Renin – angiotensin – aldosterone system in patients with septic shock (literature review)
https://doi.org/10.24884/2078-5658-2025-22-5-132-141
Abstract
The objective was to summarize current data on the role of renin-angiotensin-aldosterone system (RAAS) in patients with septic shock (SS) and to highlight indications for the use of Angiotensin II in the complex of intensive care of septic shock.
Materials and methods. The literature search was conducted in the MEDLINE, Embase, and Cochrane Library databases. It was limited to articles published from January 1, 1991 to May 1, 2025. The selection criteria were studies on the physiology and pathophysiology of the renin-angiotensin-aldosterone system in the experiment and clinic in septic shock. The selection of clinical studies was carried out in patients over 18 years of age with septic shock if they presented data on the dose of all vasopressors used, the effect of Angiotensin II on the clinical course of septic shock and indicated complications caused by its use.
Result. The search yielded 58 publications devoted to the study of the RAAS state in patients with septic shock and the use of Angiotensin II. Of these, 44 (76%) studies and meta-analyses met the inclusion criteria. All publications demonstrated the role of the renin-angiotensin-aldosterone system in the pathophysiology of septic shock development and the effectiveness (in most studies) of reducing the doses of vasopressors, which made it possible to overcome refractory shock and reduce the duration of renal replacement therapy. However, thromboembolic disorders described in some publications may complicate the use of Angiotensin II.
Conclusions. Various unresolved issues remain regarding the use of Angiotensin II in septic shock. Although published data suggest that Angiotensin II is a promising vasopressor therapy for septic shock, they are few and small in sample size, requiring further study.
About the Author
L. L. Plotkin
Chelyabinsk Regional Clinical Hospital
Russian Federation
Russian Federation
Plotkin Leonard L., Dr. of Sci. (Med.), Leading Intensivist
70, Vorovskogo str., Chelyabinsk, 454048
References
1. Raff G. Secrets of Physiology. Translated from English. Moscow – St. Petersburg, “BINOM Publishing House”, 2001, 448 p. (In Russ.).
2. Rudnov A. V., Belsky D. V., Dekhnich A. V. et al. Infections in the intensive care units of Russia: results of a national multicenter study. Clinical microbiology and antimicrobial chemotherapy, 2011, vol. 13, no. 4, pp. 294–303. (In Russ.).
3. Sepsis (in adults). Clinical guidelines / Ministry of Health of the Russian Federation. Moscow, 2024, 158 p. (In Russ.).
4. Antonucci E., Gleeson P. J., Annoni F. et al. Angiotensin II in refractory septic shock. SHOCK, 2017, vol. 47, no. 5, pp. 560–566. https://doi.org/10.1097/SHK.0000000000000807.
5. Bellomo R., Zarbock A., Landoni G. Angiotensin II. Intensive Care Med, 2024, vol. 50, pp. 279–282. https://doi.org/10.1007/s00134-023-07290-7.
6. Bernstein K. E., Ong F. S., Blackwell W. L. et al. A modern understanding of the traditional and nontraditional biological functions of angiotensin-converting enzyme. Pharmacol Rev, 2012, vol. 65, no. 1, pp. 1–46. https://doi.org/10.1124/pr.112.006809.
7. Bokoch M. P., Tran A. T., Brinson E. L. et al. Angiotensin II in liver transplantation (AngLT 1): protocol of a randomised, double blind, placebo controlled trial. BMJ Open, 2023, vol. 13, no. 11, e078713. https://doi.org/10.1136/bmjopen-2023-078713.
8. Busse L. W., Schaich C. L., Chappell M. C. et al. Association of active renin content with mortality in critically ill patients: a post hoc analysis of the vitamin C, thiamine, and steroids in sepsis (VICTAS) trial. Crit Care Med, 2024, vol. 52, pp. 441–451. https://doi.org/10.1097/CCM.0000000000006095.
9. Carà G. A., Pasin L., Alborino E. et al. Angiotensin II-a brief review and role in severe SARS-COV-2 Sepsis. J Cardiothorac Vasc Anesth, 2022, vol. 36, pp. 4496–4500. https://doi.org/10.1186/s13054-015-0802-3.
10. Caragata R., Johnston S. A., Chan J. W. et al. Angiotensin II and thromboembolic events: a systematic review. Crit Care Med, 2024, vol. 23, pp. 143–156. https://doi.org/10.1097/CCM.0000000000006433.
11. Garcia B., Zarbock A., Bellomo R. et al. The alternative renin-angiotensin system in critically ill patients: pathophysiology and therapeutic implications. Critical Care, 2023, vol. 27, pp. 453–461. https://doi.org/10.1186/s13054-023-04739-5.
12. Garcia B., Zarbock A., Bellomo R. et al. The role of renin-angiotensin system in sepsis-associated acute kidney injury: mechanisms and therapeutic implications. Curr Opin Crit Care, 2023, vol. 29, no. 6, pp. 607–613. https://doi.org/10.1097/MCC.0000000000001092.
13. Chaba А., Zarbock A., Forni L. et al. Angiotensin II for catecholamine-resistant vasodilatory shock in patients with acute kidney injure: A post hoc analysis of the ATHOS-3 trial. Shock, 2025, vol. 63, no. 1, pp. 88–93. https://doi.org/10.1097/SHK.0000000000002481.
14. Chappell M. C., Schaic C. L., Busse L. W. et al. Stronger association of intact angiotensinogen with mortality than lactate or renin in critical illness: post-hoc analysis from the VICTAS trial. Critical Care, 2024, vol. 28, pp. 333–339. https://doi.org/10.1186/s13054-024-05120-w.
15. Chawla L. S., Busse L., Brasha-Mitchell E. et al. Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study. Crit Care, 2014, vol. 18, no. 5, pp. 534–540. https://doi.org/10.1186/s13054-014-0534-9.
16. Denton K. M., Anderson W. P., Sinniah R. Effects of angiotensin II on regional afferent and efferent arteriole dimensions and the glomerular pole. Am J Physiol Regul Integr Comp Physiol, 2000, vol. 279, no. 2, pp. 629–638. https://doi.org/10.1152/ajpregu.2000.279.2.R629.
17. Evans L., Rhodes A., Alhazzani W. et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med, 2021, vol. 47, pp. 1181–1247. https://doi.org/10.1007/s00134-021-06506-y.
18. Khanna A., English S. W., Wang X. S. et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med, 2017, vol. 377, pp. 419–430. https://doi.org/10.1152/ajpregu.2000.279.2.
19. Kasugai D., Hirakawa A., Ozaki M. et al. Maximum norepinephrine dosage within 24 hours as an indicator of refractory septic shock: a retrospective study. J Intensive Care Med, 2019, vol. 27, pp. 325–337. https://doi.org/885066619860736.
20. Kotani Y., Belletti A., Filippo D’Amico F. et al. Non-adrenergic vasopressors for vasodilatory shock or perioperative vasoplegia: a meta-analysis of randomized controlled trials. Critical Care, 2024, vol. 28, pp. 439–445. https://doi.org/10.1186/s13054-024-05212-7.
21. Leisman D. E., Handisides D. R, Chawla L. S. et al. Angiotensin II treatment is associated with improved oxygenation in ARDS patients with refractory vasodilatory shock. Ann Intensive Care, 2023, vol. 13, R.128. https://doi.org/10.1186/s13613-023-01227-5.
22. Leisman D. E., Handisides D. R., Busse L. W. et al. ACE inhibitors and angiotensin receptor blockers differentially alter the response to angiotensin II treatment in vasodilatory shock. Crit Care, 2024, vol. 28, pp. 130–138. https://doi.org/10.1186/s13054-024-04910-6.
23. Leisman D. E., Wieruszewski P. M., Busse L. W. et al. An index of the initial blood pressure response to angiotensin II treatment and its association with clinical outcomes in vasodilatory shock. Critical Care, 2025, vol. 29, pp. 81. https://doi.org/10.1186/s13054-025-05311-z.
24. Legrand M., Khann A. K., Ostermann M. et al. The renin-angiotensin-aldosterone-system in sepsis and its clinical modulation with exogenous angiotensin II. Critical Care, 2024, vol. 28, pp. 389–396. https://doi. org/10.1186/s13054-024-05123-7.
25. Levy M. M., Evans L. E., Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 update. Intensive Care Med, 2018, vol. 44, pp. 925–928. https://doi.org/10.1007/s00134-018-5085-0.
26. Miesbach W. Pathological role of angiotensin ii in severe COVID-19. Open, 2020, vol. 4, pp. 2-8.e138-e144. https://doi.org/10.1055/s-0040-1713678.
27. Meersch M., Weiss R., Massoth C. et al. The association between angiotensin II and renin kinetics in patients after cardiac surgery. Anesth Analg, 2020, vol. 134, pp. 1002–1009. https://doi.org/10.1213/ANE.0000000000005953.
28. Nethathe G. D., Lipman J., Anderson R. et al. CIRMI-a new term for a concept worthy of further exploration: a narrative review. Ann Transl Med, 2022, vol. 10, no. 11, pp. 646. https://dx.doi.org/10.21037/atm-21-5572.
29. See E. J., Chaba A., Spano S. et al. Renin levels and angiotensin II responsiveness in vasopressor dependent hypotension. Crit Care Med, 2024, vol. 52, pp. 1218–1227. https://doi.org/10.1097/CCM.0000000000006273.
30. Senatore F., Balakumar P. Dysregulation of the renin-angiotensin system in septic shock: Mechanistic insights and application of angiotensin II in clinical management. Pharmacol Res, 2021, vol. 174, 105916. https://doi.org/10.1016/j.phrs.2021.105916.
31. Serpa N. A., Landoni G., Ostermann M. et al. Angiotensin II infusion in COVID 19: an international, multicenter, registry based study. J Med Virol, 2022, vol. 94, pp. 2079–2088. https://doi.org/10.1002/jmv.27592.
32. Singer M., Deutschman C. S., Seymour C. W. et al. The third internationalconsensus definitions for sepsis and septic shock (Sepsis-3). JAMA, 2016, vol. 315, pp. 801–810. https://doi.org/10.1001/jama.2016.0289.
33. Smith S. E., Newsome A. S., Guo Y. et al. A multicenter observational cohort study of angiotensin II in shock. J Intensive Care Med, 2022, vol. 37, no. 1, pp. 75–82. https://doi.org/10.1177/0885066620972943.
34. Suzuki Y., Ruiz-Ortega M., Lorenzo O. et al. Inflammation and angiotensin II. Int J Biochem Cell Biol, 2023, vol. 35, no. 6, pp. 881–900. https://doi.org/10.1016/s1357-2725(02)00271-6.
35. Supe S., Kohse F., Gembardt F. et al. Therapeutic timewindow for angiotensin-(1-7) in acute lung injury. Br J Pharmacol, 2016, vol. 173, no. 10, pp. 1618–1628. https://doi.org/10.1111/bph.13462.
36. Thomas V. L., Nielsen M. S. Administration of angiotensin II in refractory septic shock. Crit Care Med, 1991, vol. 19, no. 8, pp. 1084–1086. https://doi.org/10.1097/00003246-199108000-00020.
37. Tumlin J. A., Murugan R., Deane A. M. et al. Outcomes in patients with vasodilatory shock and renal replace-ment therapy treated with intravenous angiotensin II. Crit Care Med, 2020, vol. 46, pp. 949–957. https://doi.org/10.1097/CCM.0000000000003092.
38. Vincent J.-L., Jones G., David S. et al. Frequency and mortality of septic shock in Europe and North America: a systematic review and meta-analysis. Critical Care, 2019, vol. 23, pp. 196–208. https://doi.org/10.1186/s13054-019-2478-6.
39. Wan L., Langenberg C., Bellomo R. et al. Angiotensin II in experimental hyperdynamic sepsis. Crit Care, 2009, vol. 13, R190. https://doi.org/10.1186/cc8185.
40. Wieruszewski P. M., Seelhammer T. G., Barreto E. F. et al. Angiotensin II for vasodilatory hypotension in patients requiring mechanical circulatory support. J Intensive Care Med, 2023, vol. 38, pp. 464–471. https://doi.org/10.1177/08850666221145864.
41. Wieruszewski P. M., Leone M., Kaas-Hansen B. S. et al. Position paper on the reporting of norepinephrine formulations in critical care from the Society of Critical Care Medicine and European Society of Intensive Care Medicine Joint Task Force. Crit Care Med, 2024, vol. 52, pp. 521–530. https://doi.org/10.1097/CCM.0000000000006176.
42. Wilkinson S. P., Williams R. Renin-angiotensin-aldosterone system in cirrhosis. Gut, 1980, vol. 21, no. 6, pp. 545–554. https://doi.org/10.1136/gut.21.6.545.
43. Williams G. H. Aldosterone biosynthesis, regulation, and classical mechanism of action. Heart Fail Rev, 2005, vol. 10, pp. 7–13. https://doi.org/10.1007/s10741-005-2343-3.
44. Wong A., Alkazemi A., Eche I. M. et al. A Retro-spective review of angiotensin ii use in adult patients with refractory distributive shock. J Intensive Care Med, 2019, vol. 3. https://doi.org/885066619872720.
45. Wray G. M., Coakley J. H. Severe septic shock unresponsive to noradrenaline. Lancet, 1995, vol. 46, pp. 1604. https://doi.org/10.1016/s0140-6736(95)91933-3.
46. Xourgia E., Aristomenis E., Athanasios K. C. et al. Angiotensin II in the treatment of distributive shock: asystematic – revive and meta-analysis. Shock, 2024, vol. 62, no. 2, pp. 155–164. https://doi.org/10.1097/SHK.0000000000002384.
47. Zambelli V., Bellani G., Borsa R. et al. Angiotensin-(1-7) improves oxygenation, while reducing cellular infiltrate and fibrosis in experimental Acute Respiratory Distress Syndrome. Intensive Care Med Exp, 2015, vol. 3, no. 1, pp. 44–50. https://doi.org/10.1186/s40635-015-0044-3.
48. Zangrillo A., Landoni G., Beretta L. et al. Angiotensin II infusion in COVID-19- associated vasodilatory shock: a case series. Critical Care, 2020, vol. 24, pp. 227–240. https://doi.org/10.1186/s13054-020-02928-0.
49. Zhang F., Ren X., Zhao M. et al. Angiotensin-(1-7) abrogates angiotensin II-induced proliferation, migration and inflammation in VSMCs through inactivation of ROS-mediated PI3K/Akt and MAPK/ERK signaling pathways. Sci Rep, 2018, vol. 6, pp. 34621. https://doi.org/10.1038/srep34621.
Review
For citations:
Plotkin L.L. Renin – angiotensin – aldosterone system in patients with septic shock (literature review). Messenger of ANESTHESIOLOGY AND RESUSCITATION. 2025;22(5):132-141. (In Russ.) https://doi.org/10.24884/2078-5658-2025-22-5-132-141
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