The Right Ventricle in COVID-19 Lung Injury: Proposed Mechanisms, Management, and Research Gaps

Abstract

CORONAVIRUS DISEASE 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is a complex multisystem disorder primarily characterized by pulmonary involvement.1Grasselli G Tonetti T Protti A et al.Pathophysiology of COVID-19-associated acute respiratory distress syndrome: A multicentre prospective observational study.Lancet Respir Med. 2020; 8: 1201-1208Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar Although lung injury leading to acute severe respiratory failure is the most feared clinical presentation of COVID-19, cardiac complications in patients without underlying heart disease also could be a feature of the syndrome and range from 20% to 30%.2Bristow MR Zisman LS Altman NL et al.Dynamic regulation of SARS-Cov-2 binding and cell entry mechanisms in remodeled human ventricular myocardium.JACC Basic Transl Sci. 2020; 5: 871-883Crossref PubMed Scopus (33) Google Scholar, 3Guo T Fan Y Chen M et al.Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020; 5: 811-818Crossref PubMed Scopus (2450) Google Scholar, 4Zheng YY Ma YT Zhang JY et al.COVID-19 and the cardiovascular system.Nat Rev Cardiol. 2020; 17: 259-260Crossref PubMed Scopus (1972) Google Scholar Right ventricular (RV) dysfunction (RVD) seems to be particularly common (20%-39%) in the COVID-19 patient group and often remains undiagnosed.5Cao Y Zhang M Guo Y et al.The overlooked chamber in coronavirus disease 2019.ESC Heart Fail. 2020; 7: 3483-3486Crossref Scopus (4) Google Scholar,6Szekely Y Lichter Y Taieb P et al.Spectrum of cardiac manifestations in COVID-19: A systematic echocardiographic study.Circulation. 2020; 142: 342-353Crossref PubMed Scopus (342) Google Scholar RVD is present when the functional and structural variables to quantify RV function are less than the lower value of the normal range: RV fractional area change <35%, RV ejection fraction <45%, tricuspid annular plane systolic excursion <17 mm, and pulsed-Doppler S wave <9.5 cm/s. RV fractional area change has been used to classify the degree of RVD as mild (25%-35%), moderate (18%-25%), and severe (<18%).7Lang RM Badano LP Mor-Avi V et al.Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.J Am Soc Echocardiogr. 2015; 28: 1-39Abstract Full Text Full Text PDF PubMed Scopus (7133) Google Scholar,8Lang RM Bierig M Devereux RB et al.Recommendations for chamber quantification: A report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology.J Am Soc Echocardiogr. 2005; 18: 1440-1463Abstract Full Text Full Text PDF PubMed Scopus (9477) Google Scholar Like previous virulent zoonotic coronavirus outbreaks, COVID-19 may predispose patients to hemostatic abnormalities, including disseminated intravascular coagulation and thrombotic events.9Tang N Li D Wang X et al.Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.J Thromb Haemost. 2020; 18: 844-847Crossref PubMed Scopus (3520) Google Scholar,10Fan BE Chong VCL Chan SSW et al.Hematologic parameters in patients with COVID-19 infection.Am J Hematol. 2020; 95: E131-E134Crossref PubMed Scopus (420) Google Scholar The most characteristic finding of COVID-19 coagulopathy seen in nonsurvivors with COVID-19 is diffuse alveolar damage accompanied by extensive microvascular thrombosis in the lungs and other extrapulmonary sites.11Zhang T Sun LX Feng RE. Comparison of clinical and pathological features between severe acute respiratory syndrome and coronavirus disease 2019.Zhonghua Jie He Hu Xi Za Zhi. 2020; 43: 496-502PubMed Google Scholar The multisystem involvement can be explained by binding of a surface glycoprotein on SARS-CoV-2 (commonly referred to as the “spike protein”) to angiotensin-converting enzyme 2 receptors, expressed not only by vascular endothelial cells but also by epithelial cells in the lungs, heart, kidney, and intestine.12Seelhammer TG Plack D Lal A et al.COVID-19 and ECMO: An unhappy marriage of endothelial dysfunction and hemostatic derangements.J Cardiothorac Vasc Anesth. 2020; 34: 3193-3196Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar The entry of the virus contributes to inflammation and damage of the endothelial cells, causing release of plasminogen activator, which explains the high D-dimer concentration in severe cases, and prothrombotic mediators, primarily factor VIIIc and von Willebrand factor multimers. The latter mediate the consequent deposit of microvascular thrombi, especially in affected pulmonary vessels.13Roberts CM Levi M McKee M et al.COVID:19 A complex multisystem disorder.Br J Anaesth. 2020; 125: 238-242Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 14Ladikou EE Sivaloganathan H Milne KM et al.Von Willebrand factor (vWF): Marker of endothelial damage and thrombotic risk in COVID-19.Clin Med (Lond). 2020; 20: e178-e182Crossref PubMed Google Scholar, 15Yusuff H Zochios V Brodie D. Thrombosis and coagulopathy in COVID-19 patients requiring extracorporeal membrane oxygenation.ASAIO J. 2020; 66: 844-846Crossref PubMed Scopus (30) Google Scholar The simultaneous presence of vascular inflammation and coagulopathy might explain the high incidence of thromboembolic complications in patients with COVID-19. Similarly, markers of coagulopathy, such as D-dimer, have been closely associated with thrombotic complications and increased mortality.13Roberts CM Levi M McKee M et al.COVID:19 A complex multisystem disorder.Br J Anaesth. 2020; 125: 238-242Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar,16Klok FA Kruip MJH van Der Meer NJM et al.Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis.Thromb Res. 2020; 191: 148-150Abstract Full Text Full Text PDF PubMed Scopus (1207) Google Scholar, 17Voicu S Bonnin P Stépanian A et al.High prevalence of deep vein thrombosis in mechanically ventilated COVID-19 patients.J Am Coll Cardiol. 2020; 76: 480-482Crossref PubMed Scopus (66) Google Scholar, 18Helms J Tacquard C Severac F et al.High risk of thrombosis in patients with severe SARS-CoV-2 infection: A multicenter prospective cohort study.Intensive Care Med. 2020; 46: 1089-1098Crossref PubMed Scopus (1705) Google Scholar Pulmonary hemodynamic alteration created by intravascular microthrombosis and vasoconstriction secondary to hypoxia may cause acute pulmonary hypertension, resulting in suboptimal RV-pulmonary arterial (PA) coupling (a determinant of RV systolic pressure and RV stroke volume) and secondary RVD in patients with COVID-19, even at the early stages of the disease.19Sylvester JT Shimoda LA Aaronson PI et al.Hypoxic pulmonary vasoconstriction.Physiol Rev. 2012; 92: 367-520Crossref PubMed Scopus (476) Google Scholar,20Vieillard-Baron A Naeije R Haddad F et al.Diagnostic workup, etiologies and management of acute right ventricle failure: A state-of-the-art paper.Intensive Care Med. 2018; 44: 774-790Crossref PubMed Scopus (89) Google Scholar In the critically ill patient with COVID-19, adaptation of the right ventricle to increased loading conditions may be limited because of systemic hypotension and inflammation, and, as a result, RVD can progress to RV failure.19Sylvester JT Shimoda LA Aaronson PI et al.Hypoxic pulmonary vasoconstriction.Physiol Rev. 2012; 92: 367-520Crossref PubMed Scopus (476) Google Scholar,20Vieillard-Baron A Naeije R Haddad F et al.Diagnostic workup, etiologies and management of acute right ventricle failure: A state-of-the-art paper.Intensive Care Med. 2018; 44: 774-790Crossref PubMed Scopus (89) Google Scholar Early reports from China identified the presence of elevated cardiac biomarkers in a considerable proportion of patients with COVID-19.3Guo T Fan Y Chen M et al.Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020; 5: 811-818Crossref PubMed Scopus (2450) Google Scholar,21Tersalvi G Vicenzi M Calabretta D et al.Elevated troponin in patients with coronavirus disease 2019: Possible mechanisms.J Card Fail. 2020; 26: 470-475Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar Specifically, increased troponin and brain natriuretic peptide levels were shown to be correlated with elevation in D-dimer and were predictive of poor outcomes.22Arcari L Luciani M Cacciotti L et al.Incidence and determinants of high-sensitivity troponin and natriuretic peptides elevation at admission in hospitalized COVID-19 pneumonia patients.Intern Emerg Med. 2020; 15: 1467-1476Crossref PubMed Scopus (19) Google Scholar Recent studies have reported cardiac complications, such as acute coronary syndromes, cardiac arrhythmias, myocarditis, pericarditis, and heart failure, in nearly 20% of patients with COVID-19, which are associated with an increased risk of death.21Tersalvi G Vicenzi M Calabretta D et al.Elevated troponin in patients with coronavirus disease 2019: Possible mechanisms.J Card Fail. 2020; 26: 470-475Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar However, it remains unclear whether RVD in the presence of myocardial complications without microvascular or macrovascular pulmonary thrombosis is caused by RV ischemia, RV-PA uncoupling, or severe inflammation.23D'Alto M Marra AM Severino S et al.Right ventricular-arterial uncoupling independently predicts survival in COVID-19 ARDS.Crit Care. 2020; 24: 670Crossref PubMed Scopus (49) Google Scholar Although severe COVID-19 infection shares many laboratory and clinical features of severe bacterial sepsis, up to 80% of patients with COVID-19 may have no microbiologic evidence of bacteremia or fungemia.24Zhou F Yu T Du R et al.Clinical course and risk factors for mortality of adult in patients with COVID-19 in Wuhan, China: A retrospective cohort study.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (16310) Google Scholar,25Lin GL McGinley JP Drysdale SB et al.Epidemiology and immune pathogenesis of viral sepsis.Front Immunol. 2018; 9: 2147Crossref PubMed Scopus (128) Google Scholar However, added severe intensive care unit–acquired infections potentially can complicate the clinical course of COVID-19 critically ill patients, leading to multiple organ dysfunction and death. Can viral sepsis explain RVD in COVID-19 “lung-injured” patients? In theory, isolated RVD in patients with sepsis reflects endothelial dysfunction, altered vasoreactivity, acute increase in pulmonary vascular resistance despite systemic vasodilation, inability of the right ventricle to adapt to physiologic stress, and it is associated with long-term mortality.26Vallabhajosyula S Kumar M Pandompatam G et al.Prognostic impact of isolated right ventricular dysfunction in sepsis and septic shock: An 8-year historical cohort study.Ann Intensive Care. 2017; 7: 94Crossref PubMed Scopus (94) Google Scholar, 27Vallabhajosyula S Shankar A Vojjini R et al.Impact of right ventricular dysfunction on short- and long-term mortality in sepsis: A meta-analysis of 1,373 patients.Chest. 2021; (Accessed January 26. [e-pub ahead of print])https://doi.org/10.1016/j.chest.2020.12.016Abstract Full Text Full Text PDF Scopus (15) Google Scholar, 28Furian T Aguiar C Prado K et al.Ventricular dysfunction and dilation in severe sepsis and septic shock: Relation to endothelial function and mortality.J Crit Care. 2012; 27 (319.e9-e15)Crossref Scopus (105) Google Scholar This mechanistic link, however, is yet to be proven in prospective COVID-19 studies. Hypoxemia and/or hypercapnia with or without acidemia in COVID-19 patients with severe acute respiratory failure may cause or exacerbate pulmonary vasoconstriction, resulting in increased (even modest) RV afterload, RV-PA uncoupling, and RVD, with potential for reduced cardiovascular performance.23D'Alto M Marra AM Severino S et al.Right ventricular-arterial uncoupling independently predicts survival in COVID-19 ARDS.Crit Care. 2020; 24: 670Crossref PubMed Scopus (49) Google Scholar,29Morimont P Lambermont B Ghuysen A et al.Effective arterial elastance as an index of pulmonary vascular load.Am J Physiol Cir Physiol. 2008; 294: 2736-2742Crossref PubMed Scopus (60) Google Scholar,30Morimont P Lambermont B Desaive T et al.Right ventriculoarterial coupling in acute respiratory distress syndrome (ARDS) and expected benefits of CO2 removal therapy [abstract].J Crit Care. 2013; 28: e30Crossref Google Scholar “Injurious” invasive ventilation in COVID-19 patients with refractory hypoxemia and/or hypercapnia with extremes of tidal volume, high transpulmonary (alveolar plus pleural) pressure and driving (plateau pressure – total positive end-expiratory pressure [PEEP]) pressures, and excessive PEEP causing non-physiologic lung “stress” and “strain” and alveolar overdistention may result in alveolar vessel collapse and an acute increase in PVR, leading to RVD.31Chiumello D Chidini G Calderini E et al.Respiratory mechanics and lung stress/strain in children with acute respiratory distress syndrome.Ann Intensive Care. 2016; 6: 11Crossref PubMed Scopus (24) Google Scholar, 32Puybasset L Cluzel P Gusman P et al.Regional distribution of gas and tissue in acute respiratory distress syndrome. I. Consequences for lung morphology: CT Scan ARDS Study Group.Intensive Care Med. 2000; 26: 857-869Crossref PubMed Scopus (224) Google Scholar, 33Schmitt JM Vieillard-Baron A Augarde R et al.Positive end-expiratory pressure titration in acute respiratory distress syndrome patients: Impact on right ventricular outflow impedance evaluated by pulmonary artery Doppler flow velocity measurements.Crit Care Med. 2001; 29: 1154-1158Crossref PubMed Scopus (130) Google Scholar In patients with acute respiratory distress syndrome (ARDS), the following one clinical and three physiologic parameters have been identified as statistically significant predictors of RVD: (1) lower respiratory tract infection as a cause of pulmonary ARDS, (2) ratio of arterial oxygen partial pressure to fractional inspired oxygen ratio <150 mmHg; (3) partial pressure of carbon dioxide ≥48 mmHg, and (4) driving pressure ≥18 cmH2O.34Mekontso Dessap A Boissier F Charron C et al.Acute cor pulmonale during protective ventilation for acute respiratory distress syndrome: Prevalence, predictors, and clinical impact.Intensive Care Med. 2016; 42: 862-870Crossref PubMed Scopus (261) Google Scholar A RVD risk score > 2 is associated with a 19% incidence of RVD (followed by 34% and 74% for risk scores of 3 and 4, respectively). Although this scoring system makes physiologicasense, it has not been validated in COVID-19 patient populations.34Mekontso Dessap A Boissier F Charron C et al.Acute cor pulmonale during protective ventilation for acute respiratory distress syndrome: Prevalence, predictors, and clinical impact.Intensive Care Med. 2016; 42: 862-870Crossref PubMed Scopus (261) Google Scholar However, it highlights the importance of “RV-protective” ventilation strategies in patients with “injured” lungs and the need for early echocardiography. Although the diagnostic approach to suspected RVD should be multimodal, echocardiography remains the cornerstone bedside tool to assess cardiac function and pathology. A large prospective echocardiography study of COVID-19 patients showed that even though RV dilation with or without dysfunction was the most common abnormality (39%), followed by left ventricular (LV) diastolic dysfunction (16%), LV systolic impairment was uncommon. Twenty percent of patients in that cohort experienced a deterioration of the RV parameters, probably secondary to increased pulmonary vascular pressure contributing to increased RV afterload.6Szekely Y Lichter Y Taieb P et al.Spectrum of cardiac manifestations in COVID-19: A systematic echocardiographic study.Circulation. 2020; 142: 342-353Crossref PubMed Scopus (342) Google Scholar Similar results were demonstrated in a more recent retrospective echocardiography study that evaluated 110 patients.35Argulian E Sud K Vogel B et al.Right ventricular dilation in hospitalized patients with COVID-19 infection.JACC Cardiovasc Imaging. 2020; 13: 2459-2461Crossref PubMed Scopus (138) Google Scholar In that cohort, although LV function and size were normal, RV dilation was present in 31% of patients. More than half (66%) of the latter group had RV hypokinesia, and 21% had moderate or severe tricuspid regurgitation.35Argulian E Sud K Vogel B et al.Right ventricular dilation in hospitalized patients with COVID-19 infection.JACC Cardiovasc Imaging. 2020; 13: 2459-2461Crossref PubMed Scopus (138) Google Scholar In another small retrospective study that included invasively ventilated patients with COVID-19, 42.2% of whom received venovenous extracorporeal membrane oxygenation (VV-ECMO), found radial RV impairment with sparing of longitudinal function to be the dominant echocardiographic phenotype.36Bleakley C Singh S Garfield B et al.Right ventricular dysfunction in critically ill COVID-19 ARDS.Int J Cardiol. 2021; (Accessed January 26. [e-pub ahead of print])https://doi.org/10.1016/j.ijcard.2020.11.043Abstract Full Text Full Text PDF Scopus (62) Google Scholar Two-dimensional speckle-tracking echocardiography also has been used to evaluate RV function in COVID-19 patients, and, interestingly, RV longitudinal strain was identified as a powerful predictor of mortality.37Li Y Li H Zhu S et al.Prognostic value of right ventricular longitudinal strain in patients with COVID-19.JACC Cardiovasc Imaging. 2020; 13: 2287-2299Crossref PubMed Scopus (259) Google Scholar There is a clear need for large-scale prospective echocardiography data in COVID-19 patients at risk of RVD in order to identify early markers of dysfunction, characterize the natural history of RVD, and monitor response to therapies. The principles of RVD management in patients with COVID-19 should follow standard general RVD management, including optimization of RV preload, increase in RV contractility, and reductions in pulmonary vascular resistance and RV afterload, leading to optimal RV-PA coupling.38Price LC Wort SJ Finney SJ et al.Pulmonary vascular and right ventricular dysfunction in adult critical care: Current and emerging options for management: A systematic literature review.Crit Care. 2010; 14: R169Crossref PubMed Scopus (235) Google Scholar Importantly, “RV-protective” strategies should be implemented early, and rescue-specific therapies, such as extracorporeal membrane oxygenation (ECMO), should be considered in refractory selected cases in centers with expertise in the use of ECMO for cardiorespiratory support.38Price LC Wort SJ Finney SJ et al.Pulmonary vascular and right ventricular dysfunction in adult critical care: Current and emerging options for management: A systematic literature review.Crit Care. 2010; 14: R169Crossref PubMed Scopus (235) Google Scholar The debate on how to ventilate patients with COVID-19 is still ongoing. A number of inter-related editorials have suggested that a subset of patients with COVID-19–induced ARDS has an unusual physiologic phenotype (“L-type” phenotype), with low elastance, low lung weight, and low recruitability. Based on these physiologic results, the authors suggested that high levels of PEEP may be detrimental and that prone positioning is unlikely to be beneficial.39Gattinoni L Chiumello D Caironi P et al.COVID-19 pneumonia: Different respiratory treatments for different phenotypes?.Intensive Care Med. 2020; 46: 1099-1102Crossref PubMed Scopus (1059) Google Scholar A recent study suggested that patients with early severe COVID-19 pneumonitis did not differ in their response to high PEEP and prone positioning from classic ARDS and, therefore, should be ventilated according to established ARDS principles and regimens.40Mittermaier M Philipp Pickerodt P Kurth F et al.Evaluation of PEEP and prone positioning in early COVID-19 ARDS.EClinicalMedicine. 2020; 28100579Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar Protective ventilation in ARDS reduces RVD and, specifically, a plateau pressure <26-to-28 cmH2O is associated with lower incidence of RVD. Despite the possible presence of distinct phenotypes of COVID-19 patients with severe respiratory failure, currently there is a lack of data relating to the best “RV-protective” ventilatory strategies.41Zhang J Whebell SF Sanderson B et al.Phenotypes of severe COVID-19 ARDS receiving extracorporeal membrane oxygenation.Br J Anaesth. 2021; (Accessed January 26. [e-pub ahead of print])https://doi.org/10.1016/j.bja.2020.12.023Abstract Full Text Full Text PDF Scopus (10) Google Scholar It would stand to reason that in patients with or at risk of RVD, an “RV-protective” ventilatory strategy should comprise the following42Paternot A Repesse X Vieillard-Baron A. Rationale and description of right ventricle-protective ventilation in ARDS.Respir Care. 2016; 61: 1391-1396Crossref PubMed Scopus (51) Google Scholar, 43Sahetya SK Hager DN Stephens SR et al.PEEP titration to minimize driving pressure in subjects with ARDS: A prospective physiological study.Resp Care. 2020; 65: 58-59Google Scholar, 44Pelosi P Ball L. Should we titrate ventilation based on driving pressure? Maybe not in the way we would expect.Ann Transl Med. 2018; 6: 389Crossref PubMed Google Scholar: (1) low “stress” ventilation (plateau pressure <27 cmH2O and driving pressure <18 cmH2O); (2) partial pressure of carbon dioxide <48 mmHg; (3) arterial oxygen partial pressure-to-fractional inspired oxygen ratio >150 mmHg; (4) consideration of driving pressure–guided PEEP titration (aiming for a PEEP range associated with lowest driving pressure); and (5) consideration of echocardiography use (transthoracic or transesophageal) during PEEP titration to monitor RV loading conditions.42Paternot A Repesse X Vieillard-Baron A. Rationale and description of right ventricle-protective ventilation in ARDS.Respir Care. 2016; 61: 1391-1396Crossref PubMed Scopus (51) Google Scholar, 43Sahetya SK Hager DN Stephens SR et al.PEEP titration to minimize driving pressure in subjects with ARDS: A prospective physiological study.Resp Care. 2020; 65: 58-59Google Scholar, 44Pelosi P Ball L. Should we titrate ventilation based on driving pressure? Maybe not in the way we would expect.Ann Transl Med. 2018; 6: 389Crossref PubMed Google Scholar Prone ventilation has the potential to recruit collapsed alveoli and reduce tidal hyperinflation, alveolar cyclic recruitment and de-recruitment, and ventilator-induced lung injury known to exacerbate RVD.45Katira BH Giesinger RE Engelberts D et al.Adverse heart-lung interactions in ventilator-induced lung injury.Am J Respir Crit Care Med. 2017; 196: 1411-1421Crossref PubMed Scopus (39) Google Scholar, 46Albert RK Keniston A Baboi L et al.Prone position-induced improvement in gas exchange does not predict improved survival in the acute respiratory distress syndrome.Am J Respir Crit Care Med. 2014; 189: 494-496Crossref PubMed Scopus (112) Google Scholar, 47Guerin C Baboi L Richard JC. Mechanisms of the effects of prone positioning in acute respiratory distress syndrome.Intensive Care Med. 2014; 40: 1634-1642Crossref PubMed Scopus (65) Google Scholar Correction of hypoxemia and hypercapnia reduces pulmonary vasoconstriction, thus unloading the right ventricle in ARDS.45Katira BH Giesinger RE Engelberts D et al.Adverse heart-lung interactions in ventilator-induced lung injury.Am J Respir Crit Care Med. 2017; 196: 1411-1421Crossref PubMed Scopus (39) Google Scholar, 46Albert RK Keniston A Baboi L et al.Prone position-induced improvement in gas exchange does not predict improved survival in the acute respiratory distress syndrome.Am J Respir Crit Care Med. 2014; 189: 494-496Crossref PubMed Scopus (112) Google Scholar, 47Guerin C Baboi L Richard JC. Mechanisms of the effects of prone positioning in acute respiratory distress syndrome.Intensive Care Med. 2014; 40: 1634-1642Crossref PubMed Scopus (65) Google Scholar, 48Zochios V Parhar K Vieillard-Baron A. Protecting the right ventricle in ARDS: The role of prone ventilation.J Cardiothorac Vasc Anesth. 2018; 32: 2248-2251Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar So far, no data are available on the effects of prone positioning on RVD (assessed with echocardiography) and pulmonary circulation in COVID-19 patients.48Zochios V Parhar K Vieillard-Baron A. Protecting the right ventricle in ARDS: The role of prone ventilation.J Cardiothorac Vasc Anesth. 2018; 32: 2248-2251Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar Given the “RV-protective” effect of prone positioning, it could be hypothesized that COVID-19-ventilated patients with RVD potentially would benefit from early prone positioning, irrespective of the degree of hypoxemia; however, this notion needs to be tested in prospective studies. Although current evidence does not support the routine use of pulmonary vasodilators and, in particular, inhaled nitric oxide (iNO) in patients with ARDS, because it does not confer survival benefit, its use as a rescue therapy has been recommended by recently published guidelines on the management of acutely ill COVID-19 patients with severe respiratory failure.49Heuts S Ubben JF Banks-Gonzales V et al.Nitric oxide ventilation improves recirculation and right ventricular function during veno-venous extracorporeal membrane oxygenation in a COVID-19 patient [e-pub ahead of print].J Cardiothorac Vasc Anesth. 2021; (Accessed January 26)https://doi.org/10.1053/j.jvca.2020.09.137Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Pulmonary vasodilators theoretically could be beneficial in selected patients through an improvement in ventilation-perfusion matching through their vasodilatory effect and subsequent reductions in pulmonary arterial pressure and RV afterload.50Kobayashi J Murata I. Nitric oxide inhalation as an interventional rescue therapy for COVID-19-induced acute respiratory distress syndrome.Ann Intensive Care. 2020; 10: 61Crossref PubMed Scopus (33) Google Scholar In a recent case report, iNO was administered to a patient with RVD and COVID-19 pneumonitis requiring VV-ECMO to improve the recirculation fraction by reducing pulmonary hypertension, RV afterload, and tricuspid regurgitation.49Heuts S Ubben JF Banks-Gonzales V et al.Nitric oxide ventilation improves recirculation and right ventricular function during veno-venous extracorporeal membrane oxygenation in a COVID-19 patient [e-pub ahead of print].J Cardiothorac Vasc Anesth. 2021; (Accessed January 26)https://doi.org/10.1053/j.jvca.2020.09.137Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar In that patient, iNO successfully offloaded a pressure-overloaded right ventricle and reduced the severity of tricuspid regurgitation and recirculation 12 hours after initiation of therapy.49Heuts S Ubben JF Banks-Gonzales V et al.Nitric oxide ventilation improves recirculation and right ventricular function during veno-venous extracorporeal membrane oxygenation in a COVID-19 patient [e-pub ahead of print].J Cardiothorac Vasc Anesth. 2021; (Accessed January 26)https://doi.org/10.1053/j.jvca.2020.09.137Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The role of other pulmonary vasodilators, such as inhaled prostanoids and analogs (prostacyclin and iloprost, respectively) and phosphodiesterase-5 inhibitors (sildenafil) in COVID-19, is unknown and should be used with caution given the lack of data and potential for worsening of hypoxemia and shunt fraction.38Price LC Wort SJ Finney SJ et al.Pulmonary vascular and right ventricular dysfunction in adult critical care: Current and emerging options for management: A systematic literature review.Crit Care. 2010; 14: R169Crossref PubMed Scopus (235) Google Scholar,51Blanch L Albaiceta GM. Sildenafil for pulmonary hypertension in ARDS: A new pleasant effect?.Intensive Care Med. 2010; 36: 729-731Crossref PubMed Scopus (6) Google Scholar Future research should focus on the potential benefit of early use of pulmonary vasodilators and inodilators (eg, phosphodiesterase-3 inhibitors) in critically ill COVID-19 patients with RVD confirmed with echocardiography or right-sided heart catheterization. VV-ECMO improves hypoxemia and reduces hypercapnia, facilitating a “lung-rest” strategy, with tight control of driving pressure, and, ultimately, can decrease pulmonary vasoconstriction and RV afterload.52Schmidt M Hajage D Lebreton G et al.Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: A retrospective cohort study.Lancet Respir Med. 2020; 8: 1121-1131Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar Contrary to preliminary results from early studies that indicated dismal outcomes in COVID-19 patients supported with VV-ECMO, recent studies have demonstrated an estimated <40% probability of 60-day mortality, similar to those treated with ECMO in the ECMO to Rescue Severe Lung Injury in Severe ARDS (EOLIA) trial.52Schmidt M Hajage D Lebreton G et al.Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: A retrospective cohort study.Lancet Respir Med. 2020; 8: 1121-1131Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar,53Barbaro RP MacLaren G Boonstra PS et al.Extracorporeal membrane oxygenation support in COVID-19: An international cohort study of the Extracorporeal Life Support Organization registry.Lancet. 2020; 396: 1071-1078Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar Because of the significant incidences of RV dilation and dysfunction in severe COVID-19, traditional VV-ECMO may not be effective, and a change in strategy to support the right ventricle may be required. This may be achieved by either venoarterial (VA), VV, veno-venous arterial (V-VA), or venopulmonary arterial ECMO.53Barbaro RP MacLaren G Boonstra PS et al.Extracorporeal membrane oxygenation support in COVID-19: An international cohort study of the Extracorporeal Life Support Organization registry.Lancet. 2020; 396: 1071-1078Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar, 54Lorusso R Raffa GM Heuts S et al.Pulmonary artery cannulation to enhance extracorporeal membrane oxygenation management in acute cardiac failure.Interact Cardiovasc Thorac Surg. 2020; 30: 215-222PubMed Google Scholar, 55Mustafa AK Alexander PJ Joshi DJ et al.Extracorporeal membrane oxygenation for patients with COVID-19 in severe respiratory failure.JAMA Surg. 2020; 155: 990-992Crossref PubMed Scopus (119) Google Scholar The conventional VA-ECMO mode has obvious hemodynamic advantages (RV unloading, peripheral oxygenation, temperature control) but carries several disadvantages. For example, patients may present with an increased LV afterload, leading to insufficient unloading and requiring an additional LV venting device, especially if there is coexisting LV impairment. A recent observational cohort study of the Extracorporeal Life Support Organization database demonstrated increased mortality associated with the use of VA-ECMO in patients with COVID-19.53Barbaro RP MacLaren G Boonstra PS et al.Extracorporeal membrane oxygenation support in COVID-19: An international cohort study of the Extracorporeal Life Support Organization registry.Lancet. 2020; 396: 1071-1078Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar Cardiac ECMO, however, was used in a small proportion of patients only (3%), and this may suggest that it was provided as a salvage therapy to patients at the extreme end of disease severity. V-VA-ECMO has the advantage of providing respiratory support and biventricular cardiac support. The right ventricle is decompressed, and the RV afterload is reduced because of oxygenated and decarboxylated blood flowing through the pulmonary circulation. Currently, there is a paucity of data to suggest that this strategy is beneficial in COVID-19 patients with RVD. A direct PA cannulation approach accessed either surgically or percutaneously to facilitate venopulmonary arterial ECMO has been suggested to unload and support the failing right ventricle while providing respiratory support.54Lorusso R Raffa GM Heuts S et al.Pulmonary artery cannulation to enhance extracorporeal membrane oxygenation management in acute cardiac failure.Interact Cardiovasc Thorac Surg. 2020; 30: 215-222PubMed Google Scholar A recent study documented the use of a single-access, dual-stage cannula in a group of patients with COVID-19 requiring VV-ECMO support. This approach demonstrated multiple advantages, including direct pulmonary artery flow, negligible recirculation, and early extubation and mobilization during ECMO support, with a survival rate of 73%.55Mustafa AK Alexander PJ Joshi DJ et al.Extracorporeal membrane oxygenation for patients with COVID-19 in severe respiratory failure.JAMA Surg. 2020; 155: 990-992Crossref PubMed Scopus (119) Google Scholar This might be the way forward to support the right ventricle in COVID-19 patients with RVD and refractory severe respiratory failure requiring extracorporeal support and in whom pharmacologic and ventilatory “RV-protective” measures fail. However, this was a single-center study, and, therefore, larger, multicenter trials would be required to demonstrate that these outcomes can be replicated. In addition, strategies to simplify and improve access to safe percutaneous PA cannulation would facilitate more widespread use of this technique. The right ventricle is intricately connected to the clinical syndrome resulting from SARS-CoV-2 infection. In less-severe states, the right ventricle is able to compensate to ensure normal physiology; however, in decompensated states, this leads to severe manifestations of the disease. As a result, RVD is associated with worse outcomes in the context of COVID-19.35Argulian E Sud K Vogel B et al.Right ventricular dilation in hospitalized patients with COVID-19 infection.JACC Cardiovasc Imaging. 2020; 13: 2459-2461Crossref PubMed Scopus (138) Google Scholar,56Moody WE Mahmoud-Elsayed HM Senior J et al.Impact of right ventricular dysfunction on mortality in patients hospitalized with COVID-19 according to race.CJC Open. 2020; 3: 91-100Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar This remains very difficult to manage, and future research should be directed at ways of protecting the right ventricle before dysfunction develops, monitoring of RVD and response to treatment, echocardiographic and hemodynamic RVD phenotyping, and effective management of established RV failure in patients with severe COVID-19.