To this date, despite being a very effective tool to guarantee proper gas exchange and reduce significantly pulmonary aggression, it is the ultimate step in the healthcare algorithm of refractory hypoxemia. This is so due to the complexity associated wth its proper management, and association with an elevated use of resources and a higher risk for developing serious complications. Currently, the indication for this kind of support should only be considered if the prone positioning maneuver has proven ineffective. The definition of maneuver ineffectiveness varies depending on the different studies and protocols regarding the duration of prone positioning trial (from 6h to 12h), and on the impact the maneuver has (from any increase up to a cut-off value of 20% of PaO2/FIO2).

One of the keys of success of the ECMO program is to indicate the technique in patients who will benefit from it, which puts ECMO in no one’s land between 2 extremes that are that scenario where the indication is futile, and that other scenario where less aggressive maneuvers would be enough to reach respiratory stability. The indications and contraindications proposed by the Extracorporeal Life Support Organization (ELSO), and the exclusion and inclusion criteria used in the CESAR and EOLIA clinical trials are shown on Table 1. In the analysis of these variables the following points should be stressed out—considered of special interest—due to their great impact in the assessment of cases and for the lack of new information from recent studies:

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  Since ECMO is not a therapy per se but a support system it is essential to identify that the baseline process is reversible. As the CESAR trial indicates, this interpretation involves, to a greater or lesser extent, a criterion of subjectivity for physicians. In any case, the indication for this treatment can be a bridge therapy until diagnosis is achieved or else to ease off disease progression after which the intensity of the support maneuvers can be adjusted. In patients with COVID-19-related ARDS and extended ECMO therapy, the possibility of lung transplantation has been proposed as a final therapy of the baseline process.4 This clinical situation is controversial due to the criterion of irreversibility of the pulmonary process and the adjustment of this de novo indication in a difficult context of available resources, especially in the current pandemic situation. In any case, the cases considered eligible (young patients with multi organ failure with possibility of active rehabilitation waiting for transplation) should be assessed at a lung transplantation center.

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  Regarding the identification limits of a situation of hypoxemia and hypercapnia, rather than defining a strict cut-off value regarding PaO2/FIO2 and/or pH or PaCO2, what we should be doing is to examine disease progression in every patient especially if the patient is under distant assessment by the ECMO center.

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  Except for the uncommon use of the Murray score, respiratory system compliance when ECMO is indicated has not been included as a criterion under consideration. However, data shows that this variable could play a relevant role in the success of the decision-making process. A still not very well-defined role to this date since excessive pulmonary elastance can translate into an irreversible pulmonary insult or else precisely patients with poorly compliant lungs may be the ones who benefit the most from the ultraprotective ventilation provided by ECMO. In the EOLIA clinical trial, the benefit ot ECMO support was especially significant in patients with an indication for respiratory acidosis compared to the control group.2 On the other hand, in the multivariate analysis of in-hospital mortality of the ECMOVIBER clinical trial that included 24 centers from the Iberian Penninsula that provided extracorporeal respiratory support to 319 patients with COVID-19-related ARDS, driving pressure was identified as one of the variables most associated with a higher mortality risk (higher pressure is equivalent to higher risk).5 In addition to this context of uncertainty, we should mention the difficulties involved trying to obtain accurate measurements of this parameter, and the revelanve of the extrapulmonary component in the values obtained. Therefore, more solid data is required to identify the actual role of respiratory system compliance when ECMO is indicated in patients with ARDS.

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  The duration of mechanical ventilation (MV) when extracorporeal support is indicated is a variable that is often poorly interpreted, which has had a tremendous impact on the indication for this therapy, especially during the COVID-19 pandemic. ELSO defines this variable as a relative and specific contraindication that this criterion involves the use of aggressive MV with elevated oxygen concentration and plateau pressure levels for a 7-day period. Also, in the same chapter, ELSO claims that many centers do not consider it a contraindication. The ECMOVIBER trial did not identify any associations between this variable and in-hospital survival, a finding that is consistent with other studies.5,6 However, taking this time interval into consideration in the indication for starting ECMO support is advised, not as a direct effect but by including other factors indirectly in this variable that would play a more relevant role in the risk of failure after starting ECMO support like extended sedorelaxation or a higher risk for respiratory infectious events.

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  There is a clear correlation between mortality and age. Establishing a specific limit is controversial being 65 years old the most common cut-off value as a relative contraindication in patients with ARDS.

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  As a common practice and yet despite the biocompatibility of the current extracorporeal systems, a patient on ECMO support would require a certain degree of anticoagulation. However, the impossibility of anticoagulating the patient is not longer a contraindication (present in the CESAR trial) for starting support (not included as an exclusion criterion in the EOLIA trial).

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  Immunosuppression is a common finding as a relative contraindication to starting ECMO support. It is included by ELSO as a criterion with a remarkably non-specific definition. This is due to the negative results reported on the use of this maneuver in patients with bone marrow transplants, especially in the pediatric population. However, what probably plays a significant role is the actual impact of this immunosuppression in the clinical status of the patient. Just to mention 2 examples of this, the prognosis of a patient with Aspergillosis is worse compared to that of a patient on chronic corticoid therapy. On the other hand, this variable should be dealt with in all its complexity.

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  Obesity has a negative impact per se on disease progression due to the complex mechanisms resulting from an aberrant response to the acute process. However, it should not be considered an absolute contraindication unless cannulation is impossible.

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  As it occurs with reversibility, futility has an unquestionable subjective component that has been approached by generating different scores that can help in the decision-making process.7 As Table 1 shows, in the CESAR and EOLIA clinical trials a significant number of patients were excluded because the start of ECMO support was considered futile. In complex cases, decision has to be collaborative including the most experienced experts from each ECMO Center even looking for opinions from other expert centers and using collaborative clinical networks. On this matter, it is extremely important that the ECMO Center stays in touch with all the centers it provides coverage to through fluid bidirectional dialogue.

The complexity of the clinical scenario of a critically ill patient with extracorporeal life support has to do with the presence of multiple factors that have a direct impact on the patient’s survival. A well-defined anticoagulation protocol, adequate adjustment of mechanical ventilation parameters, protocolized training for the entire staff, and multidisciplinary teamwork to guarantee the patients’ safety are some of these important variables that modulate the actual impact of the technique during disease progression. Table 2 shows the key takeaways in the management of a patient with ARDS and VV-ECMO support. The healthcare algorithm includes:

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  The concentration of cases in high volume centes is essential to guarantee good results.8 Recommendation for centers that start a program and, therefore, have few cases at the beginning is to join forces with another more consolidated ECMO Centers with which to stay in touch to monitor results and receive advice from both for indication and management purposes, and even on the association between training and retraining programs.9 Bases on this, it is essential to structure healthcare based on the territory at stake,10 and then establish collaborative networks among the different ECMO Centers both at clinical and reseach levels.3,5

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  The ECMO team has to be multidisciplinary and involved in all the medical specialites associated with the technique like cardiac surgery, anesthesiology, and cardiology. This teams needs to be led by the physician who is treating the critically ill patient. This has been associated with better outcomes and with a more comprehensive vision of this specialist in a multidimensional clinical context where a decentralized or fragmented model is accompanied by an inherent risk of oversimplifying the complexity associated with all the stages involved in ECMO support from indication through weaning, and even later stages.11 From an organizational perspective, a director and a coordinator of the program should be defined to supervise all the clinical and organizational aspects of the team according to the recommendations detailed by the ELSO (https://www.elso.org/Resources/Guidelines.aspx).

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  The training of this ECMO team is directly associated with patient’s safety and, therefore, is one of the cornerstones of the ECMO program. Training needs to be protocolized and follow the recommendations established by the ELSO (https://www.elso.org/Resources/Guidelines.aspx). Practical training of the entire ECMO team through workshops where the teams come into direct contact with the material used in this therapy (pumps, ventilators, cannulas, circuits, monitoring systems) is especially relevant. Also, training through advanced simulations to facilitate the creation of complex clinical settings where multidimensional competences can be more easily acquired. Maintaining these competences is also important so we should take into consideration both the volume of cases managed by the center and the number of healthcare workers with specific training.

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  One of the keys of success is select the right configuration of cannulation that should be individualized based on the clinical situations. As an example of this, patients with COVID-19-related ARDS often require an elevated blood flow that requires the insertion of a thick drainage cannula.5 On the other hand, patients who require an aggressive negative fluid balance will benefit from placing drainage into the jugular vein for keeping the stability of extracorporeal flow in this context. Finally, patients with residual pulmonary function who benefit from early rehabilitation (awake ECMO) can benefit from placing a dual-lumen cannula into the right jugular vein although rehabilitation—even walking—in patients treated with femoral cannulation is feasible as well.

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  ECMO is not a therapy per se, but it facilitates the application of diagnostic-therapeutic maneuvers that would have been unacceptably life-threatening without ECMO support. The computed tomography scan allows more refined assessments of the situation of the pulmonary parenchyma, as well as the identification of concomitant conditions due to treatment like pulmonary thromboembolism, a common finding in COVID-19. Similarly, extracorporeal respiratory support allows performing a fiber bronchoscopy that facilitates the secretion drainage and sample drawing to adjust the antibiotic therapy of these patients.

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  Another 2 actions facilitated by extracorporeal support that have a relevant impact on the evolution of these patients are the adjustment of MV parameters towards ultraprotective ventilation facilitating the total weaning of the patient from the ventilation, and the early start of rehabilitation even before pulmonary recovery.12 Several approaches have been described to adjust ventilation, but there is not such a thing as a gold standard yet. The algorithm used in the EOLIA trial, described in the supplementary material is not very specific including 2 different setting modes (ACV or APRV), wide adjustment ranges (0.3-0.5 for the FIO2, 10-30rpm for the heart rate), and a very general recommendation to participant centers to withdraw sedatives as early as possible. In its recommendations, ELSO is a little bit more precise (https://www.elso.org/Resources/Guidelines.aspx). It defines 2 phases, one 24-48h early phase of moderate-deep sedation while on the APRV mode (25/15cmH2O) followed by further phases where sedation removal is advised, and spontaneous breathing is promoted on CPAP at 20cmH2O. Prone positioning is not proposed in either one of the 2 protocols as the maneuver that should be used in patients with ARDS on ECMO supoprt. Its use has been associated with potential complications and the benefits derived from its use are not very clear yet.13 A clinical trial would be very much welcomed to find more solid evidence on its effect as an additional lung protection maneuver and/or recruitment.

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  Weaning from MV can be performed before ECMO. These are 2 different respiratory support systems with different peculiarities each one of them. The decision to put the weaning of one before the weaning of the other is based on a risk/benefit ratio regarding the patient who is being treated with either one of these 2 support systems (eg, in patients with barotrauma, minimizing IPPV should be the priority; in patients with bleeding issues, removing extracorporeal support should be the priority) based on the characteristics of each ECMO Center and the healthcare context.

In conclusion, the use of extracorporeal support in the adult patient with ARDS should be perfomed in the ECMO program setting of the centers managing the cases (ECMO Center) with multidisciplinary teams (ECMO team) and led by specially trained experts in the management of critically ill patients specifically trained with this technique. The success of these programs is based on the accurate identification of indication criteria, and on the capacity to balance futility and rush based on solid analysis of the scientific evidence available. Also, thanks to multidimensional healthcare protocols the include the entire complexity inevitably associated with this healthcare maneuver.

None whatsoever.