In VA ECMO, oxygenated and decarboxylated blood is returned to the arterial system (Jayaraman et al., 2017). Since the left ventricle (LV) must eject against an increased aortic pressure caused by the ECMO inflow, this inherently increases LV afterload. Depending on the LV state, this may have severe negative effects (Burkhoff et al., 2015). In a pressure-volume plot, this is seen as a rightward-upward shift of the loop, with an increase in aortic elastance (E_a) along with an increase in LV filling volume and end-diastolic pressure (Burkhoff et al., 2015). Because the LV end-diastolic pressure increases exponentially at higher filling volumes, this may be most relevant for an already distended and impaired left ventricle, as is frequently seen in cardiogenic shock (Burkhoff et al., 2015). These effects lead to reduced LV ejection fraction and decreased stroke volume (Truby et al., 2017), and can promote pulmonary edema and cardiac ischemia, and may increase the risk for LV thrombus - all factors ultimately impairing myocardial and patient recovery (Grandin et al., 2022). Right heart function further determines the extent of LV overload, where an increased right ventricular function, e.g., increased end-systolic pressure volume relationship (ESPVR) may overload a dysfunctional LV further (Donker et al., 2021). Strategies to reduce LV afterload and the accompanying distension include either pharmacological afterload reduction, primarily through the use of vasodilators, or blood volume reduction, or if necessary mechanical unloading by means of an Impella device, intra-aortic balloon pump or LV venting catheters (Burkhoff et al., 2015; Donker et al., 2019; Kowalewski et al., 2020). Recent studies and meta analyses show that between 26.7% and 49.0% of patients undergoing VA ECMO receive mechanical unloading and mechanical unloading was associated with a decreased mortality (Kowalewski et al., 2020; Schrage et al., 2020; Grandin et al., 2022), but data from prospective trials are missing. Mechanical unloading has been associated with an increased VA ECMO weaning success (Kowalewski et al., 2020), but a higher complication rate has been observed (Schrage et al., 2020; Grandin et al., 2022). Entry and exit strategies for mechanical unloading in VA ECMO will need further clarification in future research and management strategies for LV overload should be tailored to the underlying pathophysiological process (Donker et al., 2022). If mechanical unloading is applied, an early strategy may be beneficial (Schrage et al., 2023).

Guyton’s model of venous return (VR) has been the subject of debate. Using a series of carefully designed physiological experiments (Berger et al., 2016a; Moller et al., 2017; Moller et al., 2019) we have addressed arguments previously raised against the model (Werner-Moller et al., 2020). Although the full nuance of the debate is beyond the scope of this review, the following reasoning rests unaffected by any remaining controversies. Since the blood volume exceeds the unstressed capacitance, the circuit is pressurized by a stressing volume which creates a positive transmural vascular pressure, present also at zero flow. This is a manifestation of the static energy stored in the vessel walls (Magder, 2016). Mean systemic filling pressure (MSFP) is the equilibrated arteriovenous pressure at zero flow and equals the ratio of stressed vascular volume to the systemic vascular compliance (Werner-Moller et al., 2022). During flow, ventricular and/or ECMO pump work shifts part of this stressing volume from the venous to the arterial compartment. A prerequisite for flow is the presence of a pressure gradient pushing blood from points of higher pressure to points of lower pressure. Venous return requires MSFP to exceed right atrial (RA) pressure (P_RA) and the flow is opposed by the resistive properties of (mainly, but not exclusively) venous vessels (resistance to VR: R_VR) (Berger et al., 2016b; Berger et al., 2019). While acknowledging that R_VR is a mathematical abstraction representing complex physiology, it nevertheless can be expressed with the following relationship: V e n o u s   r e t u r n = M S F P − P R A R V R

The soft vessel walls of the vascular circuit will start to collapse as the distending transmural pressure decreases to zero (Moller et al., 2017; Moller et al., 2019). When right-sided pump function (the native RV or an ECMO pump) drains more volume than the VR return function can push from the periphery into the RA, vessels collapse, further limiting flow as resistance increases towards infinity. In this situation, cardiac output and/or ECMO flow cannot be increased by increases in pump speed unless VR be increased firstly. According to the above presented formula, this can only be achieved by increasing stressed volume and MSPF, by means of vasopressors and/or volume expansion, or decreasing the resistance to venous return (R_VR) (Moller et al., 2019).

In the setting of VA ECMO, the native arterial and artificial flows with differing oxygen and carbon dioxide contents, both enter the arterial system (Berger et al., 2023). In addition to an increase in left ventricular afterload, oxygenated blood from the artificial circuit may not reach all organs depending on cannulation strategy and left ventricular function (Wilson et al., 2022). In patients treated with peripherally cannulated VA ECMO with an improving left ventricular function but poor pulmonary function, differential hypoxia (a.k.a. north-south or harlequin phenomenon) may become a concern: Poorly oxygenated blood from the LV reaches the right and upper quadrants of the body, including heart and brain, while the highly oxygenated blood from the membrane lung injected into the femoral artery cannot reach these important organs (Blandino Ortiz et al., 2021). Monitoring of differential hypoxia may be done comparing blood gas analyses from the right radial artery against blood drawn from the left radial or femoral artery. Differential hypoxia may also be present in the venous system during VA ECMO: oxygen saturations in the blood drained from the IVC may differ substantially from the oxygen saturations in the pulmonary artery (Berger et al., 2023) and SVC (Hou et al., 2015). Progressively decreasing pulmonary artery saturation may further decrease left ventricle saturation due to an increase in venous admixture (Takala, 2007). Resolution may be achieved through either repositioning the drainage cannula towards the SVC (Hou et al., 2015; Falk et al., 2022) or modification of the cannulation strategy. A common solution is V-AV ECMO (blood is drained from the IVC and injected in the SVC as well as the femoral artery) or in the case of a failing right ventricle VV-A ECMO (drainage from both the IVC and SVC) (Blandino Ortiz et al., 2021; Wilson et al., 2022). The key to improve differential hypoxia is increased drainage from the SVC, as oxygen-rich blood from the IVC then enters the RA and attenuates differential hypoxia (Hou et al., 2015; Berger et al., 2023).

Lung function often deteriorates during VA ECMO, mainly due to increased LV filling pressures with subsequent congestion of the pulmonary vasculature (Pasero et al., 2014). The artificial lung may provide complete gas exchange for the patient, and the mechanical power necessary for lung ventilation is transferred to the membrane lung (Bachmann et al., 2020a). The extent of this transfer is directly linked to the amount of blood passing through the native lung (Bachmann et al., 2021). Monitoring of native lung function is difficult, but may be achieved with assessment of true oxygen uptake and CO₂ removal through volumetric measurements (Berger et al., 2023). To fully wean and remove the ECMO circuit, the native lung must tolerate sufficient cardiac output and provide adequate gas exchange. Monitoring the native cardiopulmonary unit in terms of gas exchange and cardiac output may therefore guide the weaning process. While traditional measurement of cardiac output by thermodilution may fail (Bachmann et al., 2020b), measurements of gas exchange allow assessment of native cardiac output and lung function (Berger et al., 2023). However, depending on differential hypoxia and varying CO₂ content between the arterial and venous compartments of the artificial and native circuits, gas exchange in the artificial circuit may provide only limited information about the native circuit (Berger et al., 2023).

Experimental data suggests that flow cessation and the absence of pulmonary blood flow may lead to fibrosis, reduced pulmonary compliance and lung necrosis (Koul et al., 1991). It appears that several pathophysiological interactions exist which may significantly impact the native pulmonary function. Increased pulmonary edema due to increases in left ventricular filling pressures, structural changes due to inflammation and absence of pulsatile flow worsened by systemic inflammation may lead to long-term lung injury (Roumy et al., 2020). Strategies to improve lung function may include unloading of the left ventricle, prompt and adequate treatment of pneumonia and pre-weaning bronchoscopy (Luedi et al., 2018; Roumy et al., 2020), and optimized ventilation strategies (Rali et al., 2023).

Veno-venous ECMO has the potential benefit of reducing ventilator induced lung injury. In animal studies, near apneic ventilation has significantly decreased histological lung damage in a model of severe ARDS (Grandin et al., 2022). It is possible to transfer the work of CO₂ removal from the native to the artificial lung, and native CO₂ removal is inversely proportional to artificial CO₂ removal (Berger et al., 2023). However, transitional changes in CO₂ removal may readily be compensated by extensive CO₂ storages in the body (Giosa et al., 2021). Reducing mechanical power may prove to be the goal in VV ECMO therapy, but optimal ventilator settings remain unknown. Although, in a model of iso-energetic ventilation, similar power application led to similar lung damage independently of the components of the mechanical power (Cressoni et al., 2016), ventilation strategies should aim to optimize and protect lung, heart and remote organ function.

A hallmark of acute respiratory distress syndrome is RV failure due to the burdens of increased afterload from hypoxic pulmonary vasoconstriction and mechanical ventilation (Zochios et al., 2017). Echocardiography may promptly identify patients with acute cor pulmonale and treatment strategies include initiation of VV ECMO (Vieillard-Baron et al., 2002; Petit et al., 2021). The findings of acute cor pulmonale in the setting of ARDS have led to the concept of RV protective ventilation (Vieillard-Baron et al., 2016; Petit et al., 2021), which may be facilitated by VV ECMO. In VV ECMO oxygenated blood is pumped into the pulmonary vasculature which ameliorates the effects of hypoxic pulmonary vasoconstriction (Holzgraefe et al., 2020; Zante et al., 2021). This effect depends on the prevailing degree of alveolar hypoxia, but substantial decreases in pulmonary vascular resistance and pulmonary artery pressures have been demonstrated through VV ECMO initiation (Reis Miranda et al., 2015; Holzgraefe et al., 2020). Furthermore, transfer of gas exchange to the artificial lung may reduce the need for mechanical ventilation with the potential to further reduce RV strain (Bunge et al., 2018). Right ventricular function may become an important factor in future strategies for VV ECMO initiation and weaning. Importantly, the level of support during ECMO therapy may also impact RV function: Total transfer of gas exchange and absolute lung rest may promote atelectasis with associated RV-strain while support at an inadequate level may risk exacerbation of lung injury caused by mechanical ventilation (Spinelli et al., 2021). Optimal settings should be chosen considering both RV strain and the mechanical power applied to the lung. Figure 1 provides a theoretical illustration of this concept.

Arterial saturations are dependent on cardiac output, V/Q ratio in the lung, and venous oxygen content. In states of high shunt, as may be present in up to 50% of ARDS patients, low cardiac output states with low venous oxygen saturations may heavily impact oxygen saturation in the arterial system (Takala, 2007). In the setting of VV ECMO, the venous admixture is dependent on the ratio of ECMO flow to cardiac output (Schmidt et al., 2013) as well as the respective oxygen contents. In cases of high cardiac output and significant shunt, arterial saturations may decrease in a curvilinear function as the ratio of ECMO flow to cardiac output decreases (Zante et al., 2021). However, even if arterial oxygen saturation decreases with higher cardiac output, oxygen delivery will improve (Zante et al., 2021).

Gas exchange from an artificial lung will affect the gas content in the pulmonary artery and thereby modify gas exchange ratios in the native lung. With inadequate oxygenation and CO₂ removal mainly occurring through the artificial lung, the respiratory quotient (RQ = VCO₂/VO₂) of the native lung is reduced (Cipriani et al., 2020; Gattinoni et al., 2022). This impacts the alveolar gas composition, in particular the alveolar pO₂ and oxygenation. Gattinoni and others demonstrated already in 1978 that depending on the RQ, higher fractions of inspired oxygen concentrations are necessary to produce an arterial saturation of 90%–94% (Gattinoni et al., 1978). A recently published theoretical analysis demonstrated that if CO₂ removal is provided completely through the artificial lung and the RQ of the native lung reaches values <0.1, an FiO₂ of 1.0 may be necessary to reach pO₂ values of only 100 mmHg (Cipriani et al., 2020). Physicians operating ECMO or ECCO₂R should be aware that inadvertent hypoxia may occur if the artificial lung is primarily used to remove CO₂ without providing oxygenation. If the artificial lung also provides oxygenation, this effect is drastically diminished. The gas content in the pulmonary artery not only impacts the respiratory quotient, but also affects the nitrogen content of blood and alveoli. High oxygen fractions in the native lung will increase alveolar nitrogen washout over time, potentially leading to resorption atelectasis (Gattinoni, 2016). Although also demonstrated already in the 1970s (Kolobow et al., 1978), this effect has not been investigated in the setting of modern ECMO therapy for ARDS. Therefore, future physiological studies of severe ARDS should examine whether changes in sweep gas oxygen fraction may help to stabilize end-expiratory lung volumes.