- Objective: Provide a narrative review of all potential complications that can arise from the use of venovenous extracorporeal membrane oxygenation for severe respiratory failure.
- Findings: V-V ECMO is associated with a considerable number of complications, including those rising from erroneous patient selection, timing of initiation, ECMO configuration, cannulation related complications, and short- and long-term severe critical illness sequelae.
- Meaning: An adequate understanding of the implications of ECMO initiation and management decisions, and ECMO-related complications across patients, families, and healthcare teams is crucial to both minimize and address the many patient harms associated with ECMO.
The use of venovenous extracorporeal membrane oxygenation (V-V ECMO) in patients with severe respiratory failure reduces the intensity of mechanical ventilation, thereby decreasing ventilator-induced lung injury (1–6). In a subset of patients, ECMO may be lifesaving (7–10). However, complications related to ECMO are common and affect patient outcomes (10–13). The use of V-V ECMO has increased steadily over time, punctuated by more acute increases during the influenza H1N1 and COVID-19 pandemics (4). The increased demand for V-V ECMO during resource constraints throughout the COVID-19 pandemic led to provision of ECMO outside high-volume tertiary centers, increasing the rate of complications, and worsening outcomes (14,15). Despite clinical practice guidelines from the Extracorporeal Life Support Organization (16) and data from randomized controlled trials (7), patient selection remains challenging and requires ECMO complications to be weighed against the anticipated benefit. This narrative review highlights the implications of decision-making around selection, configuration, and removal, and the short- and long-term complications that can occur during treatment with ECMO (Fig. 1).
Selection criteria for V-V ECMO are influenced by the inclusion and exclusion criteria of randomized controlled trials and outcome data from large cohort studies (7,17). Overall, medically eligible patients have a reversible cause of respiratory failure and severe hypoxemia and/or hypercapnia refractory to the maximization of the mechanical ventilator within the limits of lung-protective ventilation and adjunctive therapies such as prone positioning (7). Although no absolute contraindications exist, ECMO is often avoided in patients with an exceedingly poor prognosis (18,19) or lack of a viable exit strategy (16).
Other characteristics important to the patient’s outcome include advanced age, immunocompromised status, severity of hypercapnia and peak inspiratory pressure, cardiac arrest prior to ECMO, and mechanical ventilation days prior to ECMO among others (20–22). However, these data are derived from studies without a comparator group, so although the prognosis of patients with acute respiratory distress syndrome receiving ECMO can be estimated, the margin of benefit provided by ECMO is less clear. Obesity is not considered a contraindication as higher body mass index does not appear to worsen outcomes (22–25). However, severe obesity (body mass index >40 kg/m2) poses important clinical management challenges including prone positioning prior to and during ECMO, obtaining vascular access during cannulation, and achieving the flow rates necessary to meet metabolic demands (24).
Most contraindications are considered relative because no single factor excludes a patient from receiving ECMO, and the importance of these characteristics may vary by the clinical circumstance. For example, evidence from large cohort studies demonstrated worse outcomes among patients for whom ECMO was initiated after 7 days of mechanical ventilation (21,22,26). However, a patient who experiences a rapid decline due to a new reversible insult (e.g., ventilator-associated pneumonia) after an initial period of improvement allowing for low-intensity (lung protective) mechanical ventilation may be different from the patient who has received 7 days of high-intensity (potentially injurious) mechanical ventilation. Selecting patients based on intubation days alone may lead to the premature use of ECMO. Therefore, for patients with gas exchange parameters nearing ECMO initiation thresholds, yet tolerating mechanical ventilator settings considered lung protective, we defer ECMO and continue conventional management directed as per clinical guidelines (27).
Ultimately, when selecting patients for ECMO, we consider the margin of benefit ECMO would provide, whether the benefit outweighs the potential ECMO-related complications and whether the patient has clinical characteristics consistent with a reasonable prognosis using ECMO.
TIMING OF ECMO OR TRANSFER TO ECMO CENTER
Data from the Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome trial suggested that delayed cannulation, as seen in the crossover group, led to higher mortality compared with patients who did not receive ECMO (7). Earlier cannulation along the trajectory of respiratory failure has been associated with improved outcomes in some studies of patients with COVID-19 treated with ECMO (28,29). However, these differences in outcomes were not consistent when clinicians strictly adhered to lung protective ventilation (30,31). Likewise, transfer to centers capable of providing ECMO for patients in whom transport is safe but severe respiratory failure is worsening, facilitates continuous assessment of the patient’s clinical trajectory and rapid escalation of treatment when necessary, and has been shown to improve outcomes (17). These data may suggest that: 1) proactive decisions about patient eligibility, especially in the context of injurious levels of mechanical ventilation, may optimize outcomes and 2) attempting to rescue patients after prolonged severe respiratory failure and exposure to high-pressure mechanical ventilation may worsen outcomes.
The configuration that best meets the patient’s physiologic deficit should be selected in order to optimize treatment with ECMO. In our experience, providing the appropriate physiologic platform at the outset has mitigated consequences of inadequate support such persistent use of injurious ventilator settings or adjunctive therapies, reconfigurations, or circuit modifications.
V-V ECMO provides no direct hemodynamic support; hence, an assessment of hemodynamic conditions and cardiac function is required prior to cannulation, particularly among patients with accompanying hemodynamic instability. In hypoxemic patients with shock receiving high-dose vasopressors in whom echocardiography shows isolated acute cor pulmonale, V-V ECMO allows for rapid correction of hypoxemia, hypercapnia, and reduction of transpulmonary pressures, thereby improving right ventricular afterload and hemodynamics (32,33). In septic hypoxemic patients whose hemodynamic instability is due to severe left, or biventricular failure, venoarterial (V-A) ECMO provides hemodynamic support and corrects hypoxemia, improving survival (34). However, providers should be aware that additional return cannulas to the venous circulation (V-A-venous ECMO) may be required as a result of differential hypoxemia (35). In contrast, in severely hypoxemic patients with refractory shock in whom biventricular function is normal or mildly reduced, ECMO may be ineffective and may expose patients to complications without any meaningful benefit (34). Erroneously selecting the ECMO configuration may lead to reconfiguration via additional cannula insertion and circuit modifications, introducing additional complications associated with V-A ECMO, such as differential hypoxemia, left ventricular distension, and limb ischemia—which lay outside the scope of this review (36,37).
MECHANICAL VENTILATION CONSIDERATIONS
The optimal level of respiratory system unloading in patients supported with V-V ECMO is unknown (5,38–40). Ventilation strategies during ECMO are heterogeneous (41,42). Targeting the lowest achievable driving pressure, modest levels of positive end-expiratory pressure, low respiratory rates, and low Fio2 are recommended (16). However, rapid reduction in lung volumes, apneic ventilation, or total lung collapse may offset the hemodynamic benefits of V-V ECMO in patients with acute cor pulmonale (32,33). The effect of lung recruitment on lung recovery (via surfactant abnormalities), risk of pneumonia (via atelectasis), inflammation, and survival remains elusive (42–46). In patients with severe hypercapnia prior to cannulation, rapid reduction in ventilatory support may prompt clinicians to use higher levels of sweep gas early after cannulation. Rapid overcorrection of hypercapnia has been shown to increase the risk of neurologic complications in patients supported with ECMO (47,48). Given the paucity of data informing optimal mechanical ventilator management and risks of rapid and extreme changes to settings, we gradually titrate both mechanical ventilation and ECMO based on the patient’s individual physiology and clinical circumstance.
WEANING AND DECANNULATION
Similar to patients on mechanical ventilation, where timely liberation leads to reduced complications and improved outcomes, decannulation at the earliest and safest possible time would be expected to follow a similar path. Evidence on how to wean and liberate patients from V-V ECMO is scarce, and practice patterns vary across centers. Current liberation strategies generally rely on iterative reductions in support and clinician judgment, potentially leading to the underrecognition of readiness for liberation or unsafe liberation attempts. Further, no universal definition of successful decannulation exists (49). Recent data have described standardized approaches to liberation (50,51), showing promising reductions in ECMO duration (52) and potentially reducing complications and costs. Deciding when to liberate patients from V-V ECMO is complex, and while more evidence is generated, a standardized approach is needed.
Additional challenges surrounding decannulation occur when bridging strategies fail. ECMO centers should consider pathways for alternative exit strategies in the event of recovery failure (e.g., lung transplant). Otherwise, suboptimal patient management, conflict amongst family and healthcare providers, and strain and stress in healthcare providers and hospital resources may occur.
Complications related to vascular access are similar to complications observed during the insertion of central lines. Vascular access under ultrasound guidance is the standard of care in most institutions and becomes particularly relevant during the insertion of large bore cannulas (53). Accidental arterial cannulation requires surgical repair and increases the risk of hematoma and retroperitoneal hemorrhage (54). ECMO cannulation requires experienced operators, in particular in obese patients, in whom vessel identification becomes challenging (24). Pneumothorax during cannulation can become a life-threatening situation, as patients are already hypoxemic and receiving high-intensity mechanical ventilation. Echocardiographic guidance can identify guide wire misplacement, pneumothorax, and early right ventricular free-wall perforation (55). Inadvertent arterial cannulation is suspected in the event of acute limb ischemia in patients supported with V-V ECMO (54). Forced blind cannula advancement can result in severe vascular injury, retroperitoneal hemorrhage, hemothorax, or pericardial tamponade (54).
Double-lumen single cannulae are typically inserted in the right internal jugular vein and used to enhance mobilization and conditioning (56). However, disadvantages include blood flow rate restrictions, complex positioning, susceptibility to malpositioning (56), and increased risks of pneumothorax or tamponade at insertion due to right ventricular perforation (57).
Bleeding and Thrombosis
Bleeding and patient and circuit thrombosis are common during V-V ECMO. Thrombosis is more frequent than bleeding, although the occurrence of bleeding has been associated with a higher mortality than thrombosis (58,59). Bleeding occurs in 21–66% of patients supported with V-V ECMO (59–61). Although most bleeding complications are minor (59), hemothorax, retroperitoneal hematomas, and gastrointestinal bleeding may cause hemorrhagic shock and death. Bleeding and thrombosis are provoked by exposure of blood to nonbiologic circuit components, causing activation of the coagulation system and degradation of hemostatic factors (62). Differential risk factors for bleeding and thrombosis include age, higher weight, higher pH at initiation, and lower ratio of fraction of Po2 to Fio2 (59). Systemic anticoagulation increases the risk of bleeding; however, bleeding may also be observed in patients treated without anticoagulation via thrombocytopenia, hypofibrinogenemia, and shear mediated loss of key platelet surface molecules, selectin, and high-molecular-weight von Willebrand multimers (63). Hemolysis and platelet dysfunction are common and can occur at high- and low-blood flow states, although more data are needed to understand the impact on outcomes (64). Thrombocytopenia is often multifactorial due to sepsis, medications, and the circuit, among others (65,66). Heparin-induced thrombocytopenia in the treatment of ECMO is rare (3.7%) (66), although carries a high risk of thrombosis to the circuit and patient (2).
Neurologic complications are uncommon in patients receiving ECMO and include seizures, intracranial hemorrhage, ischemic stroke, and brain death. Intracranial hemorrhage is a devastating complication of ECMO affecting 1–6% of cases (59,67). Risk factors for intracranial hemorrhage include COVID-19 (68,69) and rapid overcorrection of hypercapnia early after cannulation (47,48). Survival and functional outcomes after hemorrhagic stroke are generally poor (70–72). Various degrees of ischemic complications, varying from stroke to microvascular thrombosis or microhemorrhages, have been described (73,74). The mechanisms leading to ischemic neurologic events in patients on V-V ECMO are less clear than for intracranial hemorrhage, and treatment options are limited (59).
Infections are estimated to complicate 30–55% of ECMO runs and impact survival (75,76). Ventilator-associated pneumonia is the most frequent nosocomial infection in patients receiving V-V ECMO (76). Blood stream infections in patients on V-V ECMO occur in 13% of ECMO runs and are associated with longer duration of ECMO support (77). ECMO device infection and colonization rates of 10% and 32%, respectively, have been reported (78). The lack of a standardized definition of ECMO-related infections, discerning colonization from infection, and unreliable clinical markers of infection during ECMO makes understanding the relationship between infection and outcomes challenging (75). Further, source control may be difficult due to the impracticalities of exchanging or removing circuit components, leading to longer or recurrent antibiotic treatment courses.
Acute Kidney Injury
Acute kidney injury can occur in up to 60% of patients receiving ECMO (79) and is likely due to concomitant comorbidities and critical illness (79,80). Acute insults driven by bleeding or sepsis further exacerbate injury mediated by congestive nephropathy and hypoxia in patients with acute cor pulmonale (80,81). Renal replacement therapy is sometimes unavoidable, and prevention of intradialytic hypotension will help achieve renal recovery (82). Techniques to provide renal replacement therapy while on ECMO may include the addition of an in-line hemofilter to the circuit, a parallel dialysis system (independent vascular access), or integrated systems (dialysis machine connected to the ECMO circuit); each has distinct advantages or disadvantages (80). Severe acute renal failure in patients on V-V ECMO is associated with higher 90-day mortality (83). Prolonged renal replacement therapy (≥ 7 d) is associated with higher ventilator dependence and readmission rates (84).
Circuit Component Malfunctions
Oxygenator or circuit malfunction is the most common ECMO-related complication (59,67). Membrane aging results in decreased oxygenator efficiency and membrane compartmentalization (85,86). Oxygenator fibrin deposition/thrombosis, and condensation within the hollow fibers generate membrane dead space and shunt. Degradation of circuit components over time and circuit component exchanges can be problematic, particularly in patients with extremely poor native lung function and dependent on ECMO for gas exchange. Air entrainment can occur through fractured circuit connectors, sampling ports, or via central access lines in close proximity to the drainage cannula (87). Management generally consists on deairing the premembrane chamber; significant air entrainment will lead to pump air lock or air embolism (87). Other mechanical complications include pump failure, power failure, and inadvertent decannulation. Any interruption to the ECMO circuit to address these complications can lead to rapid gas exchange abnormalities, hemodynamic instability, hemorrhage, and death.
In a subset of patients on V-V ECMO, refractory hypoxemia may develop or persist despite high extracorporeal blood flow. A structured approach is required to identify causes of persistent hypoxemia, including recirculation, high cardiac output states, oxygenator dysfunction, and worsening native lung function (88). Clinically significant recirculation can be identified by reduced color differential in cannulas and high oxygen saturation in premembrane gases (88,89). High cardiac output states increase the fraction of circulating blood bypassing the ECMO circuit (88,89). If a mismatch persists between native cardiac output and maximum extracorporeal blood flow, sedation, paralysis, or cooling may reduce oxygen consumption, but may increase delirium, weakness, and infection (88). Beta blockers may reduce intrinsic cardiac output but may be prohibitive due to hypotension and further impairment of tissue oxygen delivery (89). Prone position on ECMO has shown mixed results and introduces management challenges including cannula displacement or dislodgment, endotracheal tube obstruction, and pressure sores (90–92). Higher hemoglobin targets may improve oxygen delivery at the cost of volume overload, infection, and sensitization (88). Additional interventions for refractory hypoxemia that have been used in clinical practice include increasing ventilatory support beyond lung protective ventilation and hemodynamic tolerance, insertion of additional drainage cannulas if blood flow is not already maximized through the single oxygenator, or adding a second oxygenator in series or additional circuit in parallel. Additional mechanical support poses further risk of vascular access complications, coagulopathies, and hemolysis, and evidence is limited to case series (93,94). Finally, oxygenation goals on ECMO are controversial, and many ECMO centers target Spo2 greater than 80–85% while monitoring for evidence of organ dysfunction.
Long-term complications and outcomes related to ECMO are vastly underreported and reflect those inherent to critical illness. Nutritional requirements in patients supported with ECMO are undefined; protein dosing in obese and nonobese V-V ECMO patients may be inadequate (95,96). Early mobilization and rehabilitation in ECMO patients can be limited by hypoxemia, sedation, and hemodynamic instability (97). However, cannulation site is not a contraindication for mobilization (98,99). Cardiopulmonary dynamics should inform adequate levels of extracorporeal support and titration during physical rehabilitation. When available, patients should be referred to post-ICU follow-up clinics.
Survivors of severe respiratory failure supported with ECMO may experience decrements in health-related quality of life; half return to work (100). The healthcare team should inform patients and families of the potential long-term physical and emotional challenges and promote a shared decision-making model that aligns possible outcomes with patient’s expectations and goals of care. ECMO should be introduced to patients and families as a time-limited trial with continuous reassessment of hope toward a meaningful outcome. Without this approach, unrealistic expectations may be generated by patients, family, and the multidisciplinary team. Prolonged nonbeneficial care increases healthcare provider dissatisfaction and burnout (101). Decisions to withdraw ECMO for futility induce significant stress in clinicians, especially in awake patients. Lacking goal-concordant-care results in futility, poor outcomes, and fractured relationships.
Complications caused, mediated, or compounded by ECMO can occur across the spectrum of ECMO delivery (Fig. 1). Poor patient selection can lead to unnecessary exposure of the broad range of ECMO-related complications or futile care. An inadequate ECMO configuration can lead to insufficient physiologic support requiring injurious adjunctive therapies and avoidable technical complications. Premature or delayed weaning and liberation from ECMO can lead to recannulation or needless prolonged exposure to ECMO. The use of ECMO can introduce a variety of complications including bleeding, thrombosis, and hemolysis, neurologic and kidney injury, concomitant infections, circuit malfunctions, and others. Long-term complications parallel those of critical illness, including functional, and quality-of-life deficiencies. ECMO can introduce unique ethical challenges and emotional burdens, particularly as bridging strategies fail. An adequate understanding of the implications of ECMO initiation and management decisions, and ECMO-related complications across patients, families, and healthcare teams is crucial to both minimize and address the many patient harms associated with ECMO.
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