Ann Pharmacother 1994;28:1165-8.
46Chooi C, Cox JJ, Lumb RS, Middleton P, Chemali M, Emmett RS, et al. Techniques for preventing hypotension during spinal anaesthesia for caesarean section. Cochrane Database Syst Rev 2017;8:CD002251.
47Ramin SM, Ramin KD, Cox K, Magness RR, Shearer VE, Gant NF, et al. Comparison of prophylactic angiotensin II versus ephedrine infusion for prevention of maternal hypotension during spinal anesthesia. Am J Obstet Gynecol 1994;171:734-9.
48Vincent RD Jr., Werhan CF, Norman PF, Shih GH, Chestnut DH, Ray T, et al. Prophylactic angiotensin II infusion during spinal anesthesia for elective cesarean delivery. Anesthesiology 1998;88:1475-9.
49Hall A, Busse LW, Ostermann M. Angiotensin in critical care. Crit Care 2018;22:69.
50Jentzer JC, Vallabhajosyula S, Khanna AK, Chawla LS, Busse LW, Kashani KB, et al. Management of refractory vasodilatory shock. Chest 2018;154:416-26.
51Coquerel D, Sainsily X, Dumont L, Sarret P, Marsault É, Auger-Messier M, et al. The apelinergic system as an alternative to catecholamines in low-output septic shock. Crit Care 2018;22:10.
52Rudiger A, Singer M. Decatecholaminisation during sepsis. Crit Care 2016;20:309.
53Tumlin JA, Murugan R, Deane AM, Ostermann M, Busse LW, Ham KR, et al. Outcomes in patients with vasodilatory shock and renal replacement therapy treated with intravenous angiotensin II. Crit Care Med 2018;46:949-57.