The Renin–Angiotensin–Aldosterone System in Cardiac Surgery and Angiotensin II Therapy for Vasoplegia

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Cardiac surgery remains associated with major complications, ranging from persistent postoperative vasoplegia, defined as a persistently low blood pressure due to a low systemic vascular resistance and normal cardiac output, acute kidney injury (AKI), and cardiovascular events to cognitive dysfunction.1,2 The renin–angiotensin–aldosterone system (RAAS) plays a role in cardiopulmonary bypass (CPB) induced vasoplegia and is a potential target for interventions aimed at decreasing its associated complications.3,4 Cardiac surgery–associated vasoplegia affects up to one-third of patients, depending on the population considered, the type of surgery, and definitions used.3,4 The management of hypotension during and after cardiac surgery includes the use of fluids to optimize intravascular filling and cardiac output, and the use of vasopressor drugs to restore arterial smooth muscle tone.3 Vasopressors such as norepinephrine and vasopressin are typically used to restore and maintain the target mean arterial pressure when vasoplegia results. However, side effects of these agents include arrhythmias and end-organ ischemia. Recently, angiotensin II has been approved as a vasopressor agent for the treatment of vasoplegia.1,5–10 We report a state-of-the-art clinical update regarding the RAAS in patients undergoing cardiac surgery with a focus on the use of angiotensin II in cardiac surgery patients. Finally, we discuss the rationale for using exogenous synthetic angiotensin II as a vasopressor and provide guidance regarding the patient population in which angiotensin II is most likely to be effective. PHYSIOLOGY OF THE RAAS The RAAS is a hormone system that regulates fluid, and electrolyte balance, vascular resistance, and blood pressure, and systemic vascular resistance. Renin is produced and secreted by juxtaglomerular cells in the afferent arterioles of the kidney. Renin secretion is upregulated by 4 different mechanisms in the kidney: (1) renal baroreceptor mechanism: decrease of blood pressure in the afferent arterioles; (2) macula densa mechanism: decrease of sodium chloride concentration in the distal tubule; (3) sympathetic nervous system: β1-adrenergic receptor stimulation; and (4) feedback: low levels of angiotensin II. Plasma renin converts angiotensinogen into angiotensin I, which is subsequently converted to the active angiotensin II by the angiotensin-converting enzyme (ACE). Angiotensin II has a short life (approximately 1 to 2 minutes) and is rapidly degraded into angiotensin III by angiotensinases. Angiotensin III increases blood pressure and induces aldosterone secretion from the adrenal cortex. Angiotensin II is a potent vasopressor that causes vasoconstriction, resulting in increased blood pressure. In addition, angiotensin II also increases the secretion of aldosterone. Aldosterone triggers tubular sodium reabsorption, resulting in sodium retention and an increase in blood pressure. This effect increases the volume of extracellular fluid in the body, which also increases blood pressure. THE PATHOPHYSIOLOGY OF THE RAAS IN CARDIAC SURGERY Vasoplegia is a syndrome and a frequent complication of cardiac surgery, especially following CPB. It is defined as a state of shock (hypotension) in which cardiac output is normal or even high and vascular tone (systemic vascular resistance) is decreased.3 The RAAS, particularly angiotensin II, plays a role in maintaining or restoring vascular tone. In vasoplegia caused by CPB, the use of angiotensin II thus represents targeted therapy. During CPB, the pulmonary circulation is bypassed; therefore, the exposure of angiotensin I to ACE is limited, and hence, production of endogenous angiotensin II decreases.11 As ACE and ACE2 are also located in the kidneys and renal blood flow is redistributed away from the kidneys during CPB, the RAAS is also activated. Though a vast majority of the ATHOS-3 trial patients had septic shock, a small subset of 17 patients had post-CPB vasoplegia, and 9 received angiotensin II. 89% of those patients exhibited an improvement in blood pressure compared to none in the placebo group (n=7).10 These observations support the involvement of RAAS-asociated pathophysiological processes in cardiac surgery-associated vasoplegia.12,13 Preliminary biomarker data also suggest dysregulation of the RAAS after cardiac surgery, which may also be associated with poor postoperative outcomes.12,13 In a 2021 study, Küllmar et al reported that high plasma renin concentrations, potentially indicating an angiotensin II deficit, were associated with a higher risk of vasoplegia and postoperative AKI after cardiac surgery.13 Existing evidence supports the relevance of angiotensin metabolism (higher angiotensin I/II ratio) in predicting the response to angiotensin II. In a 2022 study, patients with high plasma renin concentrations were more likely to show an increase in blood pressure in response to the infusion of angiotensin II after cardiac surgery than with norepinephrine.12 Among patients enrolled in the ATHOS-3 trial, which recruited patients with vasodilatory shock (mostly sepsis), the median angiotensin I/II ratio was 1.63 (interquartile range (IQR) 0.98–5.25).14 In a subgroup of patients with vasoplegia after cardiac surgery with CPB (n = 16), the authors reported a median angiotensin I/II ratio of 2.3 (0.6–3.3),10 values much higher than in healthy controls (0.39 (IQR, 0.28–0.64)).14 Patients in ATHOS III with severe AKI also had a higher angiotensin I/II ratio, suggesting a deficit in the conversion of angiotensin I to angiotensin II.14 Patients undergoing cardiac surgery frequently receive chronic treatment with RAAS modulators (ie, ACEi or ARB) due to a history of arterial hypertension, diabetes, or ischemic cardiomyopathy. Chronic and perioperative exposure to RAAS inhibitors before cardiac surgery is associated with higher baseline plasma renin concentrations.15 RAAS-inhibiting agents affect the response to angiotensin II differently (Figure). In the ATHOS-3 trial,9 patients exposed to ACEi showed full responsiveness in blood pressure to angiotensin II infusion, whereas those exposed to ARBs had a significantly attenuated response.9,15 This discrepancy is consistent with known physiology and confirms that the receptor blockade induced by ARB can reduce responsiveness to both endogenous and exogenous angiotensin II. Of note, stopping RAAS inhibitors the day before noncardiac surgery does not alter postoperative outcomes.16 Whether this relatively short time frame for drug withdrawal is sufficient to activate the RAAS is unclear and requires further investigation, as many compounds in these classes possess a half-life longer than 24 hours. In a pilot RCT (n = 121) of patients undergoing nonemergent cardiac surgery, discontinuation of ACEi or ARB 2 days before surgery vs. continuation did not change postoperative intravenous vasopressor use (78.3% in the continuation versus 75.4% in the discontinuation group, P = .703) or development of vasoplegic shock (31.7% vs 27.9% respectively, P = .648).17 Altogether, RAAS dysregulation in the context of ACEi/ARB use and CPB exposure appears to play a key role in postcardiac surgery vasoplegia. Taken together, these data suggest that elevated renin itself may result from different mechanisms and that ACEi and ARBs act through completely different mechanisms to modulate the RAAS. ACEis increase the effect of angiotensin II, whereas ARBs significantly diminish the effects. Because of these considerations, several clinical trials focused on cardiac surgery have been conducted to compare angiotensin II infusion in cardiac surgery patients.18,19Figure.: Suggested algorithm for cardiac surgery associated vasoplegia including angiotensin II. ACEi indicates angiotensin-converting enzyme inhibitor; Ang II, angiotensin II; ARB, angiotensin receptor blocker; CI, cardiac index.VASOPRESSORS TO TREAT VASOPLEGIA: NOREPINEPHRINE, VASOPRESSIN, AND ANGIOTENSIN II The most c

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