Protecting the Injured Right Ventricle in COVID-19 Acute Respiratory Distress Syndrome: Can Clinicians Personalize Interventions and Reduce Mortality?

Abstract

THE ABNORMAL INTERACTION between the right ventricle (RV) and pulmonary vasculature in various disease states is associated with adverse clinical outcomes.1Mekontso-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 Impaired RV physiology in acute respiratory distress syndrome (ARDS) is a major determinant of mortality.1Mekontso-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 Right ventricular and pulmonary vascular dysfunction are particularly prevalent in patients with ARDS secondary to coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 infection.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 In this issue of the Journal of Cardiothoracic and Vascular Anesthesia, Paternoster et al5Paternoster G Bertini P Innelli P et al.Right ventricular dysfunction in patients with COVID-19: A systematic review and meta-analysis [e-pub ahead of print].J Cardiothorac Vasc Anesth. 2021; (Published April 11th 2021)https://doi.org/10.1053/j.jvca.2021.04.008Abstract Full Text Full Text PDF Scopus (21) Google Scholar sought to determine if echocardiographic evidence of deranged RV and/or pulmonary vascular physiology is associated with mortality in patients with COVID-19 ARDS. The authors performed a systematic review and meta-analysis of nine high-quality observational studies (n = 1,450), reporting on mortality in patients with COVID-19 with acute respiratory failure and echocardiographic evidence of RV dysfunction and/or RV dilatation and/or pulmonary arterial hypertension (PAH).5Paternoster G Bertini P Innelli P et al.Right ventricular dysfunction in patients with COVID-19: A systematic review and meta-analysis [e-pub ahead of print].J Cardiothorac Vasc Anesth. 2021; (Published April 11th 2021)https://doi.org/10.1053/j.jvca.2021.04.008Abstract Full Text Full Text PDF Scopus (21) Google Scholar Right ventricular dysfunction and dilatation were defined according to the American Society of Echocardiography and European Association of Cardiovascular Imaging guidelines, and PAH was defined using the European Society of Cardiology and European Respiratory Society criteria.6Lang 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 (1-39.e14)Abstract Full Text Full Text PDF Scopus (7133) Google Scholar,7Galiè N Humbert M Vachiery JL et al.2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).Eur Heart J. 2016; 37: 67-119Crossref PubMed Scopus (4102) Google Scholar Abnormal function and/or dimensions of the RV, as well as PAH, were found to be major determinants of mortality.5Paternoster G Bertini P Innelli P et al.Right ventricular dysfunction in patients with COVID-19: A systematic review and meta-analysis [e-pub ahead of print].J Cardiothorac Vasc Anesth. 2021; (Published April 11th 2021)https://doi.org/10.1053/j.jvca.2021.04.008Abstract Full Text Full Text PDF Scopus (21) Google Scholar There is clearly an association between abnormal RV and pulmonary vascular physiology and adverse outcomes in patients with COVID-19 with acute respiratory failure,5Paternoster G Bertini P Innelli P et al.Right ventricular dysfunction in patients with COVID-19: A systematic review and meta-analysis [e-pub ahead of print].J Cardiothorac Vasc Anesth. 2021; (Published April 11th 2021)https://doi.org/10.1053/j.jvca.2021.04.008Abstract Full Text Full Text PDF Scopus (21) Google Scholar but what are the mechanistic links and how should one define abnormal RV/PA physiology to capture and treat pathologies that lead to mortality and potentially identify targets of therapeutic interventions and RV phenotyping? Understanding RV biomechanics and, in particular, the relationship between the RV and PA is key to identifying different phases of RV dysfunction leading to RV failure and death. RV-PA coupling is determined by end-systolic and pulmonary arterial elastance (Ees and Ea, representing RV contractility and afterload, respectively).8Vonk Noordegraaf A Westerhof BE Westerhof N. The relationship between the right ventricle and its load in pulmonary hypertension.Am Coll Cardiol. 2017; 69: 236-243Crossref PubMed Scopus (381) Google Scholar,9Naeije R Brimioulle S Dewachter L. Biomechanics of the right ventricle in health and disease (2013 Grover Conference series).Pulm Circ. 2014; 4: 395-406Crossref PubMed Scopus (74) Google Scholar In acute PAH states, RV contractility increases to maintain RV-PA coupling and the Ees:Ea ratio between 1.5-to-2 (homeometric mechanism).8Vonk Noordegraaf A Westerhof BE Westerhof N. The relationship between the right ventricle and its load in pulmonary hypertension.Am Coll Cardiol. 2017; 69: 236-243Crossref PubMed Scopus (381) Google Scholar,9Naeije R Brimioulle S Dewachter L. Biomechanics of the right ventricle in health and disease (2013 Grover Conference series).Pulm Circ. 2014; 4: 395-406Crossref PubMed Scopus (74) Google Scholar In patients with COVID-19 ARDS, the presence of systemic inflammation, microvascular thrombosis, hypercapnia, hypoxemia, and acidemia, as well as high driving pressure and mechanical power in those requiring invasive ventilation, result in worsening PAH, reduction in the Ees:Ea ratio (<1), and RV dilatation to maintain flow (heterometric adaptation).8Vonk Noordegraaf A Westerhof BE Westerhof N. The relationship between the right ventricle and its load in pulmonary hypertension.Am Coll Cardiol. 2017; 69: 236-243Crossref PubMed Scopus (381) Google Scholar,9Naeije R Brimioulle S Dewachter L. Biomechanics of the right ventricle in health and disease (2013 Grover Conference series).Pulm Circ. 2014; 4: 395-406Crossref PubMed Scopus (74) Google Scholar As Paternoster et al5Paternoster G Bertini P Innelli P et al.Right ventricular dysfunction in patients with COVID-19: A systematic review and meta-analysis [e-pub ahead of print].J Cardiothorac Vasc Anesth. 2021; (Published April 11th 2021)https://doi.org/10.1053/j.jvca.2021.04.008Abstract Full Text Full Text PDF Scopus (21) Google Scholar stated in their systematic review, there is also a possibility that in patients with COVID-19 with severe disease, high levels of proinflammatory cytokines exert a direct negative inotropic effect on the RV. The resultant RV-PA uncoupling leads to the inability of the RV to meet the flow demands without excessive use of the Frank-Starling mechanism, and systemic congestion ensues.8Vonk Noordegraaf A Westerhof BE Westerhof N. The relationship between the right ventricle and its load in pulmonary hypertension.Am Coll Cardiol. 2017; 69: 236-243Crossref PubMed Scopus (381) Google Scholar, 9Naeije R Brimioulle S Dewachter L. Biomechanics of the right ventricle in health and disease (2013 Grover Conference series).Pulm Circ. 2014; 4: 395-406Crossref PubMed Scopus (74) Google Scholar, 10Vieillard-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 It has become apparent that both loading conditions and direct insult to the RV can adversely affect outcomes. In this editorial, the authors are using “RV injury” as an umbrella term that encompasses one or more of the following echocardiographic RV phenotypes: RV dilatation, RV dysfunction, Acute Cor Pulmonale (ACP), and Acute PAH. This potentially could enable clinicians to better characterize the spectrum of RV pathology, individualize therapies, and systematically protect the RV; however, this notion must be confirmed and validated in prospective studies. In the meta-analysis by Paternoster et al, approximately 50% of patients were invasively ventilated.5Paternoster G Bertini P Innelli P et al.Right ventricular dysfunction in patients with COVID-19: A systematic review and meta-analysis [e-pub ahead of print].J Cardiothorac Vasc Anesth. 2021; (Published April 11th 2021)https://doi.org/10.1053/j.jvca.2021.04.008Abstract Full Text Full Text PDF Scopus (21) Google Scholar Data on utilization rates of prone ventilation; noninvasive ventilation; continuous positive airway pressure or high-flow nasal oxygen, including duration and level of support; and failure rates were not available. Data relating to the use of extracorporeal membrane oxygenation (ECMO), ventilatory parameters, and pulmonary mechanics, such as driving pressure, positive end-expiratory pressure, and mechanical power (known to adversely affect RV-PA coupling when they exceed certain thresholds), also were not provided.1Mekontso-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,5Paternoster G Bertini P Innelli P et al.Right ventricular dysfunction in patients with COVID-19: A systematic review and meta-analysis [e-pub ahead of print].J Cardiothorac Vasc Anesth. 2021; (Published April 11th 2021)https://doi.org/10.1053/j.jvca.2021.04.008Abstract Full Text Full Text PDF Scopus (21) Google Scholar It would be important to explore mechanisms of refractory RV injury in COVID-19 despite “RV-protective” measures (eg. veno-venous ECMO, low stress and/or strain-invasive ventilation, prone ventilation), and whether there is a link between noninvasive respiratory support and potential patient self-inflicted lung injury and ‘RV-injury’ in spontaneously breathing patients with COVID-19.11Gattinoni L Marini JJ Busana M et al.Spontaneous breathing, transpulmonary pressure and mathematical trickery.Ann Intensive Care. 2020; 10: 88Crossref PubMed Scopus (22) Google Scholar Given the effect COVID-19 ARDS has been shown to have on the pulmonary vascular physiology, it is fundamental that signs of early RV injury are identified and protective strategies are introduced with the goal of individualizing therapies and preventing RV failure. Two-dimensional echocardiography remains the most widely used tool to assess RV function in critical illness.12Hockstein MA Haycock K Wiepking M et al.Transthoracic right heart echocardiography for the intensivist [e-pub ahead of print].J Intensive Care Med. 2021; (Published April 15th 2021)https://doi.org/10.1177/08850666211003475Crossref PubMed Scopus (5) Google Scholar It is essential in assessing the RV geometrics, myocardial function, and hemodynamic data and can reliably identify RV chamber dilatation and evidence of impaired systolic function. Conventional parameters, such as tricuspid annular plane systolic excursion, tissue Doppler imaging-derived systolic velocity, and fractional area change (FAC) all have data to support their use in RV systolic assessment.6Lang 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 (1-39.e14)Abstract Full Text Full Text PDF Scopus (7133) Google Scholar Right ventricular diastolic dysfunction is common in patients with ARDS in the absence of RV dilatation; it is, therefore, important to consider that increases in pulmonary vascular resistance will also adversely affect diastolic function, possibly earlier than that demonstrated on systolic assessment.13Tavazzi G Bergsland N Alcada J et al.Early signs of right ventricular systolic and diastolic dysfunction in acute severe respiratory failure: The importance of diastolic restrictive pattern.Eur Heart J Acute Cardiovasc Care. 2020; 9: 649-656Crossref PubMed Google Scholar Assessment of RV diastolic function (morphologic assessment of the inferior vena cava, Doppler interrogation of tricuspid inflow, tissue Doppler at the lateral tricuspid annulus, and pulsed-wave Doppler sampling of hepatic vein flow) should be considered and included in future clinical prediction models determining RV injury risk in ARDS.14Zaidi A Knight DS Augustine DX et al.Echocardiographic assessment of the right heart in adults: A practical guideline from the British Society of Echocardiography.Echo Res Pract. 2020; 7 (27): G19-G41Crossref PubMed Scopus (64) Google Scholar A recent observational study exploring myocardial phenotypes and clinical associations of RV dysfunction in COVID-19 ARDS showed that severe COVID-19 ARDS is associated with a specific phenotype characterized by radial impairment with sparing of longitudinal function.15Bleakley C Singh S Garfield B et al.Right ventricular dysfunction in critically ill COVID-19 ARDS.Int J Cardiol. 2021; 327: 251-258Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Longitudinal parameters, such as tricuspid annular plane systolic excursion, RV systolic velocity, and RV free wall strain, identified significantly fewer patients with RV dysfunction than when used with RV velocity time integral and RV FAC, an important reminder that a complete dataset, including both static and dynamic data, is needed to fully evaluate the RV in this subset of patients.15Bleakley C Singh S Garfield B et al.Right ventricular dysfunction in critically ill COVID-19 ARDS.Int J Cardiol. 2021; 327: 251-258Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar In the same study, RV-PA coupling expressed as an FAC:RV systolic pressure ratio was found to provide additional information above standard RV performance measures.15Bleakley C Singh S Garfield B et al.Right ventricular dysfunction in critically ill COVID-19 ARDS.Int J Cardiol. 2021; 327: 251-258Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar An important consideration is the frequency when echocardiographic assessment is performed. Measurements derived from a single echocardiogram provide only a snapshot of the RV size and function. It is of the opinion of the authors that either serial transthoracic or transesophageal (TEE) echocardiograms, or ideally continuous monitoring using TEE, are required to evaluate RV health through critical illness and the effects that preload, afterload, and contractility augmentation have on its functionality. Continuous noninvasive RV monitoring potentially can provide constant insight into the health of the RV and may identify patients in whom the RV is deteriorating before RV systolic dysfunction occurs. One real-time technology that is of particular interest is the disposable, miniaturized TEE that remains in the patient for up to 72 hours without major complications.16Fletcher N Geisen M Meeran H et al.Initial clinical experience with a miniaturized transesophageal echocardiography probe in a cardiac intensive care unit.J Cardiothorac Vasc Anesth. 2015; 29: 582-587Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar This would allow the clinical team to observe the effects of interventions to improve the RV preload, contractility, and afterload continuously and in real-time.16Fletcher N Geisen M Meeran H et al.Initial clinical experience with a miniaturized transesophageal echocardiography probe in a cardiac intensive care unit.J Cardiothorac Vasc Anesth. 2015; 29: 582-587Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar,17Cioccari L Baur HR Berger D et al.Hemodynamic assessment of critically ill patients using a miniaturized transesophageal echocardiography probe.Crit Care. 2013; 17: R121Crossref PubMed Scopus (33) Google Scholar However, the major disadvantage to this technology is that it only provides a monoplane image, with no capability to perform a Doppler (color, spectral) assessment of flow. In addition, there currently is a lack of large-scale data to support its use in ARDS patient populations with RV injury. Advanced technology PA catheters (Edwards Lifesciences, Irvine, CA) or PA catheters with an RV port (Paceport, Edwards Lifescience, Irvine, CA) enable invasive dynamic assessment of RV function (Fig 1).18Denault AY Chaput M Couture P et al.Dynamic right ventricular outflow tract obstruction in cardiac surgery.J Thorac Cardiovasc Surg. 2006; 132: 43-49Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Real-time invasive monitoring of preload (RV end-diastolic volume index, PA wedge pressure, PA diastolic pressure), contractility (RV ejection fraction, RV stroke work index), and afterload (pulmonary vascular resistance [PVR]) RV indices may detect early RV stress as it occurs, therefore allowing risk stratification and diagnostic and therapeutic decisions to be made earlier in the patient's clinical course.18Denault AY Chaput M Couture P et al.Dynamic right ventricular outflow tract obstruction in cardiac surgery.J Thorac Cardiovasc Surg. 2006; 132: 43-49Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Although the aforementioned diagnostic approaches make physiologic sense, the assumption that they may confer a benefit and guide appropriate interventions must be confirmed in rigorous and large prospective studies. The injured RV is supported best by strategies that optimize myocardial perfusion and reduce RV afterload. The goal is to reduce RV work and halt any adaptation mechanisms that may be occurring in the context of ARDS. Unfortunately, the perfect therapy to achieve these aims does not exist; hence, a combination of therapies often is indicated. In patients with severe COVID-19, the intense inflammatory response may be associated with significant systemic vasodilatation. The reduction in perfusion pressure, combined with dilatation of the RV, result in reduced myocardial perfusion. Vasopressors, such as norepinephrine and vasopressin, theoretically would improve myocardial perfusion pressure, but they have no role in reducing the PVR and may even increase it.19Kwak YL Lee CS Park YH et al.The effect of phenylephrine and norepinephrine in patients with chronic pulmonary hypertension.Anaesthesia. 2002; 57: 9-14Crossref PubMed Scopus (108) Google Scholar, 20Rana M Yusuff H Zochios V. The right ventricle during selective lung ventilation for thoracic surgery.J Cardiothorac Vasc Anesth. 2019; 33: 2007-2016Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 21Leather HA Segers P Berends N et al.Effects of vasopressin on right ventricular function in an experimental model of acute pulmonary hypertension.Crit Care Med. 2002; 30: 2548-2552Crossref PubMed Scopus (83) Google Scholar Norepinephrine improves RV-PA coupling; however, at high doses, this effect is diminished.19Kwak YL Lee CS Park YH et al.The effect of phenylephrine and norepinephrine in patients with chronic pulmonary hypertension.Anaesthesia. 2002; 57: 9-14Crossref PubMed Scopus (108) Google Scholar, 20Rana M Yusuff H Zochios V. The right ventricle during selective lung ventilation for thoracic surgery.J Cardiothorac Vasc Anesth. 2019; 33: 2007-2016Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 21Leather HA Segers P Berends N et al.Effects of vasopressin on right ventricular function in an experimental model of acute pulmonary hypertension.Crit Care Med. 2002; 30: 2548-2552Crossref PubMed Scopus (83) Google Scholar In very severe vasoplegic states, norepinephrine and vasopressin in combination would act synergistically to improve perfusion pressure. Vasopressin at low doses (0.01-0.03 U/min) may reduce PVR through endothelial nitric oxide release, but this is lost at higher doses from which it also may contribute to coronary vasoconstriction.19Kwak YL Lee CS Park YH et al.The effect of phenylephrine and norepinephrine in patients with chronic pulmonary hypertension.Anaesthesia. 2002; 57: 9-14Crossref PubMed Scopus (108) Google Scholar,21Leather HA Segers P Berends N et al.Effects of vasopressin on right ventricular function in an experimental model of acute pulmonary hypertension.Crit Care Med. 2002; 30: 2548-2552Crossref PubMed Scopus (83) Google Scholar A commonly preferred combination is an inodilator (milrinone, enoximone, or levosimendan) with a vasopressor, which is intended to ensure positive inotropy is provided while ensuring myocardial perfusion is not compromised.22Morelli A Teboul JL Maggiore SM et al.Effects of levosimendan on right ventricular afterload in patients with acute respiratory distress syndrome: A pilot study.Crit Care Med. 2006; 34: 2287-2293Crossref PubMed Scopus (186) Google Scholar As much as this strategy conforms to the physiologic principles required to support the RV, there are no data or evidence that it confers outcome benefit in this context.22Morelli A Teboul JL Maggiore SM et al.Effects of levosimendan on right ventricular afterload in patients with acute respiratory distress syndrome: A pilot study.Crit Care Med. 2006; 34: 2287-2293Crossref PubMed Scopus (186) Google Scholar Epinephrine often is described as an inopressor; hence, in the context of RV failure it would provide inotropy and facilitate the preservation of myocardial perfusion. However, this may be compromised by the presence of tachyarrhythmias often associated with its use.23Price 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 Inhaled pulmonary vasodilators (prostaglandins and nitric oxide) often are used to facilitate a reduction in PVR and reduce RV work, with a consequent increase in RV cardiac output. This effect is appreciated most when patients are in an unstable state attributable to severely impaired RV function; however, it often is not sustained because these drugs exhibit tachyphylaxis, and their use is not associated with an improvement in mortality.24Gebistorf F Karam O Wetterslev J et al.Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults.Cochrane Database Syst Rev. 2016; 2016CD002787PubMed Google Scholar In the context of severe acute respiratory failure, the injured RV is likely to benefit from correction of hypoxemia and/or hypercapnia and/or acidemia provided by veno-venous ECMO (VV ECMO) when conventional lung-protective and RV-protective ventilation (low stress and/or strain, low driving pressure, low mechanical power) measures fail.1Mekontso-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,25Costa ELV Slutsky A Brochard LJ et al.Ventilatory variables and mechanical power in patients with acute respiratory distress syndrome [e-pub ahead of print].Am J Respir Crit Care Med. 2021; (Accessed May 31st 2021)https://doi.org/10.1164/rccm.202009-3467OCCrossref Scopus (62) Google Scholar The reduction in arterial carbon dioxide and improvement in arterial oxygenation have been shown to be associated with a reduction in the mean pulmonary artery pressures within just 15 minutes of commencing VV ECMO support.26Miranda DR van Thiel R Brodie D et al.Right ventricular unloading after initiation of venovenous extracorporeal membrane oxygenation.Am J Respir Crit Care Med. 2015; 191: 346-348Crossref PubMed Scopus (63) Google Scholar However, the presence of RV injury often is not factored into the processes of either the selection or timing of the commencement of ECMO support. There is a notable paucity of rigorous data supporting this practice routinely; however, there is equipoise to investigate this given the burden of RV dysfunction in patients with COVID-19.5Paternoster G Bertini P Innelli P et al.Right ventricular dysfunction in patients with COVID-19: A systematic review and meta-analysis [e-pub ahead of print].J Cardiothorac Vasc Anesth. 2021; (Published April 11th 2021)https://doi.org/10.1053/j.jvca.2021.04.008Abstract Full Text Full Text PDF Scopus (21) Google Scholar COVID-19 is associated with immunothrombosis, myocarditis, and vascular injury, which pose further challenges in managing RV injury in this context despite VV ECMO support (Fig 2). There are reports of patients presenting with significant remixing on VV ECMO due to poor RV ejection, which could be improved only temporarily with inhaled vasodilators.27Heuts 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; (Published October 5th 2020)https://doi.org/10.1053/j.jvca.2020.09.137Abstract Full Text Full Text PDF Scopus (7) Google Scholar Current evidence suggests that patients requiring mechanical cardiac support (veno-arterial or veno-arterial venous ECMO) have worse outcomes, suggesting that this is a state associated with high mortality.28Barbaro 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 A different approach would be to provide both respiratory and RV mechanical support. Mustafa et al29Mustafa 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 supported 40 patients with COVID-19 ARDS and pulmonary hypertension, with veno-pulmonary arterial ECMO using percutaneous right ventricular assist device. This was provided as part of a bundle of care that included awake ECMO (88% of patients were extubated), early corticosteroids, and optimization of preload.29Mustafa 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 survival to hospital discharge was 73%, which was considerably higher than most current reports of outcomes of ECMO support in patients with COVID-19 ARDS.30Tsikala Vafea M Zhang R Kalligeros M et al.Mortality in mechanically ventilated patients with COVID-19: A systematic review [e-pub ahead of print].Expert Rev Med Devices. 2021; (Published April 30th 2021)https://doi.org/10.1080/17434440.2021.1915764Crossref PubMed Scopus (6) Google Scholar In another recent small retrospective analysis, Cain et al31Cain MT Smith NJ Barash M et al.Extracorporeal membrane oxygenation with right ventricular assist device for COVID-19 ARDS.J Surg Res. 2021; 264: 81-89Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar found that the early use of a percutaneous right ventricular assist device (at the time of ECMO initiation) may improve mortality in patients with severe COVID-19 ARDS. Mechanistically, these approaches are congruent with the pathophysiologic process associated with COVID-19 (Fig 3). However, there is a need to investigate this further to evaluate if such outcomes are reproducible in prospective trials. In the meta-analysis by Paternoster et al,5Paternoster G Bertini P Innelli P et al.Right ventricular dysfunction in patients with COVID-19: A systematic review and meta-analysis [e-pub ahead of print].J Cardiothorac Vasc Anesth. 2021; (Published April 11th 2021)https://doi.org/10.1053/j.jvca.2021.04.008Abstract Full Text Full Text PDF Scopus (21) Google Scholar approximately 50% of patients with RV injury did not receive invasive ventilation. This raises the question of RV injury onset and its natural history in spontaneously breathing patients with COVID-19. Does the onset of RV injury correlate with the need for respiratory support? What is the effect of continuous positive airway pressure, noninvasive ventilation, high-flow nasal oxygen, and patient self-inflicted lung injury on the RV? Can these patients be risk-stratified based on the degree of RV injury? These questions should be addressed in future research to timely identify therapeutic targets. Identifying patients at risk and a multimodal assessment of RV biomechanics (eg, a combination of invasive and noninvasive diagnostic modalities) potentially could aid a personalized approach to the management of patients with COVID-19 with respiratory failure and RV injury. Mekontso-Dessap et al1Mekontso-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 developed a clinical risk score for the early identification of ACP in invasively ventilated patients with moderate-to-severe non–COVID-19 ARDS. The score included four variables: (1) pneumonia as cause of ARDS; (2) driving pressure ≥18 cmH2O; (3) arterial oxygen partial pressure-to-fractional inspired oxygen (PaO2/FIO2) ratio <150 mmHg; and (4) arterial carbon dioxide partial pressure ≥48 mmHg. The prevalence of ACP was 20% and 75% for ACP scores of 2 and 4, respectively.1Mekontso-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 There is merit in validating this clinical score in patient cohorts with COVID-19 ARDS, performing early echocardiography in those at risk of RV injury, and considering invasive RV and PA pressure monitoring in those with a high RV injury score. A combined PAC-based and echocardiography-based RV assessment in ECMO candidates who fail to respond to conventional measures potentially could aid in decision-making regarding ECMO configuration (VV v veno-pulmonary arterial). Right ventricular injury in COVID-19 ARDS increases the risk of death. Severe RV injury remains challenging to manage with conventional lung-protective and RV-protective strategies. Future RV research should focus on mechanisms of RV injury in different disease states leading to ARDS, identification of subclinical RV-PA uncoupling, and RV injury phenotyping. These data will inform further research and subsequently enable evaluation of timely interventions (pharmacologic and mechanical) that potentially could protect the RV and mitigate RV injury and progression to RV failure.