key: cord-300805-apli48ih authors: Augoustides, John G. title: The Renin-Angiotensin-Aldosterone System in Coronavirus Infection – current considerations during the pandemic date: 2020-04-16 journal: J Cardiothorac Vasc Anesth DOI: 10.1053/j.jvca.2020.04.010 sha: doc_id: 300805 cord_uid: apli48ih nan The renin-angiotensin-aldosterone system (RAAS) is a complex peptide cascade that has a prominent role in multiple important physiological processes such as vascular tone, vascular permeability, and myocardial remodeling. [1] [2] [3] The pharmacologic modulation of this system with agents such as angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBS) has resulted in major clinical benefits in the medical management of hypertension and heart failure. 3 Furthermore, the consequences of this pharmacologic blockade of the RAAS in perioperative cardiothoracic and vascular practice has been well-recognized, leading to the emergence of rescue therapies for support of vascular tone. [4] [5] The severe acute respiratory syndrome coronavirus-2 infects human cells such as alveolar endothelium in the lung by binding to the membrane receptor, angiotensin-converting enzyme 2 (ACE2). [1] [2] [3] Although the physiologic functions of ACE2 include counteracting the effects of RAAS activation, it also functions as a membrane receptor for the coronavirus. [1] [2] [3] This binding results in endocytosis of the viral complex with consequent local activation of the RAAS, resulting in acute lung injury that may progress to adult respiratory distress syndrome. 1-2 ; 6-7 The purpose of this freestanding editorial is to highlight the considerations concerning the RAAS in patients presenting with severe coronavirus disease 2019 . This perspective will focus on the clinical relevance of these considerations to inform the management of these challenging patients. [8] [9] [10] [11] The references provide further detail for healthcare teams as they manage the demands of the pandemic at their respective institutions. 3 The prevalence of coexisting hypertension has been estimated to be in the (10-25)% range amongst patients presenting with COVID-19. [11] [12] [13] [14] The coexisting conditions such as hypertension, older age, diabetes, cardiovascular disease have all been reported to be more common in patients with severe COVID-19 requiring intensive care. [14] [15] [16] [17] The comorbidities, including hypertension, have also been significantly associated with adverse outcomes in COVID-19 such as adult respiratory distress syndrome, cardiovascular compromise, and mortality. [14] [15] [16] [17] [18] Since the comorbidity of hypertension has been associated with severe COVID-19 and its consequences, the question has emerged about the roles of RAAS inhibitors such as ACEI and ARBS in the pathogenesis of severe COVID-19. Given that these RAAS inhibitors are common therapies for hypertension and that they may up-regulate the expression of ACE2, the clinical concern has been formulated that therapy with these agents may increase the risk and severity of coronavirus infection. [19] [20] [21] [22] There is currently insufficient evidence to address this question in a definitive fashion. 1; 14 The published literature both in preclinical and clinical studies has conflicting results about the potential for harm with respect to the interactions between RAAS inhibitors and coronavirus 19. Further trials will likely focus on the current evidence gaps related to this question in severe COVID-19 including mechanisms, the prevalence of RAAS inhibitors, and careful correlation of this prevalence with clinical outcomes. 1; 18-19 Although hypertension and consequent exposure to ACEI and ARBS are likely common in severe COVID-19, this association does link to causality, as outlined above. [23] [24] There may also be confounding by association here in that patients with severe COVID-19 are more likely to be 4 hypertensive, diabetic and older. This comorbidity burden rather than the associated drug therapy may better explain the adverse outcomes in coronavirus infection. [17] [18] [19] In contrast, animal studies have clearly documented that ACE2 may have a protective role in acute lung injury related to coronavirus infection. [25] [26] Functional ACE2 typically converts angiotensin II to angiotensin 1-7, thereby reducing the adverse effects of angiotensin II via the angiotensin type I receptor in the lung that lead to acute lung injury. 1; 21 Since therapy with ACEI and/ot ARBS also reduces angiotensin II levels, it follows that these agents may also protect against acute lung injury in the setting of COVID-19. Patients with severe COVID-19 may also develop vasoplegic shock with or without concomitant sepsis. 30 In the initial wave of COVID-19 in Seattle, patients with cardiovascular compromise seldom had superinfection, suggesting that the cardiovascular instability was mostly due to the consequences of viral infection. 6 Furthermore, in this patient cohort, echocardiography also rarely identified ventricular dysfunction, although myocarditis is a possibility in this disease. 30 This latest data from the pandemic in the United States suggests that vasoplegic shock from the effects of the coronavirus is a likely clinical presentation in severe COVID-19. The status quo with respect to ACEI and ARBS in COVID-19 can be confusing to clinicians in the front lines of patient care during the pandemic, given the possibilities for both benefit and 6 harm. [14] [15] This priority for clinical guidance during the coronavirus virus has prompted recent statements from multiple professional societies including the Canadian Cardiovascular Society, the European Society of Hypertension, the International Society of Hypertension, the European Society of Cardiology and American College of Cardiology. [13] [14] In summary, the expert consensus from all these professional societies is that patients with COVID-19 should continue their regular home blood antihypertensive regimen, even if it includes ACEI and ARBS. 14 In patients with COVID-19 who develop shock, the vasodilator regimen with RAAS inhibitors can be discontinued. 14 Although not specifically addressed in these multiple professional guidelines, the roles of rescue therapy for vasoplegic shock can also be considered in refractory cases, including angiotensin II. 2;4-5 Furthermore, in treatment-resistant cases of COPVID-19, the mechanisms for cardiogenic shock and the supportive roles of extracorporeal membrane oxygenation should be entertained early, as these considerations can often lead to therapeutic breakthroughs. [29] [30] [31] The spectrum of severe COVID-19 includes significant disruption of the RAAS, with significant implications for organ dysfunction, vascular tone, as well as therapy with ACEI and ARBS. Although clinical trials are in progress to close the current evidence gaps, the current expert consensus has recommended that in most cases, existing therapy with ACEI and ARBS be continued. In the setting of circulatory shock, these agents may be discontinued and early consideration of therapies for medical and mechanical rescue may be lifesaving. The management of patients through this pandemic must also consider infection control to prevent further viral transmission. Renin-angiotensin-aldosterone system inhibitors in patients with COVID-19 Angiotensin II for the treatment of COVID-19-related vasodilatory shock The vasoactive Mas receptor in essential hypertension Vasoplegia during cardiopulmonary bypass: current literature and rescue therapy options Vasoplegia after cardiovascular procedurespathophysiology and targeted therapy COVID-19 in critically ill patients in the Seattle region -case series Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study Outbreak of a new coronavirus: what anaesthetists should know Chinese Society of Anesthesiologists expert consensus on anesthetic management of cardiac surgical patients with suspected or confirmed coronavirus disease 2019 Anesthetic management of patients undergoing aortic dissection repair with suspected severe acute respiratory syndrome Coronavirus-2 infection Clinical characteristics of coronavirus disease 2019 in China Clinical features of patients with 2019 novel coronavirus in Wuhan Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected -interim guidance. (the full details are available at this link -last accessed March Cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (COVID-19) pandemic Potential effects of coronaviruses on the cardiovascular system: a review CSC expert consensus on principles of clinical management Coronavirus disease 2019 (COVID-19) and cardiovascular disease COVID-19 and the cardiovascular system Coronaviruses and the cardiovascular system: acute and long-term implications Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic? SARS-CoV2: Should inhibitors of the reninangiotensin system be withdrawn in patients with COVID-19? Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19 Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic review and meta-analysis Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis Angiotensin-converting enzyme 2 protects from severe acute lung failure A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics Angiotensin-converting enzyme 2 (ACE2) as a SARS CoV-2 receptor: molecular mechanisms and potential therapeutic target Cardiovascular consequences and considerations of coronavirus infectionperspectives for the cardiothoracic anesthesiologist and intensivist during the coronavirus crisis Management strategies for severe and refractory acute respiratory distress syndrome: where do we stand in 2018? Extracorporeal membrane oxygenation -crucial considerations during the coronavirus crisis