**2. Background**

#### **2.1 An overview of COVID-19 pathophysiology**

Since its isolation in December 2019 in Wuhan China, the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and its resultant syndrome COVID-19, have affected nearly 567 million people across the globe, with a death toll of over 6 million according to the latest data from the World Health Organisation [5]. Its clinical presentation has been variable, ranging from asymptomatic "happy hypoxaemia", to one of refractory severe acute respiratory failure in the intensive care unit requiring potentially lifesaving extracorporeal support. Approximately 20% of patients with COVID-19 develop severe COVID pneumonitis, which is similar to conventional acute respiratory distress syndrome (ARDS) as defined by the Berlin criteria [6, 7].

Severe COVID-19 is the consequence of a virally triggered cytokine storm, resulting in initial endothelial inflammation and hypercoagulopathy, rapidly followed by pulmonary oedema, progressive lung parenchymal consolidation, diffuse alveolar damage, and pulmonary fibrosis. The interaction between the SARS-CoV-2 spike proteins and the angiotensin converting enzyme-2 (ACE2) receptor present on type 2 pneumocytes via receptor-mediated endocytosis, has been postulated as the fundamental mechanism driving this cytokine response [8]. Although patients generally present with isolated respiratory failure, progression to multiorgan failure may be rapid. COVID-related multiorgan failure and secondary infection related multiorgan failure are the leading causes of mortality, accounting for 37% and 26% of deaths respectively [9]. A hypercoagulable state is particularly common, and is reflected by increased fibrinogen and D-dimer levels in almost all patients, with a concomitant increased incidence of both venous and arterial thrombosis, pulmonary thromboembolism, and associated increased mortality [10]. Post-mortem studies have demonstrated that the histological hallmark of COVID ARDS is diffuse alveolar infiltration with varying degrees of pulmonary vascular thrombosis [11–13].

#### **2.2 Hypoxaemia and respiratory system compliance**

Although there is progressive hypoxaemia and dyspnoea, the hypoxaemia in COVID-19 is often more severe than that expected from the anatomical shunt alone. In fact, despite a PaO2/FiO2 ratio < 200 mmHg (26.7 kPa) in moderate-to-severe disease, approximately 40–50% of patients have preserved respiratory system

#### *The Role of VV-ECMO in Severe COVID-19 ARDS DOI: http://dx.doi.org/10.5772/intechopen.107047*

compliance (CRS), with peripherally distributed ground glass opacification and minimal parenchymal consolidation, which is in stark contrast to the majority of non-COVID ARDS [14]. There is a small subgroup of classic ARDS that may have high compliance [15]. The underlying mechanisms for the disproportionate hypoxaemia are multifactorial, determined by a temporal and spatial heterogeneous mismatch of pulmonary ventilation and perfusion, a loss of hypoxic pulmonary vasoconstriction, and dysregulated pulmonary blood flow, mainly associated with immunothrombosis, endothelial inflammation and neovascularisation [16–18].

COVID-19 patients tend to have preserved CRS despite significant pulmonary fibrosis, pulmonary infiltration, pulmonary vascular micro and/ or macro thrombosis and resulting hypoxaemic respiratory failure. A range of clinical phenotypes may exist. Maiolo et al. proposed 3 distinct groups. Firstly, a high elastance-poor compliance group ("H-type") with a CRS < 40 ml/cm H2O, increased right-to-left shunt, increased lung weight, and potentially more recruitable lung. This group accounts for 20–30% of COVID ARDS patients in critical care [19]. The second group is "Intermediate CRS", defined as a compliance of 40–50 ml/cm H2O, and finally a reduced elastance group ("L-type") characterised by preserved/ high compliance (CRS >50 ml/cm H2O), low ventilation-perfusion ratio, low lung weight, and minimal recruitable lung. Camporota et al. have proposed that the earlier phase of COVID ARDS is characterised by a high compliance phenotype, with a transition to a poorer compliance state as the disease progresses [20]. However, further data has questioned the phenotype concept. Several single centre observational studies, including the recent COVADIS study, have demonstrated that the mean CRS is actually rather poor, c. 30–40 mL/cm H2O. The COVADIS results demonstrated a unimodal distribution of CRS around a mean value of 37 ml/ cm H2O, similar to that observed in non-COVID-19 ARDS. CRS decreased from day 1 to day 14, and interestingly patients with higher CRS did not demonstrate faster weaning of mechanical ventilation or increased survival in multivariate analyses [21]. Ferrando et al. demonstrated a similar mean CRS distribution of 35 ml/cm H2O (IQR: 27–45). However, their findings were likely limited by a high proportion of incomplete data [22]. Factors that may partly explain some of the variability in compliance data may be the time since disease onset and time from disease onset to intubation. Early in the pandemic, intubation tended to occur based on hypoxaemia alone. However, as the pandemic progressed, intubation was often deferred until more clinical disease progression occurred at which point compliance would have been poor, and of a more typical ARDS nature. Mortality in COVID-ARDS does however correlate with poorer compliance (CRS < 48 ml/cm H2O) and increased driving pressure, independent of tidal volume per kilogramme based on ideal body weight, and even with tidal volumes above the accepted 6–8 ml/kg threshold [23]. Notably, patients with COVID ARDS who have a reduced CRS together with increased D-dimer concentrations have a worse survival prognosis [14].

#### **2.3 Pulmonary hypertension**

Pulmonary hypertension leading to acute right ventricular (RV) dysfunction +/− failure may occur in COVID ARDS and is associated with a significantly increased mortality (48.5% versus 24.7% in patients with and without RV dysfunction respectively; 56.3% versus 30.6% in patients with or without RV dilatation). Mortality is high even in patients with pulmonary hypertension (PH) without RV strain (52.9% versus 14.8%) [24]. The underlying mechanism is primarily an increase in RV afterload due to increased pulmonary vascular resistance (PVR). Multiple factors in COVID ARDS contribute to PH, elevated PVR, increased RV afterload and, eventually, RV failure. These include hypoxaemia, hypercapnia, acidosis, hypoxic pulmonary vasoconstriction, endothelial inflammation, pulmonary vascular thrombosis, and vascular remodelling. RV dilatation increases the RV distending pressure, thereby increasing the pressure gradient for subendocardial myocardial perfusion, resulting in impaired RV contractility. Pressure volume overload consequently impairs left ventricular function and cardiac output. Although possibly more severe in COVID-19 ARDS, RV dysfunction can be alleviated by improving gas exchange with VV ECMO [25].

#### **2.4 Management principles in severe COVID-19**

The management of severe COVID-ARDS is multimodal, and the intensity of support required depends on the phenotype and severity of the disease at presentation. Potentially reversible severe COVID pneumonitis that is refractory to protective lung ventilation, ventilatory adjuncts i.e., prone positioning, inhaled pulmonary vasodilators, neuromuscular blockade etc., and also to targeted pharmacological therapy i.e., steroids, immunotherapy, and antimicrobial agents may require extracorporeal membrane support oxygenation as a bridge to recovery or in exceptional cases, lung transplantation [26]. Venovenous (VV) ECMO support is the modality of choice in 95.9% of cases, as demonstrated in a systematic review and meta-analysis of 18,211 COVID-19 patients by Ling et al. [27] ECMO may also represent an efficient support in cases of severe cardiogenic/septic shock refractory to maximal therapy in these patients. However, venoarterial (VA) ECMO, conversion to VA ECMO from VV ECMO, or use of hybrid ECMO circuits are rare in COVID-19, accounting for <5% of all cases [27]. It is also important to consider that patients with other potential indications for ECMO support, such as massive pulmonary embolism, myocarditis or acute myocardial infarction, may also be COVID-19 positive [28]. Although seen as an established therapy in potentially reversible severe respiratory failure, ECMO remains controversial. Over the last 50 years, only 4 large scale randomised controlled trials have been conducted in patients with non-COVID-ARDS [29–32]. Overall, these studies have not demonstrated superiority of ECMO over maximal conventional support i.e., protective lung ventilation, prone positioning etc. However, a meta-analysis of the CESAR and EOLIA studies demonstrated a 90-day mortality benefit in the ECMO group (36% vs. 48%; relative risk, 0.75, 95% confidence interval 0.6–0.94; p = 0.013), in addition to more ventilator free days and days out of ICU [33].
