key: cord-0868767-mg7fynwa
authors: Zochios, Vasileios; Lau, Gary; Conway, Hannah; Yusuff, Hakeem O
title: Protecting The Injured Right Ventricle In COVID-19 ARDS: Can We Personalize Interventions And Reduce Mortality?
date: 2021-06-05
journal: J Cardiothorac Vasc Anesth
DOI: 10.1053/j.jvca.2021.05.059
sha: 5ad1101b6d931fa475b6f2bcfd8e66e573215e69
doc_id: 868767
cord_uid: mg7fynwa

nan

how should one define abnormal RV/PA physiology in order to capture and treat pathologies that lead to mortality and potentially identify targets of therapeutic interventions and RV phenotyping?

Understanding of RV biomechanics and in particular the relationship between RV and PA is key to identifying different phases of RV dysfunction leading to RV failure and death. Right ventricular -PA coupling is determined by end-systolic and pulmonary arterial elastance (E es and E a , representing RV contractility and afterload respectively). 8, 9 In acute PAH states, RV contractility increases in order to maintain RV-PA coupling and E es :E a ratio between 1.5-2 (homeometric mechanism) . 8, 9 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 E es :E a ratio (<1) and RV dilatation to maintain flow (heterometric adaptation). 8, 9 As Paternoster and colleagues state in their systematic review, there is also a possibility that in COVID-19 patients with severe disease, high levels of pro-inflammatory cytokines exert a direct negative inotropic effect on the RV. 5 The resultant RV-PA uncoupling leads to inability of the RV to meet the flow demands without excessive use of Frank-Starling mechanism and systemic congestion ensues. [8] [9] [10] It has become apparent that both loading conditions and direct insult to the RV can adversely affect outcomes. In this editorial we will be using 'RV injury' as an umbrella term which encompasses one or more of the following echocardiographic RV phenotypes: 'RV dilatation', 'RV dysfunction (RVD)', 'Acute Cor Pulmonale (ACP)', 'Acute PAH'. This could potentially 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 and colleagues, approximately 50% of patients were invasively ventilated. 5 Data on utilization rates of prone ventilation, non-invasive ventilation (NIV), continuous positive airway pressure (CPAP) or high-flow nasal oxygen ((HFNO) including duration and level of support, and failure rates) were not available. Data relating to use of extra-corporeal membrane oxygenation (ECMO), ventilatory parameters and pulmonary mechanics such as driving pressure, positive end-expiratory pressure (PEEP) and mechanical power (known to adversely affect RV-PA coupling when they exceed certain thresholds) were not provided either. 1, 5 It would be important to explore mechanisms of refractory 'RV injury' in COVID-19 despite 'RV-protective' measures (eg.

veno-venous ECMO, low stress/strain invasive ventilation, prone ventilation), and whether there is a link between non-invasive respiratory support and potential patient self-inflicted lung injury (P-SILI) and 'RV-injury in spontaneously breathing COVID-19 patients. 11

Can we protect the 'injured' ventricle and prevent further injury?

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 (2DE) remains the most widely used tool to assess RV function in critical illness. 12 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 (TAPSE), tissue doppler imaging derived systolic velocity (S′) and fractional area change (FAC) all have data to support their use in RV systolic assessment. 6 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 and possibly earlier than that demonstrated on systolic assessment. 13 Assessment of RV diastolic function (morphological 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. 14 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. 15 Longitudinal parameters: TAPSE, RV systolic velocity (RVS') and RV free wall strain (FWS), identified significantly fewer patients with RV dysfunction, than when using RV velocity time integral (VTI) and RV FAC; an important reminder that a complete dataset, including both static and dynamic data, is needed in order to fully evaluate the RV in this subset of patients. 15 In the same study, RV-PA coupling expressed as FAC:RV systolic pressure ratio was found to provide additional information above standard RV performance measures. 15 An important consideration is the frequency by which 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 authors that either serial transthoracic (TTE) or transesophageal (TEE) echocardiograms or ideally continuous monitoring using TEE, is required to evaluate RV health through critical illness, and the effects that preload, afterload and contractility augmentation has on its functionality.

Continuous non-invasive RV monitoring can potentially provide constant insight into the health of the RV and may identify cases where 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. 16 This would allow the clinical team to observe the effects of interventions to improve the RV pre-load, contractility and afterload continuously and in real-time. 16, 17 However, the major disadvantage to this technology is that it only provides a monoplane image, with no capability to perform doppler (colour, spectral) assessment of flow. In addition, there is currently lack of large-scale data to support its use in ARDS patient populations with RV injury.

Advanced technology PA catheters (Edwards Lifesciences, One Edwards Way, Irvine, CA 92614 USA) or PA catheters with RV port (Paceport, Edwards Lifescience, Irvine, CA) enable invasive dynamic assessment of RV function (figure 1). 18 Real-time invasive monitoring of preload (RV enddiastolic 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. 18 Although the aforementioned diagnostic approaches make physiological sense the assumption that they may confer benefit and guide appropriate interventions must be confirmed in rigorous large prospective studies.

The 'injured' RV is best supported 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 the context of ARDS. Unfortunately, the perfect therapy to achieve these aims does not exist hence a combination of therapies is often 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 results in reduced myocardial perfusion. Vasopressors such as norepinephrine and vasopressin would theoretically improve myocardial perfusion pressure but they have no role in reducing the PVR and may even increase it. [19] [20] [21] Norepinephrine improves RV-PA coupling; however, at high doses this effect is diminished. [19] [20] [21] In very severe vasoplegic states, norepinephrine and vasopressin in combination would act synergistically to improve perfusion pressure. Vasopressin at low doses (0.01-0.03U/min) may reduce PVR through endothelial nitric oxide release but this is lost at higher doses where in addition it may contribute to coronary vasoconstriction. 19, 21 A commonly preferred combination is an inodilator (milrinone, enoximone or levosimendan) with a vasopressor which is intended to ensure positive inotropy is provided whilst ensuring myocardial perfusion is not compromised. 22 As much as this strategy conforms with the physiological principles required to support the RV there is no data or evidence that it confers outcome benefit in this context. 22 Epinephrine is often 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. 23 Inhaled pulmonary vasodilators (prostaglandins and nitric oxide) are often used to facilitate a reduction in PVR and hence reduced RV work with a consequent increase in RV cardiac output. This effect is often appreciated most when patients are in an unstable state attributable to severely impaired RV function; however, it is often unsustained as these drugs exhibit tachyphylaxis and their use is not associated with an improvement in mortality. 24 

In the context of severe acute respiratory failure, the 'injured' RV is likely to benefit from correction of hypoxemia/hypercapnia/acidemia provided by veno-venous ECMO (VV ECMO) when conventional lung-and RV-protective ventilation (low stress/strain, low driving pressure, low mechanical power) measures fail. 1, 25 The reduction in arterial carbon dioxide and improvement in arterial oxygenation has been shown to be associated with a reduction in the mean pulmonary artery pressures within just 15 minutes of commencing VV ECMO support. 26 However, the presence of RV injury is not often factored into the processes of either the selection or timing of the commencement of ECMO support. There is 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 Coronavirus disease 2019 is associated with 'immunothrombosis', myocarditis and vascular injury which poses further challenges in managing RV injury in this context despite VV ECMO support (figure 2). There are reports of patients presenting with significant remixing on VV ECMO due to poor RV ejection which could only be improved temporarily with inhaled vasodilators. 27 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. 28 A different approach would be to provide both respiratory and RV mechanical support. Mustafa and colleagues, supported 40 patients with COVID-19 ARDS and pulmonary hypertension, with venopulmonary arterial (V-Pa) ECMO using percutaneous right ventricular assist device (RVAD) . 29 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. 29 The survival to hospital discharge was 73% which is considerably higher than most current reports of outcomes of ECMO support in COVID-19 patients with ARDS. 30 In another recent small retrospective analysis, Cain and colleagues found that early use of percutaneous RVAD (at the time of ECMO initiation) may improve mortality in patients with severe COVID-19 ARDS. Mechanistically, these approaches are congruent with the pathophysiological process associated with COVID-19 ( figure 3 ). 31 However, there is a need to investigate this further in order to evaluate if such outcomes are reproducible in prospective trials.

In the meta-analysis by Paternoster and colleagues, approximately 50% of patients with RV injury did not receive invasive ventilation. 5 This raises the question of RV injury onset and its natural history in COVID-19 spontaneously breathing patients. Does the onset of RV injury correlate with the need for respiratory support? What is the effect of CPAP, NIV, HFNO, P-SILI on the RV? Can these patients be risk stratified based on the degree of RV injury? These questions should be addressed in future research in order to timely identify therapeutic targets.

Identifying patients at risk and a multimodal assessment of RV biomechanics (eg. combination of invasive and non-invasive diagnostic modalities) could potentially aid a personalized approach to management of the COVID-19 patient with respiratory failure and RV injury. Mekontso-Dessap and colleagues developed a clinical risk score for early identification of ACP in invasively ventilated patients with moderate to severe non-COVID-19 ARDS. 1 The score included four variables: pneumonia as cause of ARDS; driving pressure > 18 cmH 2 O; arterial oxygen partial pressure to fractional inspired oxygen (P a O 2 /F i O 2 ) ratio <150 mmHg; and arterial carbon dioxide partial pressure ≥48 mmHg. The prevalence of ACP was 20% and 75% for ACP scores of 2 and 4 respectively. 1 There is a merit in validating this clinical score in COVID-19 patient cohorts with ARDS, perform early echocardiography in those at risk of RV injury, and consider invasive RV and PA pressure monitoring in those with high RV injury score. A combined PAC-and echocardiography-based RV assessment in ECMO candidates who fail to respond to conventional measures could potentially aid in decisionmaking regarding ECMO configuration (VV-vs V-Pa).

Right ventricular injury in COVID-19 ARDS increases the risk of death. Severe RV injury remains challenging to manage with conventional lung-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. This data will inform further research and subsequently enable evaluation of timely interventions (pharmacological and mechanical) that could potentially protect the RV and mitigate RV injury and progression to RV failure.

Financial disclosures:

None.

The authors (on behalf of PRORVnet) have received honoraria from Edwards Lifesciences. 

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The authors thank Dr. Asif Mustafa MD PhD (Department of Cardiovascular and Thoracic Surgery, Rush University Medical Center, Chicago, Illinois) for providing figures 3a and 3b (anonymized and depersonalized), and Edwards Lifesciences for providing figure 1.The abnormal interaction between the right ventricle (RV) and pulmonary vasculature in various disease states is associated with adverse clinical outcomes. 1 Impaired RV physiology in acute respiratory distress syndrome (ARDS) is a major determinant of mortality. 1 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 (SARS COV2) infection. [2] [3] [4] In this issue of the Journal of Cardiothoracic and Vascular Anesthesia, Paternoster and colleagues sought to determine if echocardiographic evidence of deranged RV and/or pulmonary vascular physiology is associated with mortality in patients with COVID-19 ARDS. 5 The authors performed a systematic review and meta-analysis of nine high quality observational studies (n=1450) reporting on mortality in COVID-19 patients with acute respiratory failure and echocardiographic evidence of 'RV dysfunction (RVD)' and/or 'RV dilatation' and/or pulmonary arterial hypertension (PAH). 5 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. 6, 7 Abnormal function and/or dimensions of the RV as well as PAH were found to be major determinants of mortality. 5

There is clearly an association between abnormal RV and pulmonary vascular physiology and adverse outcomes in COVID-19 patients with acute respiratory failure; 5 but what are the mechanistic links and