Section: Therapy Effective Date: July 15, 2015 Subsection: Original Policy Date: June 19, 2015 Subject:

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1 Last Review Status/Date: June 2015 Page: 1 of 28 Summary Extracorporeal membrane oxygenation (ECMO) provides extracorporeal circulation and physiologic gas exchange for temporary cardiorespiratory support in cases of severe respiratory and cardiorespiratory failure. ECMO has generally been used in clinical situations in which there is respiratory or cardiac failure, or both, in which death would be imminent unless medical interventions can immediately reverse the underlying disease process or physiologic functions can be supported for long enough that normal reparative processes or treatment can occur (e.g., resolution of acute respiratory distress syndrome [ARDS] or treatment of infection) or other life-saving intervention can be delivered (e.g., provision of a lung transplant). Potential indications for ECMO in the adult population include acute, potentially reversible respiratory failure due to a variety of causes; as a bridge to lung transplant; in potentially reversible cardiogenic shock; and as an adjunct to cardiopulmonary resuscitation (ECMO-assisted CPR). The evidence related to the use of ECMO in adult acute respiratory failure consists of one moderatelysized randomized controlled trial (RCT), several nonrandomized comparative studies, and multiple case series. The most direct evidence about the efficacy of ECMO in adult respiratory failure comes from the CESAR trial. Although the CESAR trial had limitations, including nonstandardized management in the control group and unequal intensity of treatment between the treatment and control groups, for the study s primary outcome of disability-free survival at 6 months, there was a large effect size, with an absolute risk reduction in mortality of 16.25%. Recent nonrandomized comparative studies generally report improvements in outcomes with ECMO. Therefore, the use of ECMO may be considered medically necessary for patients meeting the definitions of acute respiratory failure in the CESAR trial. However, questions remain about the generalizability of findings from the CESAR trial and nonrandomized study results to other patient populations, and further clinical trials in more specific patient populations are needed. The evidence related to the use of ECMO as a bridge to lung transplantation consists of small case series. For this population, there are no other options, the alternative is likely death, and controlled trials would be extremely difficult to perform. Although the available evidence about whether the use of ECMO increases the rate of successful lung, heart, or heart-lung transplantation is limited, clinical input supported the use of ECMO as a short-term bridge to transplant. Therefore, ECMO may be considered medically necessary for this indication.

2 Page: 2 of 28 Less evidence exists about the use of ECMO for primary cardiac causes and ECMO-assisted CPR. For these indications, case series do not provide evidence on efficacy compared with standard care, and nonrandomized comparative studies are limited by selection bias that likely leads to noncomparability of patient groups. As a result, ECMO for primary cardiogenic shock and ECMOassisted CPR are considered investigational. Related Policies Inhaled Nitric Oxide Policy *This policy statement applies to clinical review performed for pre-service (Prior Approval, Precertification, Advanced Benefit Determination, etc.) and/or post-service claims. The use of extracorporeal membrane oxygenation (ECMO) in adults may be considered medically necessary for the management of adults with acute respiratory failure when all of the following criteria are met: Respiratory failure is due to a potentially reversible etiology (see Policy Guidelines section) AND Respiratory failure is severe, as determined by one of the following: o A standardized severity instrument such as the Murray score (see Policy Guidelines section); OR o One of the criteria for respiratory failure severity outlined in the Policy Guidelines. AND None of the following contraindications are present: o High ventilator pressure (peak inspiratory pressure >30 cm H2O) or high FIO2 (>80%) ventilation for more than 168 hours; o Signs of intracranial bleeding; o Multisystem organ failure; o Prior (i.e., before onset of need for ECMO) diagnosis of a terminal condition with expected survival <6 months; o A do-not-resuscitate (DNR) directive; o Cardiac decompensation in a patient already declined for ventricular assist device (VAD) or transplant; o KNOWN neurologic devastation without potential to recover meaningful function; o Determination of care futility (see Policy Guidelines section). The use of ECMO in adults may be considered medically necessary as a bridge to heart, lung, or combined heart-lung transplantation for the management of adults with respiratory, cardiac, or combined cardiorespiratory failure refractory to optimal conventional therapy. The use of ECMO in adult patients is considered investigational when the above criteria are not met, including but not limited to acute and refractory cardiogenic shock and as an adjunct to cardiopulmonary resuscitation.

3 Page: 3 of 28 Policy Guidelines Extracorporeal membrane oxygenation (ECMO) is considered investigational for most cases of cardiogenic shock. However, In individual clinical situations, ECMO may be considered beneficial/lifesaving for relatively short-term support (ie, days) for cardiogenic shock refractory to standard therapy in specific situations when shock is thought to be due to a potentially reversible condition, such as ST elevation acute myocardial infarction, acute myocarditis, peripartum cardiomyopathy, or acute rejection in a heart transplant, AND when there is reasonable expectation for recovery. Policy Applications and Definitions Adults are considered patients older than age 18. This policy addresses the use of long-term (ie, over 6 hours) extracorporeal cardiopulmonary support. It does not address the use of extracorporeal support, including ECMO, during surgical procedures. Respiratory Failure Reversibility The reversibility of the underlying respiratory failure is best determined by the treating physicians, ideally physicians with expertise in pulmonary medicine and/or critical care. Some of the underlying causes of respiratory failure which are commonly considered reversible are as follows: Acute respiratory distress syndrome (ARDS) Acute pulmonary edema Acute chest trauma Infectious and noninfectious pneumonia Pulmonary hemorrhage Pulmonary embolism Asthma exacerbation Aspiration pneumonitis. ARDS refers to a clinical condition characterized by bilateral pulmonary infiltrates and severe hypoxemia in the absence of cardiogenic pulmonary edema. A consensus definition for ARDS was first developed in 1994 with the American-European Consensus Conference (AECC) on ARDS. The AECC definition was revised in 2012 by a panel convened by the European Society of Intensive Care Medicine, with endorsement from the American Thoracic Society and the Society of Critical Care Medicine, into the Berlin Definition, which was validated with empirically evaluated using a patientlevel meta-analysis of 4188 patients with ARDS from 4 multicenter clinical data sets and 269 patients with ARDS from 3 single-center data sets containing physiologic information. 1 Table 1 shows the Berlin definition of ARDS. Table 1: Berlin Definition of Acute Respiratory Distress Syndrome 1 Criteria Timing Within 1 week of a known clinical insult or new or worsening respiratory symptoms Chest imaging (CT or Bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules CXR Origin of edema Respiratory failure not fully explained by cardiac failure or fluid overload. Need objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factors present.

4 Page: 4 of 28 Oxygenation Mild 200 mm Hg < PaO2/FIO2 <300 mm Hg with PEEP or CPAP >5 cm H2O Moderate 100 mm Hg < PaO2/FIO2 200 mm Hg with PEEP or CPAP 5 cm H2O Severe PaO2/FIO2 100 mmhg with PEEP or CPAP 5 cm H2O CPAP: continuous positive airway pressure; CT: computed tomography; CXR: chest x-ray; Fio2: fraction of inspired oxygen; Pao2: partial pressure of oxygen in arterial blood; PEEP: peak end expiratory pressure. Respiratory Failure Severity Murray Score One commonly used system for classifying the severity of respiratory failure is the Murray scoring system, which was developed for use in ARDS but has been applied to other indications. This score includes 4 subscales, each of which is scored from 0 to 4. The final score is obtained by dividing the collective score by the number of subscales used. A score of 0 indicates no lung injury; a score of 1 to 2.5 indicates mild or moderate lung injury; and a score of 2.5 indicates severe lung injury, e.g., ARDS. Table 2 shows the components of the Murray scoring system. Table 2: Murray Lung Injury Score Subscale Criteria Score Chest x-ray score No alveolar consolidation Alveolar consolidation confined to 1 quadrant Alveolar consolidation confined to 2 quadrants Alveolar consolidation confined to 3 quadrants Alveolar consolidation in all 4 quadrants Hypoxemia score PaO2/FIO2 >300 PaO2/FIO PaO2/FIO PaO2/FIO PaO2/FIO2 100 PEEP score (when ventilated) PEEP 5 cm H2O PEEP 6-8 cm H2O PEEP 9-11 cm H2O PEEP cm H2O Respiratory system compliance score (when available) PEEP 15 cm H2O Compliance >80 ml/cm H2O Compliance ml/cm H2O Compliance ml/cm H2O Compliance ml/cm H2O Compliance 19 ml/cm H2O CPAP: continuous positive airway pressure; FIO2: fraction of inspired oxygen; PaO2: partial pressure of oxygen in arterial blood; PEEP: peak end expiratory pressure. Alternative Respiratory Failure Severity Criteria Respiratory failure is considered severe if the patient meets one or more of the following criteria: Uncompensated hypercapnia with a ph less than 7.2; or PaO2/FIO2 of <100 mm Hg on fraction of inspired oxygen (FIO2) >90%; or

5 Page: 5 of 28 Inability to maintain airway plateau pressure (Pplat) <30 cm H2O despite a tidal volume of 4 to 6 ml/kg ideal body weight (IBW); or Oxygenation Index >30: Oxygenation Index = FIO MAP 100 = FIO2 as percentage; MAP = mean airway pressure in cm H20; PaO2=partial pressure of oxygen in arterial blood]; or CO2 retention despite high Pplat (>30 cm H2O). Assessment of ECMO Futility Patients undergoing ECMO treatment should be periodically reassessed for clinical improvement. ECMO should not be continued indefinitely if the following criteria are met: Neurologic devastation as defined by the following: o Consensus from 2 attending physicians that there is no likelihood of an outcome better than persistent vegetative state at 6 month, AND o At least one of the attending physicians is an expert in neurologic disease and/or intensive care medicine, AND o Determination made following studies including CT, EEG and exam. OR Inability to provide aerobic metabolism, defined by the following: o o Refractory hypotension and/or hypoxemia, OR Evidence of profound tissue ischemia based on creatine phosphokinase (CPK) or lactate levels, lactate-to-pyruvate ratio, or near-infrared spectroscopy (NIRS) OR Presumed end-stage cardiac or lung failure without exit plan (ie, declined for assist device and/or transplantation). Background ECMO provides extracorporeal circulation and physiologic gas exchange for temporary cardiorespiratory support in cases of severe respiratory and cardiorespiratory failure. ECMO devices use an extracorporeal circuit, combining a pump and a membrane oxygenator, to undertake oxygenation of and removal of carbon dioxide from the blood. ECMO has been investigated as an intervention since the late 1960s following the development of the first membrane oxygenator for extracorporeal oxygenation. ECMO has been widely used in the pediatric population, particularly in neonates with pulmonary hypertension and meconium aspiration syndrome. Over time, interest has developed in the use of ECMO for cardiorespiratory support for adult conditions. Early studies of the use of ECMO for adult respiratory and cardiorespiratory conditions, particularly severe ARDS, including 1 RCT conducted in the United Kingdom in the 1970s which showed poor survival and high rates of complications due to the anticoagulation required for the ECMO circuit. 2 Over time, with improvements in ECMO circuit technology and methods of supportive care, interest in the use of ECMO in adults has resurged. In particular, during the period of H1N1 pandemic influenza the occurrence of cases of influenza-related ARDS, particularly in relatively young, generally healthy people, prompted a resurgence in the interest of ECMO for ARDS.

6 Page: 6 of 28 ECMO has generally been used in clinical situations in which there is respiratory or cardiac failure, or both. In these situations, death would be imminent unless medical interventions can immediately reverse the underlying disease process or physiologic functions can be supported for long enough that normal reparative processes or treatment can occur (e.g., resolution of ARDS or treatment of infection) or other life-saving intervention can be delivered (e.g., provision of a lung transplant). Disease-Specific Indications for ECMO Venoarterial (VA) and venovenous (VV) ECMO have been investigated for a wide range of adult conditions that can lead to respiratory or cardiorespiratory failure, some of which overlap clinical categories (e.g., H1N1 influenza infection leading to ARDS and cardiovascular collapse), which makes categorization difficult. However, in general, indications for ECMO can be categorized as follows: Acute respiratory failure due to potentially reversible causes. Acute respiratory failure refers to the failure of either oxygenation, removal of carbon dioxide, or both, and may be due to a wide range of causes. In these cases, ECMO is most often used as a bridge to recovery. Specific potentially reversible or treatable indications for ECMO may include ARDS, acute pneumonias, and a variety of other pulmonary disorders. Bridge to lung transplant. Lung transplant is used for management of chronic respiratory failure, most frequently in the setting of advanced chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, cystic fibrosis, emphysema due to alpha-1-antitrypsin deficiency, and idiopathic pulmonary arterial hypertension. In the end stages of these diseases, patients may require additional respiratory support while awaiting an appropriate donor. In addition, patients who have undergone a transplant may require retransplantation due to graft dysfunction after the primary transplant. Acute-onset cardiogenic or obstructive shock is defined as shock that is due to cardiac pump failure or vascular obstruction, refractory to inotropes and/or other mechanical circulatory support. Examples of this category include postcardiotomy syndrome (ie, failure to wean from bypass), acute coronary syndrome, myocarditis, cardiomyopathy, massive pulmonary embolism, and prolonged arrhythmias. ECMO-assisted cardiopulmonary resuscitation (E-CPR). ECMO can be used as an adjunct to CPR in patients who do not respond to initial resuscitation measures. ECMO: Technology Description The basic components of ECMO include a pump, an oxygenator, sometimes referred to as a membrane lung, and some form of vascular access. Based on the vascular access type, ECMO can be described as VV or VA. More recently, these include ventilation support devices that provide oxygenation and removal of CO2 without the use of a pump system or interventional lung assist devices (e.g., ila Membrane Ventilator, Novalung GmbH); these are beyond the scope of this policy.

7 Venovenous ECMO Page: 7 of 28 Technique In venovenous extracorporeal membrane oxygenation (VV ECMO), the ECMO oxygenator is in series with the native lungs, and the ECMO circuit provides respiratory support. Venous blood is withdrawn through a large-bore intravenous line; oxygen is added and CO2 removed, and oxygenated blood is returned to the venous circulation near the right atrium. Venous access for VV ECMO can be configured through 2 single lumen catheters (typically in the right internal jugular and femoral veins), or through 1 dual lumen catheter in the right internal jugular vein. In the femorojugular approach, a single large multiperforated drainage cannula is inserted in the femoral vein and advanced to the cavo-atrial junction, and the return cannula is inserted into the superior vena cava via the right internal jugular vein. Alternatively, in the bi-femoral-jugular approach, drainage cannulae are placed in both the superior vena cava and the inferior vena cava via the jugular and femoral veins, and a femoral return cannula is advanced to the right atrium. In the dual-lumen catheter approach, a single bicaval cannula is inserted via the right jugular vein and positioned to allow drainage from the inferior vena cava and superior vena cava and return via the right atrium. Indications VV ECMO provides only respiratory support, and therefore is used for conditions in which there is progressive loss in ability to provide adequate gas exchange due to abnormalities in the lung parenchyma, airways, or chest wall. Right ventricular (RV) dysfunction due to pulmonary hypertension that is secondary to parenchymal lung disease may sometimes be effectively treated by VV ECMO. However, acute or chronic obstruction of the pulmonary vasculature (e.g., saddle pulmonary embolism) may require VA ECMO. There may be cases in which RV dysfunction due to pulmonary hypertension caused by severe parenchymal lung disease may be severe enough to require VA ECMO. In adults, VV ECMO is generally used only in situations in which all other reasonable avenues of respiratory support have been exhausted, including mechanical ventilation with lung protective strategies, pharmacologic therapy, and prone positioning. Venoarterial ECMO Technique In venoarterial extracorporeal membrane oxygenation (VA ECMO), the ECMO oxygenator is in parallel with the native lungs and the ECMO circuit provides both cardiac and respiratory support. In VA ECMO, venous blood is withdrawn and oxygen is added and CO2 removed similar to VV ECMO, but blood is returned to the arterial circulation. Cannulation for VA ECMO can done peripherally, with withdrawal of blood from a cannula in the femoral or internal jugular vein and return of blood through a cannula in the femoral or subclavian artery. Alternatively, it can be done centrally, with withdrawal of blood directly from a cannula in the right atrium and return of blood through a cannula in the aorta. VA ECMO typically requires a high blood flow extracorporeal circuit. Indications VA ECMO provides both cardiac and respiratory support. Thus, it is used in situations of significant cardiac dysfunction that is refractory to other therapies, when significant respiratory involvement is suspected or demonstrated, such as treatment-resistant cardiogenic shock, pulmonary embolism, or

8 Page: 8 of 28 primary parenchymal lung disease severe enough to compromise right heart function. Echocardiography should be used before ECMO is considered or started to identify severe left ventricular dysfunction which might necessitate the use of VA ECMO. The use of peripheral VA ECMO in the presence of adequate cardiac function may cause severe hypoxia in the upper part of the body (brain and heart) in the setting of a severe pulmonary shunt.2 Medical Management During ECMO During ECMO, patients require supportive care and treatment for their underlying medical condition, including ventilator management, fluid management, and systemic anticoagulation to prevent circuit clotting, nutritional management, and appropriate antimicrobials. Maintenance of the ECMO circuit requires frequent (ie, multiple times in 24 hours) monitoring by medical and nursing staff and evaluation at least once per 24 hours by a perfusion expert. ECMO may be associated with significant complications, which can be related to the vascular access required to the need for systemic anticoagulation, including hemorrhage, limb ischemia, compartment syndrome, cannula thrombosis, and limb amputation. Patients are also at risk of progression of their underlying disease process. Regulatory Status The regulatory status of ECMO devices is complex. Historically, FDA evaluated the components of an ECMO circuit separately, and the ECMO oxygenator has been considered the primary component of the circuit. Current Regulatory Status ECMO Oxygenator Regulatory Status The ECMO oxygenator (membrane lung, product code BYS), defined as a device used to provide to a patient for extracorporeal blood oxygenation for more than 24 hours, has been classified as a class III device but cleared for marketing through the preamendment premarket notification (510[k]) process. In 1977, the Membrane Lung (for long term respiratory support) (William Harvey Life Products Corp.) received FDA approval. This is the only device listed in a search of the product code (BYS) for membrane lungs. Patients who can be considered for ECMO are adults with ARDS that are not responding to traditional management and have a risk of death greater than 50%. The membrane lung was designated as a class II device. In 1979, FDA reclassified the membrane lung as a class III device, (it remains a class II for the neonatal/pediatric population). There has been an ongoing discussion regarding reversing the class III designation to a class II designation (see Proposed Regulatory Changes section). ECMO procedures can also be performed using cardiopulmonary bypass (CPB) circuit devices on an off- label basis. Multiple CPB oxygenators have clearance for marketing through the FDA 510(k) process (FDA product code: DTZ).

9 Page: 9 of 28 Regulatory Status of Other ECMO Components In addition to the ECMO oxygenator, FDA regulates other components of the ECMO circuit through the 510(k) process, including the arterial filter (FDA product code DTM), the roller pump (FDA product code DWB), the tubing (FDA product code DWE), the reservoir (FDA product code DTN), and the centrifugal pump (FDA product code KFM). Several dual lumen catheters have approval for use during extracorporeal life support (e.g., Kendall Veno- Venous Dual-Lumen Infant ECMO Catheter; Origen Dual Lumen Cannulas; Avalon Elite Bi- Caval Dual Lumen Catheter.) Proposed Regulatory Changes FDA has convened several Circulatory System Device Advisory Committees to discuss the classification of the ECMO oxygenator (membrane lung) and other components. On January 8, 2013, FDA issued a proposed order which, if made final, would make the class III ECMO devices class II subject to premarket notification (510[k]) and special controls. On September 12, 2013, FDA s Circulatory System Devices Advisory Committee discussed the classification of the membrane lung for long-term pulmonary support specifically for pediatric cardiopulmonary and failure-to-wean from cardiac bypass patient population. The committee approved FDA s proposed premarket regulatory classification strategy for extracorporeal circuit and accessories for long-term pulmonary/cardiopulmonary support to reclassify from class III to class II for conditions in which an acute (reversible) condition prevents the patient s own body from providing the physiologic gas exchange needed to sustain life in conditions where imminent death is threatened by respiratory failure (e.g., meconium aspiration, congenital diaphragmatic hernia, pulmonary hypertension) in neonates and infants, or cardiorespiratory failure (resulting in the inability to separate from cardiopulmonary bypass following cardiac surgery) in pediatric patients. The panel agreed with the proposed reclassification of ECMO devices from class III (premarket approval) to class II (Special Controls) for conditions where imminent death is threatened by cardiopulmonary failure in neonates and infants or where cardiopulmonary failure results in the inability to separate from cardiopulmonary bypass following cardiac surgery On May 7, 2014, FDA convened a Circulatory System Devices Advisory Committee to discuss the classification of the ECMO oxygenator (membrane lung) for adult pulmonary and cardiopulmonary indications and to discuss the overall classification of the ECMO components. FDA s Center for Devices and Radiological Health proposed a classification regulation to change the title of the regulation from Membrane Lung for Long-Term Pulmonary Support to Extracorporeal Circuit and Accessories for Long- Term Pulmonary/Cardiopulmonary Support, move the regulation from an anesthesia device regulation to a cardiovascular device regulation, and define long-term as extracorporeal support longer than 6 hours. Rationale The ideal study design for the evaluation of either venoarterial (VA) or venovenous (VV) extracorporeal membrane oxygenation (ECMO) for adult respiratory and cardiorespiratory conditions would be multicenter randomized controlled trials (RCTs) that compare treatment with ECMO with best standard therapy, using standardized criteria for enrollment and standardized management protocols for both the ECMO and control groups. Outcomes should include both short- and long-term mortality, along with

10 Page: 10 of 28 measures of significant morbidity (e.g., intracranial hemorrhage, thrombosis, vascular access site hemorrhage, limb ischemia) and short- and long-term disability and quality-of-life measures. However, there are likely significant challenges to enrolling patients in RCTs to evaluate ECMO, including the possibly of overlap in medical conditions leading to respiratory and cardiorespiratory failure, lack of standardization in alternative treatments, and the fact that ECMO is typically used as a treatment of last resort in patients who are otherwise at high risk of death. Nonrandomized comparative studies and uncontrolled studies can sometimes provide useful information on health outcomes related to ECMO. Nonrandomized studies of ECMO are unlikely to be affected by the placebo effect; in many cases, the underlying condition will have a reasonably well-defined natural history without therapy. However, these studies are prone to bias in the selection of patients for treatments, limiting their ability to provide comparisons of ECMO relative to alternative treatments. The evidence related to the use of ECMO in adults is discussed separately for studies that primarily address respiratory failure, that address primarily cardiac failure, and studies that evaluate mixed populations. Although VA and VV ECMO have different underlying indications (i.e., cardiorespiratory failure versus respiratory failure), studies reporting outcomes after ECMO do not always separate VA and VV ECMO; therefore, studies related to the use of VA and VV ECMO are discussed together next. Literature related to the use of ECMO in adults includes a single RCT and multiple noncomparative cohort studies and case series. Two RCTs of ECMO were conducted in 1979 and 1994, but are not included here because they occurred in the time period before the use of lung-protective ventilation and are not representative of current treatment practices. ECMO for Adult Respiratory Failure In adults, ECMO has been used most often in the management of acute respiratory failure due to a variety of causes, often, but not exclusively, in the setting of acute respiratory distress syndrome (ARDS). Although the largest body of literature for the use of ECMO in adults relates to its use in the management of ARDS, often but not exclusively secondary to H1N1 influenza, the single RCT evaluated the use of VV ECMO for severe acute respiratory failure due to one of several causes. Randomized Controlled Trials In 2009, Peek et al reported results of the CESAR trial, a multicenter pragmatic RCT that compared conventional management with referral to a center for consideration for VV ECMO treatment for 180 adult patients with severe acute respiratory failure.3 Inclusion criteria were age 18 to 65 years, with severe but potentially reversible respiratory failure (Murray score >3.0 or ph <7.20). Exclusion criteria were: high pressure (>30 cm H2O for peak inspiratory pressure) or high FIO2 (>0.8) ventilation for more than 7 days; intracranial bleeding; other contraindication to limited heparinization; or any contraindication to continuation of active treatment. Seven hundred sixty-six patients were screened; of those, 180 were allocated to consideration for treatment with ECMO (n=90) or conventional management (n=90). Of those in the ECMO group, 68 (75%) actually received ECMO. Patients were enrolled from 3 types of facilities: an ECMO center (to which all patients who were randomly allocated to ECMO consideration were transferred); tertiary intensive care units (ICUs; conventional treatment centers); and referral hospitals (which sent patients to conventional treatment centers if they were randomly allocated to receive conventional treatment). For patients in the conventional management group, a specific management protocol was not mandated, but treatment centers were advised to follow a low-volume,

11 Page: 11 of 28 low-pressure ventilation strategy. The primary outcome measure was death or severe disability at 6 months after randomization (defined as death by 6 months or before discharge from hospital at any time to the end of data collection). Six-month follow-up outcomes were evaluated in the patients homes by researchers masked to allocation. The primary analysis was intention-to-treat. Sixty-two patients in the ECMO group (69%) required transport to the ECMO center; a mean of 6.1 hours occurred between randomization and treatment. In the conventional management group, 11 patients (12%) required transport to a tertiary ICU. For the primary outcome, 63% (57/90) of patients allocated to consideration for ECMO survived to 6 months without disability compared with 47% (41/87) of those allocated to conventional management (relative risk [RR], 0.69; 95% confidence interval [CI], 0.05 to 0.97; p=0.03). There were differences in treatment management other than the use of ECMO between the ECMO consideration group and the conventional management group, including the fact that low-volume, low-pressure ventilation was used in more patients (93% vs 70%; p<0.001) and on a greater proportion of days (23.9% vs 15%; p<0.001) for patients allocated to the ECMO consideration group compared with those in the conventional management group. Patients allocated to the ECMO consideration group more frequently received steroids (76% vs 58%; p=0.001) and were more frequently managed with a molecular albumin recirculating system (17% vs 0%; p<0.001). The CESAR trial suggests that the use of a treatment strategy involving transfer of patients with severe respiratory failure for consideration for ECMO is associated with improved disability-free survival. Strengths of the CESAR trial include its randomized design and standard ECMO treatment protocol. However, patients randomized to conventional management were not managed by a standardized protocol, which was noted to be due to the inability of participating centers to agree on a management protocol. Several aspects of treatment other than the use of ECMO differed between the ECMO strategy and the conventional management strategy groups. In addition, it is possible that patients randomized to the ECMO consideration strategy benefited from transfer to the ECMO center, if larger patient volumes there lead to improved treatment outcomes for severe respiratory failure. About 20% of patients randomized to the ECMO consideration group improved after transport to the ECMO center sufficiently to not require ECMO; 82% of these patients survived to discharge, while 63% of patients treated with ECMO survived to discharge. The authors attribute this difference to slightly less severe lung disease in the patients who did not require ECMO. However, it is also possible that some aspect of the conventional management delivered at the ECMO center contributed to this improved outcome. Systematic Reviews and Meta-Analyses Several systematic reviews including both randomized and nonrandomized studies have addressed the use of ECMO for acute respiratory failure in general and specific etiologies of acute respiratory failure. Acute Respiratory Failure In 2013, Zampieri et al reports results of a systematic review and meta-analysis evaluating the role of VV ECMO for severe acute respiratory failure in adults. 4 The authors searched for RCTs and observational case-control studies with severity-matched patients that evaluated the use of ECMO in severe acute respiratory failure in adults. Three studies were included in the meta-analysis that comprised a total of 353 patients of whom 179 received ECMO, 1 RCT (CESAR trial, 3 previously described) and 2 casecontrol studies with severity-matched patients (Noah et al 5 and Pham et al). 6 For the primary analysis, the pooled in-hospital mortality in the ECMO-treated group was not significantly different from the control

12 Page: 12 of 28 group (odds ratio [OR], 0.71; 95% CI, 0.34 to 1.47; p=0.358). Both nonrandomized studies included only patients treated for H1N1 influenza A infection, which may limit their generalizability to other patient populations. Also in 2013, Zangrillo et al reported the results of a systematic review and meta-analysis that evaluated the role of ECMO for respiratory failure due to H1N1 influenza A infection in adults. 7 The meta-analysis included 8 studies, all observational cohort studies, that included 1357 patients with confirmed or suspected H1N1 infection requiring ICU admission, 266 (20%) of whom were treated with ECMO. The median age of those receiving ECMO was 36 years, with 43% men. In 94% of cases, VV ECMO was used, with VA ECMO used only in patients presenting with respiratory and systolic cardiac failure or unresponsive to VV ECMO. The median ECMO use time was 10 days. Reported outcomes were variable across the studies, but in a random-effects pooled model, the overall in-hospital mortality was 27.5% (95% CI, 18.4% to 36.7%), with a median ICU stay of 25 days and an overall median length of stay of 37 days. In 2010, Mitchell et al conducted a systematic review and meta-analysis to attempt to evaluate the role of ECMO in acute respiratory failure due to H1N1 influenza. 8 The authors were unable to identify any studies meeting their inclusion criteria, so they broadened their search to include studies that evaluated acute respiratory failure due to any causes. Three RCTs were identified: the CESAR trial previously described and 2 older trials, 1 from 1994 and 1 from The summary risk ratio for mortality for patients treated with ECMO compared with controls was 0.93 (95% CI, 0.71 to 1.22). However, there was significant heterogeneity across studies. Given changes in the technology over time, pooling outcomes from studies conducted over more than 30 years may not be meaningful. Acute Respiratory Distress Syndrome In 2008, Chalwin et al conducted a systematic review and meta-analysis of the use of ECMO as salvage therapy for adults with ARDS. 9 The authors identified 2 RCTs, including the 1994 and 1979 RCTs included in Mitchell et al, and 3 nonrandomized comparative studies. Pool analysis of the 2 RCTs using a Bayesian random effects model found an OR for mortality of 1.28 (95% credible interval, 0.24 to 6.55), demonstrating no significant evidence of benefit or harm. Given differences in patient populations and criteria for ECMO in the nonrandomized comparative studies, pooled analysis was not attempted. Nonrandomized Comparative Studies Pham et al reported results from a matched cohort study using data from a French national registry that evaluated the influence of ECMO on ICU mortality in patients with H1N1 influenza A related ARDS. 6 One hundred twenty-seven patients with H1N1 influenza A treated with ECMO were included in the registry; 4 were excluded for not meeting the definition of ARDS. The median ECMO duration was 11 days. Forty- four patients (36%) died in the ICU. One hundred three patients who received ECMO within in the first week of mechanical ventilation were compared with 157 patients who had severe ARDS but did not receive ECMO. ECMO-treated patients were younger, more likely to be pregnant women or obese patients, had fewer comorbidities and immune suppression and less bacterial infection on admission, were less likely to receive early steroid treatment, and had more organ failure and more severe respiratory failure. After propensity score matching without replacement, 52 pairs of patients were matched for analysis. In this group of matched pairs, there was no significant difference in ICU mortality between the ECMO group and non-ecmo controls (50% in the ECMO group vs 40% in the conventional

13 Page: 13 of 28 treatment group; OR for death of ECMO patients 1.48; 95% CI, 0.68 to 3.23; p=0.32). In a secondary matched-pair analysis that used a different matching technique that included 102 ECMO-treated patients, treatment with ECMO was associated with a significantly lower risk of ICU death (OR=0.45; 95% CI, 0.35 to 0.78; p<0.01). Noah et al reported results from a case-control study using data from a registry from the United Kingdom that evaluated the influence of referral and transfer to an ECMO center on in-hospital mortality in patients with H1N1 influenza A related ARDS. 5 The study included 80 patients with H1N1 influenza A related ARDS who were referred, accepted, and transferred to 1 of 4 ECMO centers; ECMO was initiated if adequate gas exchange could not be achieved with conventional lung-protective ventilation. Patients were matched with patients who were potential ECMO candidates with H1N1 influenza A related respiratory distress who did not receive ECMO, resulting in 3 sets of matched pairs depending on the matching methods (1 with 59 matched pairs, 2 with 75 matched pairs). In each set, ECMO referral was associated with a lower in-hospital mortality rate. Depending on the matching method, the following RRs were calculated: RR of 0.51 (95% CI, 0.31 to 0.84; p=0.008); RR of 0.47 (95% CI, 0.31 to 0.72; p=0.001); and RR of 0.45 (95% CI, 0.26 to 0.79; p=0.006). Roch et al conducted a prospective observational cohort study to compare outcomes for adults with H1N1 influenza A related ARDS treated with and without ECMO. 10 Eighteen patients were admitted to a single- center ICU for ARDS; 10 patients met institutional criteria for ECMO and had refractory hypoxemia and metabolic acidosis, but 1 died before ECMO could be organized. The remaining 9 patients were treated with mechanical ventilation. On presentation, patients who received ECMO were more likely to have shock requiring vasopressors (7/9 vs 2/9; p=0.05) and had higher median lactate levels (4.9 vs 1.6; p<0.05). In-hospital mortality was the same in both groups (56%). Four ECMO patients experienced hemorrhagic complications. A 2009 retrospective cohort study described adult and pediatric patients treated in Australia and New Zealand with H1N1 influenza A associated ARDS.11 The study included 68 patients treated with ECMO who met eligibility criteria, at 15 centers that provided ECMO support, with mean age 34.4 years (range, ). As of September 7, 2009, of the 68 included patients (78%) had been weaned from ECMO, 13 had died while receiving ECMO, and the other 2 were still receiving ECMO. Of the 53 patients weaned from ECMO, 1 had died and 52 (76%) were still alive. Patients treated with ECMO were compared with a concurrent cohort of 133 patients with influenza A and respiratory failure, although not necessarily ARDS, who were treated with mechanical ventilation but not ECMO. ECMO patients had a longer duration of mechanical ventilation (median 18 vs 8 days; p=0.001), longer ICU stay (median 22 vs 12 days; p=0.001), and greater ICU mortality (23% vs 9%; p=0.01). Guirand et al reported results of a retrospective cohort study that compared VV ECMO with conventional ventilation for the management of acute hypoxemic respiratory failure due to trauma.13 The study included 102 patients, 25 who received ECMO and 76 who received conventional ventilation. Adjusted survival was higher in the ECMO group (adjusted OR=0.193; 95% CI, to 0.884; p=0.034), although ventilator days, ICU days, and hospital days did not significantly differ between the groups. In a cohort of 17 ECMO patients and 17 conventional management patients matched for age and lung injury severity, there was significantly greater survival in the ECMO group (adjusted OR=0.038; 95% CI, to 0.407; p=0.007).

14 Page: 14 of 28 Noncomparative Studies A large number of noncomparative cohort studies and case series have reported outcomes after the use of ECMO for acute respiratory failure. The largest study of ECMO for acute respiratory failure, published by Brogan et al in 2009, is a retrospective case review of patients included in the Extracorporeal Life Support Organization (ELSO) registry from 1986 to The ELSO registry is a voluntary registry that collects patient data from 116 U.S. and 14 international centers. A total of 1473 patients were supported with ECMO for respiratory failure from 1986 to Most patients (78%) received VV ECMO initially. During the period from 2002 to 2006, 50% of subjects survived to hospital discharge. Survivors were significantly younger than nonsurvivors (mean 32.1 years vs 37.8 years; p<0.001). ECMO complications were more common in nonsurvivors; the most common complications in both groups in the period were need for inotropic medications (occurring in 52% and 67% of survivors and nonsurvivors, respectively), need for renal replacement therapy (occurring in 42% and 55% of survivors and nonsurvivors, respectively), surgical hemorrhage (occurring in 29% and 35% of survivors and nonsurvivors, respectively), and mechanical circuit complications (occurring in 25% and 36% of survivors and nonsurvivors, respectively). In multivariable modeling, during the period from 2002 to 2006, independent predictors of mortality included increasing age, pre-ecmo arterial PaCO2 of 70 or greater, VA ECMO, the need for CPR, radiographic evidence of central nervous system (CNS) infarction or hemorrhage, renal insufficiency, gastrointestinal or pulmonary hemorrhage, and abnormal arterial ph (>7.6 or <7.2). Other noncomparative studies that include at least 50 patients and report survival outcomes are summarized in Table 3. Table 3: Noncomparative Studies of ECMO in Adult Acute Respiratory Failure Study N Indications for ECMO Summary of Outcomes Acute respiratory failure: Multiple causes Camboni 127 Bilateral pneumonia due to: (2011) 15 bacterial infection (n=45) or aspiration (n=19) extrapulmonary sepsis (n=27) major surgery (n=17) severe trauma (n=12) Enger 304 Acute lung injury due to: (2014) 16 pulmonary disorder (n=163) extrapulmonary disorder (n=72) trauma (n=39) other cause (n=30) Schmid 176 Primary lung failure, including: (2012) 17 bacterial, fungal, viral, and aspiration pneumonia (n=102) Survival to hospital discharge: 51.2% Survival based on ECMO support time (p=0.029): o 0-10 d: 59% o d: 31% o >20 d: 52% Survival to hospital discharge: 61.5% Prediction model included age, presence of immunocompromised state, artificial minute ventilation, and pre-ecmo lactate and hemoglobin, and data available on day 1 of ECMO (norepinephrine dose, FIO2, C-reactive protein, fibrinogen levels) had positive and negative predictive values of 81% and 80.4%, respectively, for classifying patients as lower (<40%) or higher (>80%) mortality risk Overall survival: 56% Survival to discharge based on lung failure etiology:

15 sepsis with secondary lung failure (n=43) trauma with ARDS (n=14) other cause (n=17) Acute respiratory distress syndrome Schmidt 140 ARDS due to: (2013) 18 Bacterial infection (n=63) H1N1 influenza A (n=36) Postoperative pneumonia (n=24) Other cause (n=17) Pappalardo 60 ARDS due to (2013) H1N1 influenza A Page: 15 of 28 o Primary lung failure: 58% o Sepsis: 44.1% o Trauma: 71.4% o Other cause: 58.8% Survival to ICU discharge:64% Survival to > 6 mo after ICU discharge: 60% Survival to discharge based on lung failure etiology: Bleeding events: 46% Ventilator associated pneumonia: 74% ECMO cannula infection: 16% Requirement for RRT: 55% Primary lung failure: 58% Requirement for tracheostomy: 63% Overall survival: 68.3% Factors significantly associated with risk of death: o Bilirubin level: OR=2.32; 95% CI, 1.52 to 3.52; p<0.001 o Creatinine level: OR=7.38; 95% CI, 1.43 to 38.11; p=0.02 o Systemic MAP: OR=0.92; 95% CI, 0.88 to 0.97; p<0.001 o Hct: OR=0.82; 95% CI, 0.72 to 0.94, p=0.006 o Pre-ECMO hospital LOS: OR=1.52; 95% CI, 1.12 to 2.07; p=0.008 ARDS: acute respiratory distress syndrome; CI: confidence interval; ECMO: extracorporeal membrane oxygenation; FIO 2 : fraction of inspired oxygen; Hct: hematocrit; LOS: length of stay; MAP: mean arterial pressure; OR: odds radio; RRT: renal replacement therapy. Smaller case series describe the use of ECMO for acute respiratory failure due to other causes, including 2009 H1N1 influenza A (N=12 patients), 20 pneumonia due to Staphylococcus aureus (N=4 patients), 21 status asthmaticus (n=24 patients), 22 hypoxemic respiratory failure due to trauma (N=10), 23 ARDS due to multiple causes (N=36), 24 and ARDS due to pancreatitis (N=8). 25 Several small case series describe the use of ECMO specifically for ARDS due to H1N1 influenza A. 12,26,27 Section Summary The evidence related to the use of ECMO in adult acute respiratory failure consists of 1 pragmatic RCT, several nonrandomized comparative studies, and multiple case series. The most direct evidence about the efficacy of ECMO in adult respiratory failure comes from the CESAR trial. Although the CESAR trial had limitations, including nonstandardized management in the control group and unequal intensity of treatment between the experimental and control groups, for the study s primary outcome of disability-free survival at 6 months there was a large effect size, with an absolute risk reduction in mortality of 16.25% (95% CI, 1.75% to 30.67%). Recent nonrandomized comparative studies generally

16 Page: 16 of 28 report improvements in outcomes with ECMO, but are subject to bias if patients treated with ECMO are generally healthier. ECMO as a Bridge to Pulmonary Transplant The evidence related to the use of ECMO as a bridge to lung transplantation consists primarily of multiple small case series. Representative case series describing outcomes for patients who receive ECMO before transplant are outlined in Table 4. There has been interest in developing techniques for awake ECMO, particularly in the bridge-to-transplant population so that patients may participate in active rehabilitation while awaiting transplant. Several case series include awake ECMO patients (Nosottie et al, 28 Rehder et al 29 ). Table 4: Case Series of ECMO as Bridge to Lung Transplantation Study N Indications for Lung Transplant ECMO Technique Summary of Outcomes Bermudez 17 Retransplant (n=6) VV (n=8) Median ECMO support time:78h (2011) 30 PF (n=6) VA (n=9) Survival: 81% at 30d; 74% at 1yr; 65% at 3 yr CF (n=4) Adverse events: renal failure (n=17 [35%]), requiring COPD (n=1) temporary dialysis in 4 (23%); pulmonary infections (n=9 [52%]); sepsis (n=7 [41%]); distal digital Hammainen 13 PF (n=5) (2011) 31 Retransplant (n=2) Idiopathic PAH (n=2) AIP, ARDS, PVOD, CF (n=1 each) Hoopes 31 (2013) 32 PF (n=9) CF (n=7, 2 with prior transplant) ARDS (n=3) ILD (n=3) PVOD (n=3) PAH (n=2) BOS, coalworkers pneumoconiosis, sarcoid, AIP (n=1 each) VV (n=7) VA (n=6) VV (n=13) VA (n=17) hybrid (n=1) ischemia (n=2 [11%]) Mean EMO support time: 2.8 d For all patients; Success for bridge to transplant 81%; 1 yr survival 75% For transplant recipients: 1 y survival 92% Mean ECMO support time: 13.7 d Survival: 93% at 1 y; 80% at 3 y; 66% at 5 y. Compared with non-ecmo controls identified from the United Network for Organ Sharing database, survival significantly worse than for similar patients transplanted without ECMO Lefarge 36 CF (n=20) (2013) 33 PF (n=11) Other diagnoses (n=5) Nosotti (2013) CF (n=6) Chronic rejection (n=2) PF (n=2) VV (n=27) VA (n=9) VV (n=11) Awake ECMO (no IMV;n=7) For all patients: Success for bridge-totransplant 83%; 1-y survival 75% For transplant recipients: 75% survived transplant; 56% survived to hospital discharge; 60.5% survived to 2 y Survival: 85.7% at 1 y for awake-ecmo group and 50% in IMV-ECMO group

17 Page: 17 of 28 Systemic sclerosis(n=1) Rehder 9 CF (n=5) (2013) 29 PF (n=2) UIP, fibrosing nonspecific interstitial pneumonia (n=1 each) Schafii 19 UIP (n=13) (2012) 34 PAH (n=3) CF (n=3) IMV-ECMO (n=4) VV (n=9) Awake ECMO (with rehab; n=5) IMV-ECMO (n=4) VV (n=11) VA (n=8) Survival: 100% at 1 y For patients participating in pretransplant rehabilitation (vs no rehabilitation): shorter mean posttransplant mechanical ventilation (4 d vs 34 d; p=0.01); shorter ICU stay (11 d vs 45 d; p=0.01); shorter hospital stay (26 d vs 80 d; p=0.01) For all patients: success for bridge-totransplant 74%. For transplant recipients: 75% survived to 1 y; 63% survived to 3 y. AIP: acute interstitial pneumonitis; ARDS: acute respiratory distress syndrome; BOS: bronchiolitis obliterans syndrome; CF: cystic fibrosis; COPD: chronic obstructive pulmonary disease; ECMO: extracorporeal membrane oxygenation; ICU: intensive care unit; ILD: interstitial lung disease; IMV: invasive mechanical ventilation; PAH: pulmonary arterial hypertension; PF: pulmonary fibrosis; PVOD: pulmonary veno-occlusive disease; UIP: usual interstitial pneumonia; VA: venoarterial; VV: venovenous. Section Summary The evidence related to the use of ECMO as a bridge to lung transplantation consists of small case series, which generally report high rates of success as a bridge to transplant and survival after transplant. These studies are limited due to small numbers and lack of a comparison group. However, given the limited number of lung transplants conducted in a year, large studies would not be feasible. ECMO for Adult Cardiorespiratory Failure In adults, in addition to its use for respiratory support, VA ECMO can be used for cardiorespiratory support in conditions where there is a potentially reversible cardiac condition, pulmonary blood flow disorder, or parenchymal disease severe enough to compromise right heart function. Major categories of use of ECMO include postcardiotomy syndrome (failure to wean off bypass) and refractory refractory cardiogenic shock due to multiple causes No RCTs were identified that evaluated the use of ECMO for cardiorespiratory failure. ECMO for Postcardiotomy Failure to Wean Off Bypass The evidence related to the use of ECMO postcardiotomy consists of case series/cohort studies. A large cohort study that included 517 patients with postcardiotomy cardiogenic shock was published by Rastan et al in The study included consecutive patients treated at a single institution from 1996 to 2008 who received VA ECMO for refractory postcardiotomy syndrome, instituted intraoperatively during the primary cardiac procedure (41.9%) or secondarily within 30 minutes of deciding to support a patient with secondary postcardiotomy syndrome (58.1%). Successful ECMO weaning was possible in 63.5%, with 56.4% of the total surviving ECMO explantation for longer than 24 hours. The overall in-hospital mortality was 75.2%. There were a large number of complications, with 82.2% of patients requiring rethoracotomy, 65.0% requiring renal replacement therapy, 19.9% developing leg ischemia, and 17.4% with cerebrovascular events.