Fundamentals of weaning veno-arterial and veno-venous extracorporeal membrane oxygenation

Overview

Since its inception in the early 1970s, veno-venous extracorporeal membrane oxygenation (VV ECMO) has been a boon to countless patients in respiratory failure [4]. However, in recent years, questions have arisen regarding the appropriate application of this resource-intensive therapy for maximum patient benefit, in the context of increasing pressure on healthcare systems, while optimizing the risk–benefit equilibrium for patients. These concerns have only been intensified with the onset of the global Corona Virus Disease-19 (COVID-19) pandemic, beginning in early 2020, spurred by soaring ECMO demand in the setting of skyrocketing numbers of patients in extremis secondary to COVID-19 acute respiratory distress syndrome (ARDS). Suddenly, questions of who should receive ECMO and for how long, in intensive care units (ICUs), where demand far outstripped supply, took on a fresh urgency.

According to the Extracorporeal Life Support Organization (ELSO), which maintains the world’s largest ECMO database, data shows that since its inception in 1989, 46,523 adult VV ECMO patients have been submitted to the registry, with an overall survival of 58% [5]. In 2019, there was increased speculation that ECMO utilization had reached its ceiling due to the resource constraints required. For the first time since 2008, the number of total cases and reporting centers decreased, from 13,394 cases and 435 centers in 2018 to 12,850 cases and 430 centers in 2019. Unfortunately, the COVID-19 pandemic arrived in 2020 and revealed in no uncertain terms that systems still had capacity for ECMO expansion, resulting in a sharp ascent of VV ECMO utilization. The latest year for which data was available was 2021 and showed a combined (all forms of ECMO including neonatal, pediatric, and adult cases) total of 17,777 runs reported at 543 ECMO centers. As expected, due to the magnitude and severity of the COVID-19 pandemic, ECMO survival in this population is significantly lower, with the most current data showing an in-hospital mortality of 47% out of 14,166 confirmed COVID-19 ECMO cases, 94% of whom were given veno-venous support [6].

Patient selection

Although the focus of this review is ECMO “weaning,” much of that attendant strategy begins with patient selection and their pre-ECMO disease process and comorbidities. The last 15 years have seen a number of trials which have both stoked excitement regarding VV ECMO as a heroic therapy, but have also offered cautionary tales regarding factors which predispose patients to poor outcomes and provided guidance on patient selection. Chief among these were the Conventional Ventilatory Support vs Extracorporeal Membrane Oxygenation Severe Adult Respiratory Failure (CESAR) and Extracorporeal Membrane Oxygenation to Rescue Lung Injury in Severe Acute Respiratory Distress Syndrome (EOLIA) trials. Published in 2009, the CESAR trial enrolled 180 patients in the UK and randomized them to early referral for consideration of ECMO within 7 days of mechanical ventilation versus standard medical therapy. While questions of patient crossover and inconsistent management of ventilator settings and pressures dogged the study, this focus on early ECMO referral resulted in significantly improved survival in the ECMO group, with a 6-month survival in the ECMO group of 63% compared to that of 47% in the group randomized to medical management [7].

The French EOLIA trial enrolled 249 patients randomized to either early ECMO or standard medical therapy, with the option for salvage ECMO in the case of deterioration, and sought to clarify some of the questions born out of the CESAR trial. The trial established strict inclusion criteria into the ECMO group and, like the CESAR trial, focused on early ECMO referral (less than 7 days), postulating that reducing ventilator-induced trauma would portend better outcomes. Regrettably, the trial stopped prematurely because the difference between the groups did not reach statistical significance regarding the primary endpoint of 60-day mortality. However, the interim analysis showed a clear trend towards improved primary endpoint outcomes in the ECMO group vs. the standard therapy group, with 65% vs. 54% 60-day survival, respectively (p = 0.09). There was also significant crossover from the medical management group to the ECMO group, likely further preventing the full realization of ECMO benefit [8]. Importantly, the trial established clear inclusion criteria which are the bedrock of the selection criteria at the author’s institution and are at the heart of the recent ELSO guidelines on patient selection. These are summarized as published in the ASAIO Journal in (Fig. 3) [9]:

Fig. 3figure 3

Algorithm for management of acute respiratory distress syndrome, including indications for ECMO. With respiratory rate increased to 35 breaths per minute and mechanical ventilation settings adjusted to keep a plateau airway pressure of < 32 cm H2O. †Consider neuromuscular blockade. ‡There are no absolute contraindications that are agreed upon except end-stage respiratory failure when lung transplantation will not be considered; exclusion used in the EOLIA trial can be taken as a conservative approach to ECMO contraindications. ∫For example, neuromuscular blockade, high PEEP strategy, inhaled pulmonary vasodilators, recruitment maneuvers, and high-frequency oscillatory ventilation. ¶Recommend early ECMO as per EOLIA trial criteria; salvage ECMO, which involves deferral of ECMO initiation until further decompensation (as in the crossovers to ECMO in the EOLIA control group), is not supported by the evidence but might be preferable to not initiating ECMO at all in such patients. Credit: Abrams et al. ECMO, extracorporeal membrane oxygenation; EOLIA, Extracorporeal Membrane Oxygenation to Rescue Lung Injury in Severe Acute Respiratory Distress Syndrome; PaCO2, partial pressure of carbon dioxide in arterial blood; PaO2:FiO2, ratio of partial pressure of oxygen in arterial blood to the fractional concentration of oxygen in inspired air; PEEP, positive end-expiratory pressure.6

It is important to note that at the author’s center, in line with the recommendations of major societies, there have been no hard exclusion criteria beyond that of devastating neurologic injury or disseminated, incurable malignancy. Rather, we have adopted an inclusive, multidisciplinary approach which takes into account the patients’ entire clinical picture. Body mass index (BMI) and age, two frequent disqualifiers at many centers, are examined in the context of comorbidities and functional status, as recent data supports the notion that class III obesity (BMI > 40 kg/m2) have comparable outcomes to less obese patients and should not be precluded from ECMO consideration [10]. This seems to be especially true in the COVID-19 VV ECMO population. Obviously, it is incumbent on the ECMO center to ensure that selection criteria match their available resources.

While the technical considerations and management strategies of VV ECMO are beyond the scope of this paper, it is appropriate to comment briefly on our approach. We use a multidisciplinary approach to patient selection, generally consisting of pulmonology, ICU, and cardiac surgery attending physicians. Venous access is typically placed in both the right internal jugular and one of the femoral veins under ultrasound guidance at the first inkling of ECMO candidacy. This allows for expeditious commencement of ECMO therapy if inclusion criteria are met, which is in keeping with the findings of the CESAR and EOLIA trials, which support improved outcomes with early ECMO initiation. Increasingly, we have also been adopting the increased use of dual lumen cannulae, when expertise and fluoroscopy availability allow. This improves ambulation and rehabilitation opportunities are important in all patients, but especially crucial in transplant candidates [11]. Regarding management strategies, our center adheres to the standard protocols recommended by ELSO, including anticoagulation targets, regardless of COVID-19 status [12].

Central to the discussion surrounding ECMO initiation is a clear and frank discussion with the patient’s family and surrogates regarding endpoints and expectations. There must be agreement that once ECMO therapy is initiated, a reasonable amount of time must be allotted for the efficacy of therapy to declare itself. Barring any major status changes, we make these multidisciplinary assessments and updates with the family on at least a weekly basis. Conversely, it is made clear to the patient’s decision makers that if at any time, ECMO is determined to be futile that it will be discontinued. Also, family must be willing for early tracheostomy and percutaneous endoscopic gastrostomy (PEG) tube insertion, allowing for sedation wean and improved pulmonary toilet. Although a non-transplant site should not automatically disqualify a bridge to transplant ECMO patients, discussions with lung transplant centers should begin early in the ECMO course, preferably prior to cannulation. Discontinuation of ECMO therapy must be agreed upon, if the patient is initiated on ECMO as a presumed bridge to transplant or bridge to decision patient, but is subsequently found not to be a transplant candidate. Our institution has also found the early inclusion of the palliative care service as invaluable in navigating these discussions [13, 14].

Weaning from veno-venous (VV) ECMO

VV ECMO therapy by definition is transient and serves as a bridge to recovery. Additionally, for a subset of patients with end-stage lung disease, VV ECMO can be utilized as a bridge to lung transplant, until the patient’s condition allows for listing and/or until a suitable organ becomes available [15]. Weaning from VV ECMO should be considered for patients as soon as the native lungs show signs of recovery. This usually occurs when lung compliance and gas exchange improve and can also coincide with improvement in radiological findings. Currently, there are no universally accepted protocols for weaning VV ECMO. Consequently, each individual center follows their own weaning process.

Weaning for bridge to recovery

Treating the underlying cause of lung failure is the first step in the weaning process. Prior to weaning, it is also critical to prevent and manage multi-organ failure and other ECMO-related complications. Furthermore, patients should be close to their dry weight or at least euvolemic, which usually can be achieved with appropriate fluid balance management and diuretic therapy.

At our institution, we favor keeping flows higher (generally > 3.5–4 l/min) and preferentially wean the sweep off gradually with compensatory ventilator support changes. As the sweep gas is weaned, we establish a consensus regarding acceptable pH, partial pressure of oxygen (PaO2), and partial pressure of carbon dioxide (PaCO2) parameters. In general, we accept pH ≥ 7.30. We consider CO2 clearance as a more important marker of native lung recovery than oxygenation. We aim to maintain plateau pressures < 30 mmHg, in order to avoid barotrauma. When the sweep is off, arterial blood gases (ABGs) are checked every 1–2 h for at least 8–12 h or for 24 h, when patients are coming off longer ECMO runs. If a patient is able to tolerate no sweep gas for 12 h, based on ABGs, lung compliance, and work of breathing, VV ECMO is discontinued. It is advantageous to also consider performing a bronchoscopy the day of decannulation to ensure that retained secretions do not create a significant problem after decannulation.

Few centers around the world have reported their approach for weaning from VV ECMO. The Karolinska Institute [16] has described assessing readiness to wean by adding CO2 to the sweep gas, when the sweep gas has been reduced to 2 l/min. The ability of the native lung to clear CO2 is assessed by comparing pre and post oxygenator ABGs. When the pCO2 difference is less than 3 mmHg, the patient is considered equilibrated, which means the membrane is neither clearing nor adding CO2 and the patient’s native lungs are essentially able to clear the CO2 that is produced. At that point, the sweep gas is turned off overnight. If ABGs are appropriate, ECMO is discontinued and the patient is decannulated. At the University Hospital Regensburg [13] in Germany, the ECMO flow is stepwise reduced to 1.5 l/min and the sweep is tapered in parallel to the pump flow and then turned off for 60 min. If gas exchange remains stable, the patient is decannulated. The ECMO center at San Raffaele Hospital in Italy has reported reducing their ECMO flows to 2.5–3 l and then gradually tapering the sweep gas and fraction of inspired oxygen (FiO2) to off [16].

The ESLO has also published guidelines for weaning VV ECMO [5]. They recommend a stepwise reduction in fraction of delivered O2 (FDO2) from 1.0 to 0.21 in decrements of 20%, followed by reduction in sweep gas flow by 0.5–1 l/min to a goal of 1 l/min. Concomitantly, adjustments are made to the ventilator by gradually increasing tidal volumes to 6 ml/kg or inspiratory pressures to no more than 28 cm H2O and appropriately increasing the FiO2. If ABGs remain acceptable, without an increase in work of breathing, an off-sweep gas challenge for at least 2–3 h is performed. The whole weaning can occur over several hours to days.

There are several ways for successfully weaning from VV ECMO, but these differences in weaning strategies are based on expert opinions rather than evidence [16,17,18,19,20,21]. While some centers will keep the pump flow over 3 l, which prevents clotting of the circuit and also mitigates the need for anticoagulation, other institutions will drop flows to a minimum of 1 l. In the author’s opinion, it is not necessary to reduce flows when the sweep is at zero, given that there is no diffusion gradient between the sweep gas and the patient’s blood flow. This “diffusion equilibrium” minimizes the significance of ECMO flows during the weaning process [16].

Bridge to lung transplantation

In cases of irreversible lung disease, VV ECMO can be considered for decompensated patients who are candidates for lung transplantation [15, 22,23,24]. A small subset of lung transplant candidates with severe primary or secondary pulmonary hypertension and associated right ventricular dysfunction may require VA ECMO support instead. Most centers will initiate VV ECMO therapy for worsening gas exchange in already intubated patients who are previously listed for transplant, or who are potential transplant candidates. Recent data supports superior outcomes of pre-lung transplant ambulatory patients [25, 26]. As a result, some lung transplant programs, when indicated, will initiate VV ECMO on non-intubated patients [26,27,28]. The utilization of a single dual-lumen cannula in an upper body vein is certainly advantageous, since it allows patients to participate in pre-transplant physical therapy. Patients can remain on VV ECMO during their transplant workup and while on the waiting list. VV ECMO can be continued after lung transplantation when primary graft dysfunction occurs, in cases of marginal donor lungs or for early cellular or antibody mediated rejection.

During the lung transplant procedure, patients already on VV ECMO will be transitioned to VA ECMO. This is accomplished by adding an arterial cannula, either in the ascending aorta, when sternotomy or clamshell incision is utilized, or in the femoral or axillary artery for anterior thoracotomy approaches. Lung transplantation is then performed on VA ECMO, or on full CPB, when VA ECMO is not tolerated, or based on the surgeon’s preference. If initial graft function allows, recipients can be weaned off ECMO immediately prior to leaving the OR. In cases of marginal lung graft function, ECMO can again be converted from VA to VV and recipients can be weaned in the same fashion as bridge to recovery patients, once the lungs have recovered.

Bridge to decision

For patients with end-stage lung failure where lung transplant candidacy is unknown, ECMO can be initiated under the indication of “bridge to decision.” This should occur in the context of an ongoing multidisciplinary approach towards lung transplantation, but also considering at the same time the potential to wean VV ECMO.

VV ECMO bridge to no recovery — discontinue for futility

A significant number of patients that receive VV ECMO therapy will not recover. Mortality rates following VV ECMO have been reported as high as 50%, depending on the underlying etiology of lung failure and the patient’s co-morbidities [17, 19, 29,30,31]. When VV ECMO cannot achieve its goal as a bridge to recovery, bridge to decision or lung transplant, it then functions as a bridge to no recovery [14].

Advances in mechanical circulatory support technology, including VV ECMO, have allowed us to substantially extend the duration of ECMO therapy, even when treatment is considered futile. The term medical futility is utilized to describe situations where patients have no chance of survival to discharge and whose dying process is prolonged by some form of life support [31, 32]. Discontinuing VV ECMO support for futility should be decided on a case to case basis but should be considered in the following situations: (a) patients with a pre-existing diagnosis of irreversible lung disease that have been on prolonged VV ECMO support and are not able to wean after multiple attempts; (b) patients without any chance of lung recovery, who are not candidates for lung transplantation; (c) irreversible neurological injury or brain stem death; (d) patients with new respiratory illness which is severe or progressive and precludes any meaningful chance of recovery, especially when associated with VV ECMO-related complications, such as sepsis, disabling stroke, hemorrhage, and multi-organ failure; (e) when directed by the patient’s previously expressed wishes/advance directives. Borderline cases, that do not fulfill any of the above indications, can be very challenging when attempting to determine futility. By definition, patients on VV ECMO have intact cardiac function, which makes cardiac death unlikely, unless device malfunction or complications occur. Furthermore, most patients receiving futile VV ECMO support do not fulfill criteria for brain stem death which further complicates the decision-making process. In these situations, the responsible physicians and the patient’s family members or surrogates are faced with difficult conversations and decisions about withdrawing care and terminating VV ECMO support. We have found that frequent and honest communication with families about goals and limitations of VV ECMO are paramount during this process. End-of-life discussions with family members or with patients themselves when they are alert and able to communicate should involve a multidisciplinary team of critical care/ECMO physicians, palliative medicine, and medical ethics specialist. The more unified, skilled, and empathetic the medical team is in its approach, the more likely family members are to understand the limitations and futility of continuing VV ECMO support [32].

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