Extracorporeal gas exchange: when to start and how to end?

Table 1 was first published more than 40 years ago [4] and summarizes the main characteristics and options through which the extracorporeal support may be applied. As shown, all the possible application were foreseen and most of them actually tested in the following years. As shown, two main features characterize the extracorporeal support: cannulation (veno-venous vs veno-arterial) and extracorporeal blood flow.

The CO₂ transfer, due to the physicochemical characteristics of CO₂ in the blood, follows a complete different scheme. The CO₂ content in the blood is primarily function of the strong ion difference: for the same PCO₂, the CO₂ content depends on the difference between expected and actual strong ion difference (i.e., the base excess). As an example, at a base excess of − 10 mEq/L and PCO₂ 40 mmHg compared to a base excess of 0 mEq/L at the same PCO₂, the total amount of CO₂ in the blood (dissolved + bicarbonate + carbo-amino compounds) goes from 37 to 50 ml/dL. In normal conditions, with pH close to 7.4 and PCO₂ in the range of 40–50 mmHg, the amount of total CO₂ in the blood is roughly 1 ml per mmHg of CO₂, i.e., with a PCO₂ of 45 mmHg and base excess 0 mEq/L (strong ion difference 42 mEq/L), the CO₂ content is about 45 mL/dL. This means that the near total metabolic production of CO₂ is equivalent to the CO₂ present in about 500 ml of blood. Therefore, if the blood flowing through the membrane lung is ventilated at a very high rate, the total metabolic CO₂ production may be cleared from an amount of blood similar with the one used during continuous veno-venous hemofiltration.

Therefore, to provide 200 ml/min of oxygen, high extracorporeal blood flow is required, with minimum ventilation of the artificial lung, while the same amount of CO₂ may be cleared for less than one fourth of the blood flow, but very high ventilation is required. The physiology of the gas exchange with the artificial lung clearly indicates that the oxygenation and CO₂ removal function may be easily dissociated in the artificial extracorporeal system, and this accounts for the tremendous possibility of intervention which is possible using the artificial lung systems.

The veno-venous extracorporeal support, through different settings, recognizes two primary rationales:

The rescue applies when hypoxemia is per se “life-threatening”. Obviously, this condition cannot be defined neither by a single value of PaO2, nor by a combination of more variables (e.g., hypoxemia and hypercapnia). Indeed, the life-threatening hypoxemia is a clinical judgment, which accounts for age, comorbidities, pathophysiological alterations, and time course of the disease of the patient. As far as we know, the PaO₂ of 19 mmHg is the lowest level of arterial PO₂ recorded in healthy living subjects on the Everest [14]; this values are the same recorded in turtles [15], penguins [16], and whales [17] during deep immersions; and, most interestingly, these are the normal values during human fetal life [18]. This stresses the nonsense of considering a single value of PO₂ as life-threatening threshold, without considering the perfusion pattern. Indeed, it is common in ICU, during extracorporeal support, to observe occasionally patients without any relevant organ failure, but the lung, despite PaO₂ as low as 30 mmHg if the hemodynamics are adequate. Therefore, we believe that the attending physician is the most qualified “measuring tool” to detect hypoxemic life-threatening conditions, as he/she may integrate the myriad of information beyond PaO₂ levels, posing the patient at immediate risk of dying. In reality, the bulk of studies dealing with ECMO, since the first randomized controlled trial by Warren Zapol in the middle of 1970s [19], used the hypoxemia threshold as entry criteria for high-flow ECMO (see Table 2). Of note, the most recent ECMO study, i.e., EOLIA trial [20], used criteria not very different from those used four decades before and provided a strong signal that ECMO, used as a rescue therapy of severe hypoxemia, may lead to survival benefits.

The definition of low flow is absolutely arbitrary, as it may range from 300 to 400 ml/min up to 1000–1500 ml/min. In this range of flow, the clearing of CO₂ relative to the metabolic production may range from 20 up to 100% depending on input CO₂, membrane lung surface, and sweep gas flow [21]. The main difference between low and high-flow extracorporeal support, in our opinion, is that the contribution to the oxygenation is limited at low flow, i.e., not higher than 30% at 1500 ml/min of extracorporeal blood flow and negligible at 300–400 ml/min. The concept of extracorporeal CO₂ removal was introduced by Kolobow when the dismal results of the Zapol’s trial were informally known (90% mortality in control and ECMO groups). The initial input for extracorporeal CO₂ removal by Kolobow was to explore the possibility of CO₂ dialysis in COPD patients, aiming at quality of life improvement. For this purpose, he developed a special artificial lung with high surface and thin membrane (the carbon dioxide membrane lung, CDML) to maximize CO₂ removal [22]; however, when testing the performances of the CDML, we found that removing CO₂ in healthy spontaneously breathing sheep allowed a complete control of their ventilation [6]. Indeed, if 50% of CO₂ produced by an animal in 1 min is removed through the artificial lung, the animal reset its own ventilation by decreasing alveolar ventilation by 50%, at constant PaCO₂. This observation led to the idea of using the extracorporeal CO₂ removal to decrease the impact of high pressure/volume ventilation, which was the rule at that time in ARDS patients. The idea of CO₂ dialysis was abandoned in favor of the idea of “lung rest” in severe ARDS [4, 23]. These physiological principles are still valid today and provide a basis for introducing a “gentle” ventilation in ARDS.

Due to these premises, the indication to apply ECCO₂R as a tool to decrease the harms of mechanical ventilation should be based on a hypothetical threshold, defining the risk of unacceptable ventilation-induced lung injury (VILI). Unfortunately, as far as we know, this approach has never been used and also for ECCO₂R the indications are based on the impairment of oxygenation. In the last few years, we tried to identify a comprehensive variable to estimate the risk of VILI, i.e., the mechanical power, which accounts for excessive tidal volume, excessive driving pressure, respiratory rate, inspiratory flow, and PEEP. This approach led to consistent result in experimental animals and appears promising when the mechanical power has been tested in large ARDS population [24‐26].

Low-flow ECMO is a tool to allow the decrease of the possible damage of mechanical ventilation in the baby lung, by reducing minute ventilation, while maintaining normal CO₂. As the harm of mechanical ventilation derives from unphysiological stress and strain repeated over time up to the near-total lung capacity of the baby lung, the rationale indication for extracorporeal support should be based on thresholds derived from lung mechanics. As far as we know, however, this approach has never been used and the primary criteria for ECCO₂R application are similar to the ones used for high-flow ECMO, i.e., hypoxemia. Interestingly, even the recently proposed trial that combines low-flow extracorporeal CO₂ removal and ultra-protective lung strategy indicates as entry criteria the presence of moderate ARDS, based on oxygenation criteria [33].

We recently proposed the mechanical power as a unifying variable to select the harmful threshold of mechanical ventilation [34]: indeed, mechanical power includes tidal volume, driving pressure [35], respiratory rate [36], flow [37], and positive end-expiratory pressure [38]. Each one has been shown, isolated or in association, to cause ventilator-induced lung injury. In experimental animals of middle size, a possible threshold around 13 J/min discriminates between major and relatively minor ventilator damage and we are trying to investigate a possible threshold in human beings. Nowadays, the minimally invasive ECCO₂R is primarily suggested for the treatment of COPD exacerbation, while in severe ARDS the technique is not considered, due to low impact on blood oxygenation.

Recently, we found that a relevant amount of CO₂ may be cleared in a minute with an extracorporeal blood flow not greater than 400 ml/min, when adequate membrane lung surface and sweep gas flow are used [21]. Depending on the metabolic CO₂ production, this set may provide from 50% to near 100% of metabolic CO₂ clearing, while the oxygen added artificially is not greater than 10–20 ml/min. If we consider that the severe ARDS patients, treated with high-flow ECMO, are still ventilated with minute ventilation ranging from 6 to 10 L/min, we may wonder if such effect cannot be reached with the minimally invasive approach instead of high-flow ECMO. Indeed, in hemodynamically stable patients, even low oxygenation (circa 50 mmHg) can be well tolerated if the hypoxic vasoconstriction is maintained, while the modification of mechanical ventilation could be similarly reduced. It is possible that, in the near future, the actual difference between ECMO and ECCO₂R in severe ARDS will be reconsidered under the light of these pathophysiological mechanisms.

The logical indication to stop either ECMO or ECCO₂R should be the cessation of the condition for which ECMO or ECCO₂R have been instituted. Therefore, the condition for stopping high-flow ECMO would be the maintenance of adequate oxygenation without extracorporeal support and, for ECCO₂R, the mechanical ventilation below any harmful threshold. In practice, the approach used in the clinical practice to remove the extracorporeal support is more pragmatic than rational. Actually, the “weaning process” starts from the beginning of the extracorporeal support by progressively reducing the possible harmful component of mechanical ventilation (FIO₂ and pressures). Indeed, during full blown ARDS, the severely hypoxemic patients at the beginning are kept sedated/paralyzed with relatively high mean airway pressure, while the minute ventilation is reduced at different extent. During this phase, any attempt of a spontaneous breathing may be ineffective as the respiratory drive of the patient, independently of normal blood gases, is so high that the spontaneous breathing would be more dangerous than whatever mechanical ventilation applied [39]. However, when the disease leading to ARDS is under control, the respiratory drive tends to normalize. The steps of weaning relate first to progressive decrease of FIO₂ down to 40–50%, then to decrease of PEEP (1–2 cmH₂O/h). The steps are interrupted if the oxygenation deteriorates. When it is possible to maintain oxygenation with circa 40% oxygen and circa 10 cm H₂O of PEEP, the patients are usually ready for disconnection. Nowadays, at this stage, we test the patient capability to breathe spontaneously and/or to tolerate pressure support ventilation by a stepwise decrease of the sweep gas flow, while measuring at the same time the esophageal pressure swings. If the negative swings of esophageal pressure are < 15 cm H₂O at a respiratory rate < 30 rpm, the patient is decannulated. This is one of the several possible ways, which are anyway based on the achievement of two targets: adequate oxygenation and arterial PCO2 during safe spontaneous/mechanical ventilation.