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COVID-19 and the cardiovascular system: an update

Published:February 10, 2022DOI:https://doi.org/10.1016/j.amjms.2022.01.022

      Abstract

      As COVID-19 continues to cause an increasing number of deaths worldwide, it is important that providers stay abreast with new research related to the pathophysiology of COVID-19 disease presentation states and clinical management. It is now well recognized that COVID-19 affects extrapulmonary organs, particularly the cardiovascular system. For example, cardiogenic shock has been increasingly observed in patients with COVID-19, owing to the various mechanisms involved and the affinity of the SARS-CoV-2 virus to cells comprising the cardiovascular system. In this review, we have briefly discussed the link between the cardiovascular system and COVID-19 infection, focusing on underlying mechanisms including but not limited to cytokine storm, direct virus-induced myocarditis, and ST-elevation myocardial infarction leading to cardiogenic shock. We have highlighted the cardiovascular risk factors associated with disease prognostication in COVID-19 patients. We have also briefly discussed vasopressors and inotropes used for treating shock and presented their mechanism of action, contraindications, and side effects in the hopes of providing a quick reference to help the provider optimize management of COVID-19 patients presenting with cardiovascular complications such as shock.

      Key Indexing Terms

      Introduction

      The Coronavirus disease-19 (COVID-19) pandemic continues to wreak havoc, causing an increasing number of deaths worldwide since being first reported in Wuhan, China.
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      The death toll caused by the SARS-CoV-2 virus as of January 1st 2022 has since surpassed 824,000 in the USA despite large strides made in understanding the pathophysiology, management, and prevention of spread. While the SARS-CoV-2 virus is known principally for its pulmonary effects, including pneumonia and acute respiratory distress syndrome (ARDS), other extrapulmonary manifestations have been reported. In fact, cardiovascular, hematologic, gastrointestinal and hepatobiliary, renal, endocrinologic, neurologic, and dermatologic systems have been reported to be affected by the virus via direct or indirect means.
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      Therefore, individuals affected by COVID-19, especially the severely ill, can present with multi-organ involvement/failure requiring prompt intervention. For these severely ill COVID-19 patients known to have a high mortality rate, it is not uncommon that their presentation to the intensive care unit will involve shock of a specific or mixed type.
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      Various mechanisms responsible for shock in COVID-19 patients, such as cytokine storm, have been proposed
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      ; therefore, the provider must keep abreast and must have a clear understanding of these mechanisms as new studies emerge. In this review, we will focus on the cardiovascular complications associated with COVID-19 while highlighting how they can culminate into shock. We will discuss how severely ill COVID-19 patients can be managed by providing a summary of the different inotropes and vasopressors in the hopes that it will serve as a quick guide for the provider.

      Cardiovascular manifestations of COVID-19 and underlying pathophysiology

      The SARS-CoV-2 virus is known to cause direct myocardial injury and induce arrhythmias and acute coronary syndromes (ACS) leading to acute heart failure and shock.
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      Specifically, injury to the myocardium as evidenced by elevated cardiac biomarkers has been reported in up to 30% of hospitalized COVID-19 patients and up to 55% in those with pre-existing cardiovascular disease. Interestingly but not surprisingly, the magnitude of troponin elevations in these hospitalized patients is associated with poorer outcomes.
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      Why is the heart particularly vulnerable to the SARS-CoV-2 virus? The reason is thought to be related to the mechanism utilized by the virus to gain cell entry. The angiotensin-converting enzyme 2 (ACE2) receptor, used by the virus to gain cellular access, is highly expressed in cardiovascular tissues, including cardiac myocytes, endothelial cells, fibroblasts, and smooth muscle cells.
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      Thus, direct viral interaction through these receptors supports a direct cytotoxic effect of the virus on cardiomyocytes. Also supporting this is the finding that viral particles have been isolated from autopsied heart specimens, although the majority of recent reports have failed to demonstrate such particles in autopsied specimens while noting inflammatory infiltrates in the myocardium.
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      For example, in one study in which autopsies were performed in 21 patients with COVID-19, myocarditis was observed in three cases (14%) while various other forms of myocardial injury were also observed, including widespread increased interstitial macrophage infiltration of the myocardium (86% of cases).
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      However, no clear associated myocyte injury involving both ventricles was reported. Also, the authors did not find viral particles in cardiac macrophages either. This finding supports widespread myocardial inflammation or myocarditis, characterized by inflammatory infiltrates and injury to heart tissue, without ischemic insult as another plausible mechanism.
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      However, it is difficult to estimate the exact prevalence of myocarditis among COVID-19 patients partly because early reports lacked diagnostic modalities to assess myocarditis. Some studies have reported that up to 7% of COVID-19–related deaths were secondary to myocarditis although nearly all the information about myocarditis in these patients came from case reports or small series.
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      A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.

      Yang G, Tan Z, Zhou L, et al. Effects of Angiotensin II receptor blockers and ACE (Angiotensin-Converting Enzyme) inhibitors on virus infection, inflammatory status, and clinical outcomes in patients with COVID-19 and hypertension: a single-center retrospective study. Hypertension.2020l;76:51-58.

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      Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19.
      For example, Sawalha et al
      • Wichmann D
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      Autopsy FINDINGS and Venous thromboembolism in patients with COVID-19: a prospective cohort study.
      identified a total of 14 COVID-19 cases with myocarditis/myopericarditis, reporting a male predominance (58%), with a median age of 50.4 years. Of note, most patients did not have a previously identified comorbid condition (50%). Recovery of cardiac structure and function has been noted; for example, fulminant myocarditis with elevated troponin and improvement in left ventricular function following treatment with antivirals, intravenous immunoglobulin, and steroids, and subsequent normalization of troponins have been reported.
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      Incidence and treatment of arrhythmias secondary to coronavirus infection in humans: a systematic review.
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      Recognizing COVID-19-related myocarditis: the possible pathophysiology and proposed guideline for diagnosis and management.
      As briefly mentioned above, since the SARS-CoV-2 virus uses the angiotensin-converting enzyme 2 (ACE2) receptor, an important question is whether routine use of angiotensin-converting-enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs) in COVID-19 patients is protective or increases susceptibility to the virus, especially in patients with hypertension, heart failure, and/or diabetes, who are overrepresented among critically ill COVID-19 patients. So far, there is no evidence to support an association between ACEi and ARBs use and COVID-19 severity, while some other studies have shown potential benefits.
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      Renin-angiotensin-aldosterone system blockers and the risk of Covid-19.
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      Association of renin-angiotensin system inhibitors with severity or risk of death in patients with hypertension hospitalized for coronavirus disease 2019 (COVID-19) infection in Wuhan, China.
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      A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.
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      Effects of Angiotensin II `s and ACE (Angiotensin-Converting Enzyme) inhibitors on virus infection, inflammatory status, and clinical outcomes in patients with COVID-19 and hypertension: a single-center retrospective study.
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      Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19.
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      Renin-angiotensin system blockade in the COVID-19 pandemic.
      Therefore, currently, the routine discontinuation of these medications is not recommended based on recommendations by the European society of cardiology and the American College of Cardiology.
      Cardiac arrhythmias, including new-onset atrial fibrillation, heart block, and ventricular arrhythmias, are also prevalent in COVID-19 patients, occurring in 17% of hospitalized patients and up to 44% of ICU patients as first reported in a study of 138 patients from Wuhan, China. These arrhythmias have since been recognized as common features of COVID-19 and are associated with poorer outcomes.
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      COVID-19 and cardiac arrhythmias.
      Malaty et al have summarized more recent studies discussing the incidence and treatment of arrhythmias secondary to COVID-19 and the reader is thus directed there for more information.
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      Incidence and treatment of arrhythmias secondary to coronavirus infection in humans: a systematic review.
      Non-valvular atrial fibrillation (NVAF) seems to be the most common arrhythmia encountered in COVID-19 patients and COVID-19 is increasingly being postulated as an independent risk factor for stroke in patients with NVAF.
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      Outcomes and mortality associated with atrial arrhythmias among patients hospitalized with COVID-19: a systematic review and meta-analysis.
      Of note, although the exact mechanistic pathways leading to arrhythmias remain unknown at large, plausible mechanisms, as discussed by Siripanthong et al, include direct injury to cardiomyocytes disrupting electrical conduction, pericardial edema affecting electrical conduction, ischemia disrupting electrical conduction, re-entrant arrhythmias due to myocardial fibrosis or scars, and arrhythmias caused by proinflammatory cytokines predisposing to arrhythmogenicity.
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      Recognizing COVID-19-related myocarditis: the possible pathophysiology and proposed guideline for diagnosis and management.
      In a multicenter New York City cohort, of the 4,250 patients with COVID-19, 6% were noted to have a prolonged QTc (i.e., corrected QT; >500 ms)
      • Richardson S
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      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area.
      and in a different cohort of 393 patients with COVID-19, atrial arrhythmias were more common among patients requiring mechanical ventilation than those who did not (17.7% versus 1.9%).
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      In the New York City cohort, prolongation of QT could have been iatrogenic from the use of azithromycin and hydroxychloroquine at that time.
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      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area.
      Other indirect mechanisms leading to myocardial damage include stress-mediated myocardial dysfunction that could result from hypertensive emergency, tachycardia-induced cardiomyopathy, myocardial stunning after prolonged hypotension leading to supply-demand mismatch (i.e., type 2 MI), and hypoxia-induced myocardial damage caused by ARDS secondary to COVID-19. COVID-19 patients also have an exaggerated risk for myocardial infarction given that COVID-19 is a hypercoagulable state that can lead to widespread thrombosis in the arterial and venous systems resulting in ischemic injury and venous thromboembolism that can cause significant heart strain culminating to fatal complications. Thrombosis is a result of endothelitis triggered by direct interaction of viral particles with the endothelium or a result of hyperviscosity induced by the heightened proinflammatory state of COVID-19.
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      Third-degree heart block associated with saddle pulmonary embolism: a rare sequelae of COVID-19-induced hypercoagulable state.

      Factors increasing the risk for cardiovascular complications in COVID-19

      Cardiovascular risk factors can play a crucial role in identifying patients vulnerable to developing cardiovascular manifestations of COVID-19. The reader is directed to the review by Shifi et al for a detailed review of these risk factors.
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      Cardiac manifestations in COVID-19 patients-a systematic review.
      In brief, hypertension and diabetes have been noted to be among the most common of these risk factors. Wu and McGoogan found that when the case fatality rate (CFR) of COVID-19 was high in critically ill patients, those with pre-existing conditions experienced an even higher rate – 10.5% for those with cardiovascular disease, 7.3% for diabetes, and 6.0% for hypertension.
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      These pre-existing conditions have also been shown to correlate with mortality. For example, when 150 COVID-19 patients were analyzed, Shafi et al found that hypertension, diabetes, pre‐existing cardiovascular disease (CVD), and cerebrovascular disease were responsible for 43%, 18%, 19%, and 10% of all deaths, respectively.
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      Thirty-nine percent of these deaths were attributed to heart failure or respiratory failure. The studies by Zhou et al and Shi et al also highlighted the association of hypertension and diabetes as important risk factors.
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      Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19).
      ,
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      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      In a separate retrospective study conducted in Italy involving 188 COVID-19 patients admitted to the ICU, hypercholesterolemia was found to be another significant comorbidity predicting poorer outcomes involving cardiovascular implications.
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      Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy.
      All of the 188 patients admitted to the ICU had hypercholesterolemia, indicating the importance as a risk factor. The commonest risk factors in this cohort associated with an adverse cardiovascular complication included hypertension (27%), CVD (12.1%), and diabetes (11.5%). Guo et al found that elevated troponin levels were associated with more frequent arrhythmias and higher levels of other cardiac biomarkers.
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      Once the SARs-CoV virus enters myocytes, viral inclusions, and inflammatory cells such as macrophages, neutrophils, and lymphocytes follow.
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      This viral-mediated infiltration can cause myocardial edema or myocarditis coupled with necrosis, resulting in dilated cardiomyopathy and heart failure.
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      [Myocardial expression of Spry1 and MAPK proteins of viral myocarditis].
      Studies have shown that myocarditis is present in up to 30% of patients with COVID-19 and those with myocarditis have poorer prognoses.
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      Of note, the development of heart failure depends on comorbidities, age, and the severity of cardiac involvement, as well as other factors. As summarized by Shafi et al, based on all studies, approximately 8% of patients developed heart failure/cardiogenic shock as a complication of COVID‐19.
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      Cardiac manifestations in COVID-19 patients-a systematic review.
      The first of such reports on cardiogenic shock in otherwise healthy males with a diagnosis of COVID-19 suggest that shock is induced by direct viral-mediated myocardial injury.
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      Cardiogenic shock and Hyperinflammatory syndrome in young males with COVID-19.
      Patients presented with hyperinflammatory biomarker profiles and multiorgan dysfunction including biventricular failure and responded to treatment with methylprednisolone. In a different report, Fried et al reported some of the various cardiovascular presentations of COVID‐19 in which three out of four cases developed cardiogenic shock.
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      They highlighted how swift recognition of cardiogenic shock in these cases was crucial for appropriate clinical decision making. Tavazzi et al described the first case of acute cardiac injury directly linked to myocardial localization of the SARS-CoV-2 virus in a 69-year-old patient who presented with cardiogenic shock.
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      Myocardial localization of coronavirus in COVID-19 cardiogenic shock.
      Chnonyang et al demonstrated cardiomyocyte infection with SARS-CoV-2 virus in a patient presenting with cardiogenic shock.
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      The Enemy within: sudden-onset reversible cardiogenic shock with biopsy-proven cardiac myocyte infection by severe acute respiratory syndrome coronavirus 2.
      In one retrospective study carried out in Wuhan, China, heart failure was ranked as the fourth most common outcome of COVID-19.
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      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      In another study, 49% of all deaths were attributable to heart failure in individuals who had no prior history of cardiovascular diseases.
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      Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.
      Several other case reports of COVID‐19 patients presenting with cardiogenic shock have since been reported.
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      Cardiogenic shock complicating multisystem inflammatory syndrome following COVID-19 infection: a case report.
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      Sudden cardiogenic shock mimicking fulminant myocarditis in a surviving teenager affected by severe acute respiratory syndrome coronavirus 2 infection.
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      Case report of cardiogenic shock in COVID-19 myocarditis: peculiarities on diagnosis, histology, and treatment.
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      The mechanism leading to this outcome is multifactorial and can be linked to sepsis, respiratory failure and ARDS, direct cardiac injury, ACS caused by coronary thrombosis due to COVID-19 associated coagulopathy, and direct injury to the myocardium by the SARS-CoV-2 virus.
      The heightened proinflammatory state in COVID-19 also plays a role in myocardial damage. Pro-inflammatory cells release cytokines such as Monocyte chemoattractant protein-1 (MCP-1), a major cytokine noted to increase significantly after COVID-19 onset. MCP-1 is a major regulator of monocyte/macrophage migration to the site of SARS-CoV-2 infection.
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      Monocyte chemoattractant protein-1 (MCP-1): an overview.
      The accumulation of monocytes/macrophages around viral inclusions in the myocardium can disrupt heart function either mechanically or electrically. Interleukin-1β (IL-1β), another key regulator of inflammatory response, is pivotal in the etiology of COVID-19. IL-1β can stimulate the release of IL-21, IL-17, and IL-22 which mediate cell proliferation and differentiation that may contribute to myocardial thickening leading to cardiomyopathy. Tumor necrosis factor-alpha (TNF-α) secreted by macrophages, neutrophils, mast cells, and cardiomyocytes can also promote cellular proliferation and myocardial thickening.
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      Tumor necrosis factor-alpha produced in cardiomyocytes mediates a predominant myocardial inflammatory response to stretch in early volume overload.

      Treatment considerations of COVID-19 patients presenting with cardiovascular complications culminating to shock

      A firm comprehension of the pathophysiology of the cardiovascular complications in COVID-19 patients will aid in swiftly recognizing and targeting treatment of potentially fatal complications such as cardiogenic shock thereby prompting targeted management. Multiple etiologies underlie the different shock states, including cardiogenic, hypovolemic, distributive, obstructive, or mixed type, often encountered in COVID-19 patients (Figure 1). Irrespective of the underlying etiology, the hallmark of any type of shock in general and including COVID-19 patients is decreased organ perfusion culminating into multiorgan dysfunction and death. Quick recognition of shock decreases morbidity and mortality in hospitalized COVID-19 patients. Obstructive shock caused by a pneumothorax in ventilated patients or critically ill patients on high dose steroids, for example, warrants prompt decompression rather than treatment with vasoactive agents. Similarly, cardiogenic shock due to myocarditis/cardiomyopathy caused by cytokine storm may respond to anti-inflammatory treatments and monoclonal antibodies which are increasingly being added to the therapeutic regimens of COVID-19.
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      Figure 1:
      Figure 1Types of shock. In COVID-19 patients, similar to non-COVID-19 patients, the cause of shock can be multifactorial, and different shock types can occur simultaneously. Cardiogenic shock can result from a variety of causes given the systemic nature of COVID-19. The cause of shock can also be iatrogenic; hemorrhage can result from anticoagulation therapy while pneumothorax can be caused by barotrauma or has been associated with high dose corticosteroids use.
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      Pneumothorax and pneumomediastinum in patients hospitalized with coronavirus disease 2019 (COVID-19).
      The initial evaluation of critically ill COVID-19 patients supposedly in shock must take into consideration these potential causes.
      Vasopressors and inotropes create vasoconstriction or increase cardiac contractility, respectively, in patients with shock leading to increased mean arterial pressure (MAP) and improved organ perfusion. A summary of vasopressors and inotropes used to increase MAP is summarized in Table 1. Some less commonly used medications which should be considered in circumstances where the goal MAP cannot be achieved despite the use of multiple vesopressors/inotropes have also been highlighted. The use of a mineralocorticoid/corticosteroid such as hydrocortisone should not be overlooked in cases of refractory shock as studies have shown that it is not unusual for critically ill patients to have relative adrenal insufficiency.
      • Akbas EM
      • Akbas N.
      COVID-19, adrenal gland, glucocorticoids, and adrenal insufficiency.
      • Alzahrani AS
      • Mukhtar N
      • Aljomaiah A
      • et al.
      The impact of COVID-19 viral infection on the hypothalamic-pituitary-adrenal axis.
      • Castinetti F
      • Amodru V
      • Brue T.
      Adrenal crisis may occur even in patients with asymptomatic Covid-19.
      • Heidarpour M
      • Vakhshoori M
      • Abbasi S
      • et al.
      Adrenal insufficiency in coronavirus disease 2019: a case report.
      Table 1
      DrugClinical IndicationDose RangeReceptor BindingMajor Side EffectsContraindications
      α1β1β2DAV1
      V1 receptors (abundant in vascular smooth muscle), vasopressin stimulates GPCR, phosphatidylinositol/calcium pathway leading to vasoconstriction; V2 receptors (abundant in renal collecting duct system), vasopressin couples V2 receptors with the Gs signaling pathway, activating cAMP. Increased intracellular cAMP in the kidney triggers fusion of aquaporin-2-bearing vesicles with the plasma membrane of the collecting duct cells, thereby increasing water reabsorption.101
      V2
      V1 receptors (abundant in vascular smooth muscle), vasopressin stimulates GPCR, phosphatidylinositol/calcium pathway leading to vasoconstriction; V2 receptors (abundant in renal collecting duct system), vasopressin couples V2 receptors with the Gs signaling pathway, activating cAMP. Increased intracellular cAMP in the kidney triggers fusion of aquaporin-2-bearing vesicles with the plasma membrane of the collecting duct cells, thereby increasing water reabsorption.101
      Note on use in COVID-19 patients
      Catecholamines
      NorepinephrineVasodilatory shock

      Cardiogenic shock
      0.025 - 1 mcg/kg/min

      0.05 - 0.4 mcg/kg/min
      ++++++++++N/AN/AN/ANorepinephrine is the first-line drug. See Gubbi et al
      • Gubbi S
      • Nazari MA
      • Taieb D
      • et al.
      Catecholamine physiology and its implications in patients with COVID-19.
      for a discussion of the complex interplay between catecholamines and COVID-19
      Hypertension and arrhythmiasNo contraindications to its use in a life-threatening situation
      EpinephrineVasodilatory shock

      Cardiogenic shock

      Anaphylactic shock

      Bradycardia
      0.01 - 0.5 mcg/kg/min

      0.01 - 0.5 mcg/kg/min

      0.01 - 0.03 mg/kg

      0.1 - 0.5 mcg/kg/min
      ++++++++++++N/AN/AN/ANot the preferred initial agent in cardiogenic shock. See Gubbi et al
      • Gubbi S
      • Nazari MA
      • Taieb D
      • et al.
      Catecholamine physiology and its implications in patients with COVID-19.
      for a discussion of catecholamines and COVID-19
      Arrhythmias and hypertension
      • Dellinger RP
      • Schorr CA
      • Levy MM.
      A Users' Guide to the 2016 surviving sepsis guidelines.
      No absolute contraindications
      DopamineCardiogenic shock

      Bradycardia
      5 - 15 mcg/kg/min
      Inotropic actions predominate at doses at the lower end of this range. Low dose: Renal dopamine receptors predominate. Intermediate dose: Dopamine and beta-adrenergic effects predominate. High dose: Alpha-adrenergic effects predominate.


      5 -20 mcg/kg/min.

      ++++++++++++++N/AN/ANot the preferred initial agent in cardiogenic shock. See Gubbi et al
      • Gubbi S
      • Nazari MA
      • Taieb D
      • et al.
      Catecholamine physiology and its implications in patients with COVID-19.
      for a discussion of catecholamines and COVID-19
      Hypertension and arrhythmiasPheochromocytoma and tachyarrhythmias
      • De Backer D
      • Biston P
      • Devriendt J
      • et al.
      Comparison of dopamine and norepinephrine in the treatment of shock.
      .
      DobutamineCardiogenic shock

      Decompensated HF

      Bradycardia
      Usual dosing range is 2 - 20 mcg/kg/min+++++++++N/AN/AN/AAccording to AHA and ACCF, doses >20 mcg/kg/min are not recommended in heart failureTachycardia, PVCs, and angina pectorisPheochromocytoma and tachyarrhythmias.
      • De Backer D
      • Biston P
      • Devriendt J
      • et al.
      Comparison of dopamine and norepinephrine in the treatment of shock.
      PhenylephrineVasodilatory shock

      Post cardiac arrest
      0.5 - 6 mcg/kg/min

      0.5 - 2 mcg/kg/min
      +++++00N/AN/AN/ANot a first-line or second-line treatment for septic shock
      Except when (1) norepinephrine is associated with serious arrhythmias, (2) cardiac output is high and blood pressure persistently low, or (3) the combination of inotrope/vasopressor and low-dose vasopressin failed to achieve target MAP.94
      Hypertensive and reflex bradycardia
      • Gamper G
      • Havel C
      • Arrich J
      • et al.
      Vasopressors for hypotensive shock.
      No absolute contraindications
      IsoproterenolCardiogenic shock

      Bradyarrhythmias

      Torsade de pointes
      2 - 20 mcg/minute

      2 - 10 mcg/min

      2 - 10 mcg/min
      0++++++++++N/AN/AN/AMay further reduce systemic vascular resistanceParadoxical bradycardia, tachyarrhythmias, ventricular arrhythmiasPreexisting ventricular arrhythmias, cardiac glycoside overdose
      • Mladěnka P
      • Applová L
      • Patočka J
      • et al.
      Comprehensive review of cardiovascular toxicity of drugs and related agents.
      Phosphodiesterase

      inhibitors
      MilrinoneDecompensated HF with evidence of end-organ hypoperfusion
      Should be combined with standard therapies. For renal dose adjustment, CrCl 10 to 50 mL/minute: Initial: 0.0625 to 0.125 mcg/kg/min and titrate cautiously. Titrating to >0.375 mcg/kg/min is not recommended
      .
      0.125 to 0.75 mcg/kg/minN/ARequires renal dose adjustment
      Should be combined with standard therapies. For renal dose adjustment, CrCl 10 to 50 mL/minute: Initial: 0.0625 to 0.125 mcg/kg/min and titrate cautiously. Titrating to >0.375 mcg/kg/min is not recommended
      Ventricular and supraventricular arrhythmias and hypotension
      • Cox ZL
      • Calcutt MW
      • Morrison TB
      • et al.
      Elevation of plasma milrinone concentrations in stage D heart failure associated with renal dysfunction.
      Hypersensitivity to milrinone
      Others
      Vasopressin
      V1 receptors (abundant in vascular smooth muscle), vasopressin stimulates GPCR, phosphatidylinositol/calcium pathway leading to vasoconstriction; V2 receptors (abundant in renal collecting duct system), vasopressin couples V2 receptors with the Gs signaling pathway, activating cAMP. Increased intracellular cAMP in the kidney triggers fusion of aquaporin-2-bearing vesicles with the plasma membrane of the collecting duct cells, thereby increasing water reabsorption.101
      Vasodilatory shockInitial: ≤0.03 units/min added to norepinephrine
      • Rhodes A
      • Evans LE
      • Alhazzani W
      • et al.
      Surviving Sepsis campaign: international guidelines for management of sepsis and septic shock: 2016.
      N/A++++++++++Use in addition to norepinephrine and titrate to the lowest effective dose. Caution with doses >0.03 units/min. Taper by 0.01 units/min every 30 - 60 min97Arrhythmias, hypertension decreased CO (at doses >0.4 U/min)
      • Mladěnka P
      • Applová L
      • Patočka J
      • et al.
      Comprehensive review of cardiovascular toxicity of drugs and related agents.
      Hypersensitivity to vasopressin
      Levosimendan
      Calcium sensitizer; exerts its positive inotropic effect by increasing calcium sensitivity of myocytes by binding to cardiac troponin C. Its vasodilatory effect occurs via opening adenosine triphosphate (ATP)-sensitive K+ channels in vascular smooth muscle cells leading to vasodilation.95 Drug not currently available in the US
      Decompensated HFInitial: 6 - 12 mcg/kg infused over 10 min. Maintenance: 0.05 - 0.2 mcg/kg/minN/AN/ATachycardia and hypotension
      • Overgaard CB
      • Dzavik V.
      Inotropes and vasopressors: review of physiology and clinical use in cardiovascular disease.
      None
      Synthetic Angiotensin II
      Acts via Ang II receptors causing (1) constriction of efferent arterioles in the kidneys and (2) in the adrenal glands causing the release of aldosterone.95,99
      Septic or other distributive shocksInitial: 10 to 20 ng/kg/min (max dose of 80 ng/kg/min during the first 3 hours of treatment; max maintenance dose of 40 ng/kg/min); titrate every 5 minutes by up to 15 ng/kg/min. Down-titrate every 5 to 15 minutes by up to 15 ng/kg/min to wean
      • Khanna A
      • English SW
      • Wang XS
      • et al.
      Angiotensin II for the treatment of vasodilatory shock.
      N/AAngiotensin II Receptor Blockers may diminish therapeutic effect. Angiotensin-Converting Enzyme Inhibitors may enhance therapeutic effects
      • Khanna A
      • English SW
      • Wang XS
      • et al.
      Angiotensin II for the treatment of vasodilatory shock.
      ,
      • Antonucci E
      • Gleeson PJ
      • Annoni F
      • et al.
      Angiotensin II in refractory septic shock.
      Use with concurrent VTE prophylaxis since arterial and venous thrombotic and thromboembolic events have been reported
      • Khanna A
      • English SW
      • Wang XS
      • et al.
      Angiotensin II for the treatment of vasodilatory shock.
      ,
      • Antonucci E
      • Gleeson PJ
      • Annoni F
      • et al.
      Angiotensin II in refractory septic shock.
      None
      α1; α-1 receptor; β1, β-1 receptor; β2, β-2 receptor; DA, dopamine receptors; + through +++++, minimal to maximal relative receptor affinity; N/A, not applicable; AHA; American Heart Association, ACCF; American College of Cardiology Foundation, HF; heart failure, CO; cardiac output, MAP; mean arterial pressure, CrCl; creatinine clearance, AV; atrioventricular, VTE; venous thromboembolism. PVCs; premature ventricular contractions
      low asterisk V1 receptors (abundant in vascular smooth muscle), vasopressin stimulates GPCR, phosphatidylinositol/calcium pathway leading to vasoconstriction; V2 receptors (abundant in renal collecting duct system), vasopressin couples V2 receptors with the Gs signaling pathway, activating cAMP. Increased intracellular cAMP in the kidney triggers fusion of aquaporin-2-bearing vesicles with the plasma membrane of the collecting duct cells, thereby increasing water reabsorption.101
      # Calcium sensitizer; exerts its positive inotropic effect by increasing calcium sensitivity of myocytes by binding to cardiac troponin C. Its vasodilatory effect occurs via opening adenosine triphosphate (ATP)-sensitive K+ channels in vascular smooth muscle cells leading to vasodilation.95 Drug not currently available in the US
      § Acts via Ang II receptors causing (1) constriction of efferent arterioles in the kidneys and (2) in the adrenal glands causing the release of aldosterone.95,99
      low asterisklow asterisk Inotropic actions predominate at doses at the lower end of this range. Low dose: Renal dopamine receptors predominate. Intermediate dose: Dopamine and beta-adrenergic effects predominate. High dose: Alpha-adrenergic effects predominate.
      ## Except when (1) norepinephrine is associated with serious arrhythmias, (2) cardiac output is high and blood pressure persistently low, or (3) the combination of inotrope/vasopressor and low-dose vasopressin failed to achieve target MAP.94
      $ Should be combined with standard therapies. For renal dose adjustment, CrCl 10 to 50 mL/minute: Initial: 0.0625 to 0.125 mcg/kg/min and titrate cautiously. Titrating to >0.375 mcg/kg/min is not recommended
      Early revascularization, as demonstrated in the SHould we emergently revascularize Occluded Coronaries for cardiogenic shock (SHOCK) trial, remains the most important treatment in managing cardiogenic shock caused by acute MI.
      • Hochman JS
      • Sleeper LA
      • Webb JG
      • et al.
      Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK investigators. Should we emergently revascularize occluded coronaries for cardiogenic Shock.
      In severe COVID-19 cases with refractory shock, right ventricular failure, and extreme hypoxic lung injury, extracorporeal membrane oxygenation or other mechanical circulatory support such as Impella or intra-aortic balloon pump can be used.
      • Thiele H
      • Ohman EM
      • Desch S
      • et al.
      Management of cardiogenic shock.
      In addition to these measures, other supportive management must be used concomitantly. For example, adequate fluid resuscitation whenever required and treatment with other adjunctive therapies such as ramdesevir and tocilizumab.
      The comprehension of the hemodynamic principles and adrenergic and non-adrenergic receptor mechanisms are important to appropriately utilize vasoactive/ionotropic medications for shock management in COVID-19 patients. Carefully selecting these medications based on the desired pharmacologic effects that are matched to the patient's underlying pathophysiology of shock is likely to optimize hemodynamics, while reducing adverse effects and increasing overall survival. As highlighted, the relative hemodynamic effect of some agents can depend on the dose administered. Norepinephrine remains the reasonable first-line agent for different shock states, most notably septic shock. Whereas dobutamine is a reasonable first-line inotrope agent. We hope that this document will serve as a quick guide for all healthcare providers managing critically ill COVID-19 patients who may present with cardiogenic or other forms of shock.
      Since the start of vaccination against COVID-19, disease severity and overall mortality related to complications have been greatly mitigated. Patients fully vaccinated against COVID-19 are very less likely to have severe symptoms leading to shock and ICU hospitalization. We anticipate that as the pool of vaccinated individuals continues to increase, the less we are to encounter patients with severe symptoms and complications. That notwithstanding, they have been reports of adverse effects, including cardiovascular complications such as myocarditis and pericarditis occurring predominantly in males after receipt of the second vaccine dose of any of the available COVID-19 vaccine.
      • Ameratunga R
      • Woon ST
      • Sheppard MN
      • et al.
      First identified case of fatal fulminant necrotizing eosinophilic myocarditis following the initial dose of the Pfizer-BioNTech mRNA COVID-19 vaccine (BNT162b2, Comirnaty): an extremely rare idiosyncratic hypersensitivity reaction.
      • Gargano JW
      • Wallace M
      • Hadler SC
      • et al.
      Use of mRNA COVID-19 vaccine after reports of myocarditis among vaccine recipients: update from the Advisory committee on immunization practices - United States, June 2021.
      • Rosenblum HG
      • Hadler SC
      • Moulia D
      • et al.
      Use of COVID-19 vaccines after reports of adverse events among adult recipients of Janssen (Johnson & Johnson) and mRNA COVID-19 vaccines (Pfizer-BioNTech and Moderna): update from the advisory committee on immunization practices - United States, July 2021.
      Despite this, the Advisory Committee on Immunization Practices (ACIP) maintained that the benefits, i.e., prevention of COVID-19 disease and associated morbidity and mortality, far outweighed the risks, i.e., expected myocarditis cases after vaccination in the recommended populations.

      Conclusions

      Although known primarily for its effect on the pulmonary system, the SARS-CoV-2 virus is also notable for its extrapulmonary manifestations. Particularly, the cardiovascular system is prone to the direct and indirect effects of the virus whose affinity for tissues comprising this system remains wholly unclear, though mechanisms implicating the ACE2 receptor have been implicated. The cardiac complications of COVID-19 reported in the literature most notably include myopericarditis leading to shock and increased morbidity and mortality. Therefore, it is important that providers are made aware of these potential complications, anticipate treatment strategies, and familiarize themselves with tools at their disposal which can be utilized to improve overall outcomes

      Declaration of Competing Interest

      None.

      Acknowledgments

      This work was supported by HCA Healthcare and/or an HCA healthcare affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities.

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