Background

Extracorporeal Membrane Oxygenation
Extracorporeal membrane oxygenation (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.

Developed in the 1970s and widely used, ECMO. has proven effective in pediatric patients, particularly neonates suffering with respiratory and cardiopulmonary failure.^1, In adult populations, ECMO had little to no clinical value as an intervention for cardiorespiratory conditions such as severe acute respiratory distress syndrome (ARDS). Early trials correlated its use with higher complication rates due to the anticoagulation required for the ECMO circuit.^2,In addition, Zapol et al (1979), published a randomized controlled trial of ECMO in adults; the results indicate that both the intervention and control group had a 90% mortality rate, representing a 0% survival benefit for patients treated with ECMO.^3,

With improvements in ECMO circuit technology and methods of supportive care, interest in the use of ECMO in adults has renewed. For example, during the 2009-2010 H1N1 influenza pandemic, the occurrence of influenza-related ARDS in relatively young healthy people prompted an interest of ECMO for adults.

ECMO has generally been used in clinical situations of respiratory or cardiac failure, or both. In these situations, death is imminent unless medical interventions immediately reverse the underlying disease process, physiologic functions can be supported until normal reparative processes, treatment can occur (eg, resolution of ARDS, treatment of infection), or other life-saving interventions can be delivered (eg, provision of a lung transplant).

Disease-Specific Indications for Extracorporeal Membrane Oxygenation

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 (eg, H1N1 influenza infection leading to ARDS and cardiovascular collapse), which makes categorization difficult. However, in general, indications for ECMO can be categorized as follows: (1) acute respiratory failure due to potentially reversible causes; (2) bridge to lung transplant; (3) acute-onset cardiogenic or obstructive shock; and (4) ECMO-assisted cardiopulmonary resuscitation,

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. ARDS has been defined by consensus in the Berlin definition, which includes criteria for the timing of symptoms, imaging findings, exclusion of other causes, and degree of oxygenation.^2, In ARDS cases, ECMO is most often used as a bridge to recovery. Specific potentially reversible or treatable indications for ECMO may include ARDS, acute pneumonia, and various pulmonary disorders.

Lung transplant is used to manage chronic respiratory failure, most frequently in the setting of advanced chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis, emphysema due to α₁-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. Also, patients who have had a transplant may require retransplantation due to graft dysfunction of the primary transplant.

Acute-onset cardiogenic or obstructive shock is due to cardiac pump failure or vascular obstruction refractory to inotropes and/or other mechanical circulatory support. Examples include postcardiotomy syndrome (ie, failure to wean from bypass), acute coronary syndrome, myocarditis, cardiomyopathy, massive pulmonary embolism, and prolonged arrhythmias.

ECMO-assisted cardiopulmonary resuscitation can be used as an adjunct to cardiopulmonary resuscitation in patients who do not respond to initial resuscitation measures.

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. VA ECMO has the potential to provide cardiac and ventilatory support.

Venovenous Extracorporeal Membrane Oxygenation
Technique

In 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 two single lumen catheters (typically in the right internal jugular and femoral veins), or through one 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 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 a progressive loss in the ability to provide adequate gas exchange due to abnormalities in the lung parenchyma, airways, or chest wall. Right ventricular dysfunction due to pulmonary hypertension secondary to parenchymal lung disease can sometimes be effectively treated by VV ECMO. However, acute or chronic obstruction of the pulmonary vasculature (eg, saddle pulmonary embolism) might require VA ECMO as might cases in which right ventricular dysfunction due to pulmonary hypertension caused by severe parenchymal lung disease is severe enough. In adults, VV ECMO is generally used when all other reasonable avenues of respiratory support have been exhausted, including mechanical ventilation with lung protective strategies, pharmacologic therapy, and prone positioning.

Venoarterial Extracorporeal Membrane Oxygenation
Technique

In VA ECMO, the ECMO oxygenator operates in parallel with the native lungs, and the ECMO circuit provides both cardiac and respiratory support. In VA ECMO, venous blood is withdrawn, oxygen is added,andco₂ removed similar to VV ECMO, but blood is returned to the arterial circulation. Cannulation for VA ECMO can be done peripherally, with the withdrawal of blood from a cannula in the femoral or internal jugular vein and the return of blood through a cannula in the femoral or subclavian artery. Alternatively, it can be done centrally, with the 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 refractory to other therapies, when significant respiratory involvement is suspected or demonstrated, such as treatment-resistant cardiogenic shock, pulmonary embolism, or 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 that 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.^4,

Extracorporeal Carbon Dioxide Removal

Also, to complete ECMO systems, there are ventilation support devices that provide oxygenation and remove co₂ without the use of a pump system or interventional lung assist devices (eg, iLA® Membrane Ventilator; Novalung GmbH). At present, none of these systems has U.S. Food and Drug Administration (FDA) approval for use in the U. S. These technologies are not the focus of this evidence review but are briefly described because there is overlap in patient populations treated with extracorporeal carbon dioxide removal and those treated with ECMO, and some studies have reported on both technologies.

Unlike VA and VV ECMO, which use large-bore catheters and generally high-flow through the ECMO circuits, other systems use pumpless systems to remove co₂. These pumpless devices achieve extracorporeal carbon dioxide removal via a thin double-lumen central venous catheter and relatively low extracorporeal blood flow. They have been investigated as a means to allow low tidal volume ventilator strategies, which may have benefit in ARDS and other conditions where lung compliance is affected. Although ECMO systems can affect co₂ removal, dedicated extracorporeal carbon dioxide systems are differentiated by simpler mechanics and by no need for dedicated staff.^5,

Medical Management During Extracorporeal Membrane Oxygenation

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 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 needed 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.

Regulatory Status

The regulatory status of ECMO devices is complex. Historically, the FDA has evaluated components of an ECMO circuit separately, with the ECMO oxygenator considered the primary component of the circuit. The ECMO oxygenator (membrane lung; FDA product code: BYS), defined as a device used to provide a patient with extracorporeal blood oxygenation for more than 24 hours, has been classified as a class III device but cleared for marketing by the FDA through the preamendment 510(k) process (for devices legally marketed in the U. S. before May 28, 1976, which are considered "grandfathered" devices not requiring a 510(k) approval).

ECMO procedures can also be performed using cardiopulmonary bypass circuit devices on an off-label basis. Multiple cardiopulmonary bypass oxygenators have been cleared for marketing by the FDA through the 510(k) process (FDA product codes: DTZ, DTN). FDA also regulates other components of the 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 (eg, Kendall Veno-Venous Dual-Lumen Infant ECMO Catheter; Origen Dual-Lumen Cannulas; Avalon Elite Bi-Caval Dual-Lumen Catheter.)

Regulatory Changes

In April 2020, FDA issued an enforcement policy for ECMO during the COVID-19 public health emergency.^6, The guidance document describes non-binding recommendations, and is intended to remain in effect only for the duration of the public health emergency.

The primary components of ECMO are devices that move the blood to a component that pumps/oxygenates the blood, controls pump speed, controls or monitors gas flow for the circuit, and controls the temperature of the blood.^6, The FDA guidance states that the cardiopulmonary bypass devices are technologically capable of being used for ECMO therapy with a duration of longer than 6 h, and FDA will work with manufacturers for emergency use authorization for limited modifications to the indications or design of cardiopulmonary bypass devices to treat COVID-19 patients during the public health emergency.

In 2014, the FDA convened an advisory committee to discuss the classification of the ECMO oxygenator for adult pulmonary and cardiopulmonary indications and to discuss the overall classification of the ECMO components. Considered was a reclassification of the regulation from "Membrane Lung for Long-Term Pulmonary Support" to "Extracorporeal Circuit and Accessories for Long-Term Pulmonary/Cardiopulmonary Support," moving the regulation from an anesthesia device regulation to cardiovascular device regulation and defining "long-term" as extracorporeal support longer than six hours. These proposals were approved in 2016. Components of the long-term (>6 h) ECMO devices are classified as 3 distinct devices, an extracorporeal system for long-term respiratory/cardiopulmonary failure, an oxygenator, for long-term support greater than 6 hours, and a dual lumen ECMO cannula. FDA product codes: QJZ, BYS, PZS.

Table 1. Membrane Oxygenation Devices Cleared by the US Food and Drug Administration

Device	Manufacturer	Date Cleared	510(k) No.	Indication
Nautilus Smart ECMO Module	MC3 Inc.	4/9/2020	K191935	Oxygenator, long term support greater than 6 hours
Paragon Adult Maxi PMP Oxygenator	Chalice Medical	2/28/2020	K191246	Physiologic gas exchange in adults undergoing cardiopulmonary bypass surgery
Novalung System	Fresnius Medical Care Renal Therapies Group	2/21/2020	K191407	Long-term (> 6 hours) respiratory/cardiopulmonary support that provides assisted extracorporeal circulation and physiologic gas exchange
INSPIRE 7 Hollow Fiber Oxygenator	LivaNova USA	4/13/2019	K190690	Oxygenator, Cardiopulmonary bypass
Affinity Series Oxygenators	Medtronic Inc.	2019	K183511, K183490, K191029, K191444	To oxygenate and remove carbon dioxide from the blood and to cool or warm the blood during routine cardiopulmonary bypass (CPB) procedures up to 6 hours in duration
Terumo Capiox NX19 Oxygenator with Reservoir (east Orientation) Terumo Capiox NX19 Oxygenator with Reservoir (west Orientation) Terumo Capiox NX19 Oxygenator (east Orientation) Terumo Capiox NX19 Oxygenator (west Orientation)	Terumo Cardiovascular Systems Corporation	6/22/2018	K180950	For use in membrane oxygenation
Terumo Capiox NX19 Oxygenator with Reservoir (east orientation ) Terumo Capiox NX19 Oxygenator with Reservoir (west orientation ) Terumo Capiox NX19 Oxygenator (east orientation ) Terumo Capiox NX19 Oxygenator (west orientation)	Terumo Cardiovascular Systems Corporation	3/29/2018	K172071	For use in membrane oxygenation
INSPIRE 6M Hollow Fiber Oxygenator; INSPIRE 6F M Hollow Fiber Oxygenator with Integrated Arterial Filter; INSPIRE 8M Hollow Fiber Oxygenator; INSPIRE 8F M Hollow Fiber Oxygenator with Integrated Arterial Filter	Sorin Group Italia S.r.l	3/15/2018	K180448	For use in membrane oxygenation
Affinity Pixie Oxygenator with Balance Biosurface Affinity Pixie Oxygenator with Cardiotomy/Venous Reservoir and Balance Biosurface Affinity Pixie Oxygenator with Cortiva BioActive Surface Affinity Fusion Oxygenator with Cardiotomy/Venous Reservoir and Cortiva BioActive Surface	Medtronic Inc.	11/20/2017	K172984	For use in membrane oxygenation
Affinity Fusion Oxygenator with Balance Biosurface Affinity Fusion Oxygenator with Cardiotomy/Venous Reservoir and Balance Biosurface Affinity Fusion Oxygenator with Cortiva Biosurface Affinity Fusion Oxygenator with Cortiva BioActive Surface & Cardiotomy/Venous Reservoir	Medtronic Inc.	10/25/2017	K172626	For use in membrane oxygenation
Affinity NT Oxygenator Affinity NT Oxygenator with Trillium Biosurface	Medtronic Inc.	12/6/2016	K162896	For use in membrane oxygenation
Affinity NT Oxygenator with Cortiva BioActive Surface	Medtronic Inc.	9/21/2016	K162016	For use in membrane oxygenation
TandemLung Oxygenator	CARDIAC ASSIST INC.	2/26/2016	K153295	For use in membrane oxygenation
Capiox RX Hollow Fiber Oxygenator with/without Hardshell Reservoir	Terumo Cardiovascular Systems Corporation	12/3/2015	K153213	For use in membrane oxygenation
Terumo Capiox SX18 Oxygenator/ Hardshell Reservoir Terumo Capiox SX18 Oxygenator/ Hardshell Reservoir with Xcoating Terumo Capiox SX25 Oxygenator/ Hardshell Reservoir Terumo Capiox SX25 Oxygenator /Hardshell Reservoir with Xcoating	Terumo Cardiovascular Systems Corporation	12/2/2015	K153140	For use in membrane oxygenation
Terumo Capiox FX15 Advance Oxygenator with Integrated Arterial Filter and Reservoir Terumo Capiox FX25 Advance Oxygenator with Integrated Arterial Filter and Reservoir	Terumo Cardiovascular Systems Corporation	11/19/2015	K151791	For use in membrane oxygenation
LILLIPUP PMP LILLIPUT PMP INTEGRATED	SORIN GROUP ITALIA S.R.L.	11/6/2015	K151713	For use in membrane oxygenation
Terumo Capiox FX15 Advance Oxygenator with Integrated Arterial Filter and Hardshell Reservoir	Terumo Cardiovascular Systems Corporation	10/20/2015	K151389	For use in membrane oxygenation
EOS PMP EOS PMP Integrated	SORIN GROUP ITALIA S.R.L.	6/11/2015	K150489	For use in membrane oxygenation
QUADROX-i Adult/Small Adult Oxygenators;QUADROX-iD Adult Oxygenators	MAQUET CARDIOPULMONARY AG	5/7/2015	K150267	For use in membrane oxygenation
Affinity NT Oxygenator Affinity NT Oxygenator with Trillium Biosurface Affinity NT Oxygenator with Carmeda Biosurface	Medtronic Inc.	3/25/2015	K143073	For use in membrane oxygenation
ADVANCED MEMBRANE GAS EXCHANGE PMP STERILE (A.M.G PMP STERILE)	EUROSETS S.R.L.	2/6/2015	K141492	For use in membrane oxygenation
Affinity Fusion Oxygenator with Integrated Arterial Filter and Balance Biosurface Affinity Fusion Oxygenator with Integrated Arterial Filter and Carmeda BioActive Surface	Medtronic Inc	10/24/2014	K142784	For use in membrane oxygenation
TERUMO CAPIOX FX15 AND FX25 HOLLOW FIBER OXYGENATOR/RESERVOIR	Terumo Cardiovascular Systems Corporation	6/2/2014	K140774	For use in membrane oxygenation
MEDOS HILITE INFANT OXYGENATOR	MEDOS MEDIZINTECHNIK AG	2/19/2014	K140181	For use in membrane oxygenation
MEDOS HILITE OXYGENATOR	MEDOS MEDIZINTECHNIK AG	2/18/2014	K140177	For use in membrane oxygenation
MEDOS HILITE 7000 & 7000 LT OXYGENATOR	MEDOS MEDIZINTECHNIK AG	1/9/2014	K133261	For use in membrane oxygenation

The FDA has convened several advisory committees to discuss the classification of the ECMO oxygenator and other components. On January 8, 2013, the FDA issued a proposed order to reclassify ECMO devices from class III to class II (special controls) subject to 510(k) premarket notification. On September 12, 2013, the FDA reviewed the classification of the membrane lung for long-term pulmonary support specifically for pediatric cardiopulmonary and failure to wean from the cardiac bypass patient population. The FDA approved a 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 where imminent death is threatened by respiratory failure (eg, 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 FDA also agreed with the proposed reclassification of ECMO devices from class III to class II 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 February 12, 2016, the proposed order was approved.^7,

Related Policies

• Inhaled Nitric Oxide as a Treatment of Hypoxic Respiratory Failure (Policy #101 in the Treatment Section)

 Respiratory failure is due to a potentially reversible etiology (see Policy Guidelines section)
AND
 Respiratory failure is severe, as determined by 1 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 fraction of inspired oxygen (>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 less than 6 months;
o A do-not-resuscitate directive;
o Cardiac decompensation in a member who has already declined for ventricular assist device or transplant;
o Known neurologic devastation without potential to recover meaningful function;
o Determination of care futility (see Policy Guidelines section).

Applications and Definitions

Adults are considered patients age 18 and older. This policy addresses the use of long-term (ie, >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 underlying causes of respiratory failure, which are commonly considered reversible, are:

• Acute respiratory distress syndrome (ARDS)
• Acute pulmonary edema
• Acute chest trauma
• Infectious and noninfectious pneumonia
• Pulmonary hemorrhage
• Pulmonary embolism
• Asthma exacerbation
• Aspiration pneumonitis.

Table PG1. Berlin Definition of Acute Respiratory Distress Syndrome

Criteria
Timing	Within 1 week of a known clinical insult or new or worsening respiratory symptoms
Chest imaging (CT or CXR)	Bilateral opacities-not fully explained by effusions, lobar/lung collapse, or nodules
Origin of edema	Respiratory failure not fully explained by cardiac failure or fluid overload. Need objective assessment (eg, echocardiography) to exclude hydrostatic edema if no risk factors present.
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

Source: ARDS Definition Task Force et al (2012).
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 Lung Injury Score

One commonly used system for classifying the severity of respiratory failure is the Murray Lung Injury Score, which was developed for use in ARDS but has been applied to other indications. This score includes 4 scales, each of which is scored from 0 to 4. A final score is obtained by dividing the collective score by the number of scales 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 greater than 2.5 indicates severe lung injury (eg, ARDS). Table PG2 shows the components of the Murray scoring system.

Table PG2. Murray Lung Injury Score

Scale	Criteria	Score
Chest x-ray score	No alveolar consolidation	0
	Alveolar consolidation confined to 1 quadrant	1
	Alveolar consolidation confined to 2 quadrants	2
	Alveolar consolidation confined to 3 quadrants	3
	Alveolar consolidation in all 4 quadrants	4
Hypoxemia score	Pao2/Fio2 > 300 mm Hg	0
	Pao2/Fio2 225-299 mm Hg	1
	Pao2/Fio2 175-224 mm Hg	2
	Pao2/Fio2 100-174 mm Hg	3
	Pao2/Fio2 ≤ 100 mm Hg	4
PEEP score (when ventilated)	PEEP ≤ 5 cm H2O	0
	PEEP 6-8 cm H2O	1
	PEEP 9-11 cm H2O	2
	PEEP 12-14 cm H2O	3
	PEEP ≥15 cm H2O	4
Respiratory system compliance score (when available)	Compliance >80 mL/cm H2O	0
	Compliance 60-79 mL/cm H2O	1
	Compliance 40-59 mL/cm H2O	2
	Compliance 20-39 mL/cm H2O	3
	Compliance ≤19 mL/cm H2O	4

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
• Inability to maintain airway plateau pressure (Pplat) <30 cm H₂O despite a tidal volume of 4 to 6 mL/kg of ideal body weight; or
• Oxygenation Index >30: Oxygenation Index = Fio₂´ 100 ´ MAP/Pao₂ mm Hg (where Fio₂ x 100 = Fio₂ as percentage; MAP = mean airway pressure in cm H₂O; Pao₂ = partial pressure of oxygen in arterial blood); or
• co₂ retention despite high Pplat (>30 cm H₂O).

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:
  • Consensus from 2 attending physicians that there is no likelihood of an outcome better than "persistent vegetative state" at 6 months AND
  • At least one of the attending physicians is an expert in neurologic disease and/or intensive care medicine AND
  • Determination made following studies including computed tomography, electroencephalography, and exam.

• Inability to provide aerobic metabolism, defined by the following:
  • Refractory hypotension and/or hypoxemia, OR
  • Evidence of profound tissue ischemia based on creatine phosphokinase or lactate levels, lactate-to-pyruvate ratio, or near-infrared spectroscopy

• Presumed end-stage cardiac or lung failure without "exit" plan (ie, declined for assist device and/or transplantation).

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was created in 2015 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through April 24, 2020.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

The ideal study design to evaluate either venoarterial (VA) or venovenous (VV) extracorporeal membrane oxygenation (ECMO) for adult respiratory and cardiorespiratory conditions would be multicenter RCTs comparing treatment using ECMO with best standard therapy, using standardized criteria for enrollment and standardized management protocols for both the ECMO and control groups. However, there are likely significant challenges to enrolling patients in RCTs to evaluate ECMO, including overlapping medical conditions that lead 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 at high-risk of death.

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 that evaluate mixed populations. Although VA and VV ECMO have different underlying indications (ie, cardiorespiratory failure vs respiratory failure), studies reporting outcomes after ECMO do not always separate VA ECMO from VV ECMO; therefore, studies related to the use of VA and VV ECMO are discussed together next..

Extracorporeal Membrane Oxygenation for Adults With Acute Respiratory Failure
Clinical Context and Therapy Purpose

The purpose of ECMO is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as standard ventilator management, in patients who are adults with acute respiratory failure.

The question addressed in this policy is: Does the use of ECMO improve the net health outcome in adults with acute respiratory failure?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals who are adults with acute respiratory failure.

Interventions

The therapy being considered is ECMO.

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 long enough that normal reparative processes or treatment can occur (eg, resolution of acute respiratory distress syndrome, treatment of infection) or other life-saving intervention can be delivered (eg, provision of a lung transplant).

Patients who are adults with acute respiratory failure are actively managed by pulmonologists and intensivists in a tertiary clinical setting.

Comparators

Comparators of interest include standard ventilator management. Treatment includes portable oxygen, the use of ventilator support, and artificial airway insertion by tracheostomy. These treatments are administered by pulmonologists and primary care providers in an outpatient clinical setting for minor symptoms, and inpatient clinical settings for conditions that require ventilator support.

Outcomes

The general outcomes of interest are overall survival (OS), change in disease status, morbid events, treatment-related mortality, and treatment-related morbidity.

Outcomes should include short- and long-term mortality, along with measures of significant morbidity (eg, intracranial hemorrhage, thrombosis, vascular access site hemorrhage, limb ischemia) and short- and long-term disability and quality-of-life measures.

One study provided results indicating absolute risk reduction in mortality of 16.25%. More recent nonrandomized comparative studies have generally reported improvements in outcomes with ECMO.

Table 2. Outcomes of Interest for Individuals who are adults with acute respiratory failure

Outcomes	Details	Timing
Change in disease status	Evaluated using outcomes such as transfer to treatment centers and ventilator-free days	≥2 days
Morbid events	Evaluated using outcomes such as length of ICU stay	≥2 days
Treatment-related morbidity	Evaluated using outcomes such as severe disability or receiving steroids	≥2 days

ICU: intensive care unit.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews

Systematic reviews evaluating randomized and nonrandomized studies have addressed use of ECMO for acute respiratory failure and specific etiologies of acute respiratory failure. Meta-analyses are described in Tables 3 and 4.

Tramm et al (2015) conducted a Cochrane review on the use of ECMO for critically ill adults.^8, Reviewers included RCTs, quasi-RCTs, and cluster RCTs that compared VV or VA ECMO with conventional respiratory and cardiac support. Four RCTs were identified (Peek et al [2009],^9, Morris et al [1994],^2, Bein et al [2013],^10, Zapol et al [1979]^3,). Combined, the trials included 389 subjects. Inclusion criteria (acute respiratory failure with specific criteria for arterial oxygen saturation and ventilator support) were generally similar across studies. Risk of bias was assessed as low for the trials by Peek et al (2009), Bein et al (2013), and Zapol et al (1979), and high for the trial by Morris et al (1994). Reviewers were unable to perform a meta-analysis due to clinical heterogeneity across studies. The Morris et al (1994) and Zapol et al (1979) trials were not considered to represent current standards of care. Reviewers summarized the outcomes from these studies (described above), concluding: "We recommend combining results of ongoing RCTs with results of trials conducted after the year 2000 if no significant shifts in technology or treatment occur. Until these new results become available, data on use of ECMO in patients with acute respiratory failure remain inconclusive. For patients with acute cardiac failure or arrest, outcomes of ongoing RCTs will assist clinicians in determining what role ECMO and ECPR [extracorporeal membrane oxygenation-assisted cardiopulmonary resuscitation] can play in patient care."

Vaquer et al (2017) performed a systematic review and meta-analysis analyzing complications and hospital mortality associated with ARDS patients who underwent VV ECMO.^11, Twelve studies were included that comprised 1042 patients with refractory ARDS. The pooled mortality at hospital discharge was 37.7% (z = -3.73; 95% CI, 31.8% to 44.1%; I²=74.2%; p<0.001). This review included some H1N1 influenza A populations. H1N1 influenza A as the underlying cause of ARDS was determined to be an independent moderator of mortality.

Zampieri et al (2013) conducted a systematic review and meta-analysis evaluating the role of VV ECMO for severe acute respiratory failure in adults.^12, Studies included were RCTs and observational case-control studies with severity-matched patients. The 3 studies in the meta-analysis included 353 patients of whom 179 received ECMO: 1 RCT (CESAR trial [2009]^9,) and 2 case-control studies with severity-matched patients (Noah et al [2011]^13,; Pham et al [2013]^14,). For the primary analysis, the pooled in-hospital mortality in the ECMO-treated group did not differ significantly from the control group (odds ratio [OR], 0.71; 95% CI, 0.34 to 1.47; p=0.358). Both nonrandomized studies included only patients treated for influenza A H1N1 subtype, which limits their generalizability to other patient populations.

Zangrillo et al (2013) reported on the results of a systematic review and meta-analysis that evaluated the role of ECMO treatment for respiratory failure due to H1N1 influenza A in adults.^15, The meta-analysis included 8 studies, all observational cohorts, 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 ten days. Reported outcomes varied across studies, but in a random-effects pooled model, the overall in-hospital mortality rate 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.

Table 3. Meta-Analysis Characteristics

Study	Dates	Trials	Participants	Intervention	N	Design
Vaquer et al (2017)11,	1972 - Dec 2015	12	Refractory ARDS patients >18 years old	VV ECMO	N=1042	NR
Zampieri et al (2013)12,	NR	3	Adults receiving VV ECMO for severe & refractory ARDS	VV ECMO	N total=353; ECMO-treated N=179	RCTs, case-control studies
Zangrillo et al (2013)15,	NR - Jan 20.	8	Patients with confirmed or suspected H1N1 admitted to ICU; median age=36 years 43% men	ECMO (VV or VA)	N=1357	Observational cohort

ARDS: acute respiratory distress syndrome; ECMO: extracorporeal membrane oxygenation; ICU: intensive care unit; H1N1: influenza A; NR: not reported; RCT: randomized controlled trial; VA: venoarterial; VV: venovenous.

Table 4. Systematic Reviews & Meta-Analysis Results

Study	Mortality at discharge	In-hospital mortality	Medical complications	Mechanical complications	Device Use in Population # (%)
Vaquer et al (2017)11,
N	N=1042	NR	N=1042	N=1042	NR
% of patients affected	Pooled effect (95% CI)	NR	Pooled effect (95% CI)	11%	NR
Pooled % (z; 95% CI; I2 ; p)	37.7% (-3.73; 31.8% to 44.1%) 74.2%; p<0.001	NR	NR	NR	NR
Zampieri et al (2013)12,
N	NR	N=179	NR	NR	NR
Pooled (OR; 95% CI; p)	NR	0.71; 0.34 to 1.47; 0.358	NR	NR	NR
Zangrillo et al (2013)15,
N=1357	NR	NR	NR	NR	266 (20%)
VV ECMO	NR	NR	NR	NR	1276 (94%)
VA ECMO	NR	NR	NR	NR	NR
Pooled % N (95% CI)	27.5% (18.4%-36.7%)	NR	NR	NR	NR

CI: confidence interval; OR: odds ratio; NR: not reported; VV ECMO: venovenous extracorporeal membrane oxygenation.

Randomized Controlled Trials

Combes et al (2018) reported the findings of a French-sponsored RCT (NCT01470703) that aimed to assess the efficacy of ECMO in patients with "very severe ARDS", defined by the authors through disease-severity criteria outlined in their Supplementary Materials.^16, Efficacy was measured by comparing the 60-day mortality rates of patients randomized to the ECMO-treatment group with those randomized to the control group (conventional mechanical ventilation). After the assessment of 1,015 patients, 728 were excluded and 38 were not randomized. The 249 patients randomized were distributed into the ECMO group (n=124) and the control group (n=125). At 60 days, 44 patients (35%) in the ECMO group and 57 (46%) in the control group had died (relative risk [RR], 0.76; 95% confidence interval [CI], 0.55 to 1.04, p=.09). The hazard ratio (HR) for death <60 days after randomization in the ECMO group, compared to the control group, was 0.70 (95% CI 0.47 to 1.04; p=.07). The RR of treatment failure (defined as death prior to day 60 for both groups and included crossover to ECMO in the control group) was 0.62 (95% CI 0.47 to 0.82; p <.001). Adverse events include the death as a result of surgical intervention (two patients, one per group). Patients in the ECMO group has significantly higher rates of severe thrombocytopenia (27%) vs patients in the control group (16%) [absolute risk difference, 11%; 95% CI, 6 to 30]. While the number randomized at the onset of the study is unchanged for each group during analysis, only 121 of the 124 patients in the ECMO group received the treatment. Furthermore, of the 125 patients randomized to the control group, 35 (28%) required rescue ECMO for refractory hypoxemia, crossing from the control to the ECMO group, at a mean of 6.5±9.7 days post-randomization. One limitation of this study involves the risk of bias due to crossover, such as carryover, period effects, and missing data. Another limitation of this study was the possible confounding factors associated with non-standardized treatment protocols between the two groups. The ECMO group underwent percutaneous venovenous cannulation and was given heparin in varying doses to achieve a targeted activated partial thromboplastin time; the control group was not exposed to these variables. In contrast, the control group was exposed to ventilatory treatment, neuromuscular blocking agents, and prone positioning that differed from the comparative group, limiting the generalizability of any findings.

Peek et al (2009) reported on 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 adults with severe acute respiratory failure.^9, Inclusion criteria were patients ages 18 to 65 years, with severe but potentially reversible respiratory failure (Murray Lung Injury Score >3.0 or pH <7.20). Patients were allocated to consideration for treatment with ECMO (n=90) or conventional management (n=90). In the ECMO group, 68 (75%) received ECMO. Patients were enrolled from three types of facilities: an ECMO center, tertiary intensive care units (ICUs), and referral hospitals., A specific management protocol was not mandated for patients in the conventional management group, but treatment centers were advised to follow a low-volume, low-pressure ventilation strategy.

The primary outcome measure was death or severe disability at six months post-randomization. Sixty-two (69%) patients in the ECMO group required transport to an ECMO center.. In the conventional management group, 11 (12%) patients required transport to a tertiary ICU. Regarding the primary outcome (death or severe disability at 6 months post-randomization), 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 (RR, 0.69; 95%CI, 0.05 to 0.97; p=0.03). One confounding factor of this study is the existence of treatment differences in the groups besides the inclusion of ECMO. For example, more patients in the ECMO group used low-volume, low-pressure ventilation (93% vs 70%; p<0.001) and on a greater proportion of days (23.9% vs 15%; p<0.001).Also, the ECMO 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). These factors limit the validity of the results. The CESAR trial included a standard ECMO treatment protocol for use with the ECMO cohort, but patients randomized to conventional management had no standardized protocol. Another limitation of this study is the inability to quantify, what, if any, affect the transfer to the ECMO center for those in the intervention group had on the outcomes and whether it was the center itself, the conventional management provided at the center, or any other factors that contributed to the difference.. About 20% of patients randomized to the ECMO group improved after transport to the ECMO center and to an extent that they no longer required ECMO.. TO. However, it is also possible that some aspect of the conventional management delivered at the ECMO center contributed to this improved outcome.

Table 5. Summary of Key RCT Characteristics

Study; Trial	Countries	Sites	Dates	Participants	Interventions
					ECMO	Mechanical ventilation
Combes et al (2018)16,	France	NR	Dec 2011 - Jul 2017	Participants with very severe ARDS as defined by the author	N=124	N=125
					Transfer to ECMO; consider ECMO	Mechanical ventilation
Peek et al (2009)9,	UK	92 ICUs; 11 referral hospitals; 1 treatment hospital	Jul 2001 - Aug 2006	Adults <66 tears, severe potentially treatable respiratory failure;	N=90	N=90

RCT: randomized controlled trial; ARDS: Acute respiratory distress syndrome; NR: not reported; ICU: intensive care unit; ECMO: extracorporeal membrane oxygenation.

Table 6. Summary of Key RCT Results

Study	Mortality 1	Mortality 2
	60-day mortality	<60-day mortality
Combes et al (2018)16,	N=249	N=249
ECMO	44 (35%)	NR
Mechanical Ventilation	57 (46%)	NR
RR; 95%CI; P	0.76; 0.55 to 1.04,.09	0.62; 0.47 to 0.82; p<.001
HR; 95%CI; P	NR	0.70; 0.47 to 0.82; p<.001
	Mortality or severe-disability at 6-mos	<6-mos mortality
Peek et al (2009)9,	N=180	N=180
ECMO	57(63%)	57(63%)4
Mechanical Ventilation	42(47%)	45 (50%)4
RR; 95%CI; P; NNT	.69; 0.05 to 0.97; p=.03; 7	NR (p=0.07)
HR; 95%CI; P	NNT (95% CI)	NR

CI: confidence interval; HR: hazard ratio; NNT: number needed to treat; RCT: randomized controlled trial; RR: relative risk; NR: not reported; ECMO: extracorporeal membrane oxygenation.

¹ Elimination of troublesome regurgitation at time x
² Elimination of symptoms other than heartburn at time x
³ Weekly PPI use
⁴ Daily PPI use
⁵ Change in RDQ heartburn plus regurgitation score at time x
⁶ Change in GERD-HRQL score at time x

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Combes et al (2018)16,			4. treatment protocols not standardized between groups (e.g., control group exposed to neuromuscular blocking agents and prone positioning but not ECMO group)
Peek et al (2009)9,		1. 93% of ECMO group vs. 70% control treated with lung protective ventilation, p<0.0001

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Study	Allocationa	Blindingb	Selective Reportingc	Follow-Upd	Powere	Statisticalf
Combes et al (2018)16,				3. Emergencies requiring ECMO resulted in crossover and carryover.
Peek et al (2009)9,			2. Only 76% ECMO group received the treatment	1. High loss to follow up as information was only available in 58% and 36% in the ECMO/control group		1. ITT analysis not useful when there is high-loss to follow-up

^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Follow-Up key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Intervention is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Intervention is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Pham et al (2013) reported the results of 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.^14, Patients with H1N1 influenza A treated with ECMO (n=127) provided data to the registry; data on 4 patients were excluded . The median ECMO duration was 11 days. Forty-four (36%) patients died in the ICU. Patients who received ECMO within the first week of mechanical ventilation (n=103) were compared with patients with severe ARDS who did not receive ECMO (n=157). ECMO-treated patients were younger, more likely to be pregnant women or obese, had fewer comorbidities and immune suppression, and less bacterial infection on admission. These patients were also less likely to receive early steroid treatment and had more organ failure and more severe respiratory failure., Fifty-two pairs of patients were matched for analysis. In the matched pairs, there was no significant difference in ICU mortality between the ECMO group (50%) and non-ECMO controls (40%; OR for death of ECMO patients, 1.48; 95% CI, 0.68 to 3.23; p=0.32). In a secondary matched-pair analysis, using 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 (2011) reported on results from a case-control study using data from a UK. registry that evaluated the influence of referral and transfer to an ECMO center on in-hospital mortality in patients with H1N1 influenza A related ARDS.^13, The study included 80 patients with H1N1 influenza A-related ARDS who were referred, accepted, and transferred to 1 of 4 ECMO centers. 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 RR were calculated: 0.51 (95% CI, 0.31 to 0.84; p=0.008), 0.47 (95% CI, 0.31 to 0.72; p=0.001), and 0.45 (95% CI, 0.26 to 0.79; p=0.006).

Roch et al (2010) conducted a prospective observational cohort study comparing outcomes for adults with H1N1 influenza A-related ARDS treated with and without ECMO.^17, Eighteen patients were admitted to a single-center ICU for ARDS; ten patients met institutional criteria for ECMO and had refractory hypoxemia and metabolic acidosis, but one died before ECMO could be administered. The remaining nine 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 have higher median lactate levels (4.9 mmol/L vs 1.6 mmol/L; 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.^18, Sixty-eight patients treated with ECMO at 15 centers met eligibility criteria (mean age, 34.4 years; range, 26.6-43.1). Fifty-three (78%) of the 68 patients had been weaned from ECMO, 13 died while receiving ECMO, and the other 2 were still receiving ECMO. Of the 53 patients weaned, 1 had died and 52 (76%) were still alive. Patients treated with ECMO were compared with a concurrent cohort of 133 patients who had influenza A and respiratory failure, not necessarily ARDS, and who were treated with mechanical ventilation, but not ECMO. ECMO patients had a longer duration of mechanical ventilation (median 18 days vs 8 days; p=0.001), longer ICU stay (median 22 days vs 12 days; p=0.001), and higher ICU mortality rate (23% vs 9%; p=0.01).

Guirand et al (2014) reported the results of a retrospective cohort study comparing VV ECMO with conventional ventilation for the management of acute hypoxemic respiratory failure due to trauma.^19, The study included 102 patients (26 received ECMO, 76 received conventional ventilation). Adjusted survival was higher in the ECMO group (adjusted OR=0.193; 95% CI, 0.042 to 0.884; p=0.034), ventilator days, ICU days, and hospital days did not differ significantly between groups. The authors note that when calculating propensity score, 17 ECMO patients and 17 conventional management patients matched for age and lung injury severity, survival was significantly longer in the ECMO group (adjusted OR=0.038; 95% CI, 0.004 to 0.407; p=0.007).

Table 9. Summary of Key Nonrandomized OR Observational Comparative Study Characteristics

Study	Study Type	Country	Dates	Participants	ECMO	Conventional ventilation
Pham et al (2013)14,	matched cohort study	France	July 2009 - March 2011	Data of patients admitted for H1N1-associated ARDS to French ICUs from 2009 to 2011; adult patients hospitalized with influenza A(H1N1) pdm–related ARDS + treated with ECMO	127	157
Noah et al (2011)13,	Case control	UK	NR	Patients with H1N1 Inf-A related ARDS who are referred, accepted, and transferred to one of the 4 ECMO centers	N=80	NR
Roch et al (2010)17,	prospective observational cohort study	France	Oct 2009 - Jan 2010	Patients with H1N1 Inf-A related ARDS and treated in Marseille South Hospital	N=9	9
Davies et al (2009)18,	Retrospective cohort	Australia and New Zealand	Jun 1, 2009 – Aug 31, 2009	Patients (n=68) with inf-a A(H1N1)-associated ARDS treated with ECMO in 15 ICUs	N=68	N=133
Guirand et al (2014)19,	retrospective cohort study	US	Jan 1 2001 to Dec 2005	Trauma patients, 6-55 years of age treated for AHRF	N=26	N=76

ARDS: acute respiratory distress syndrome; AHRF: acute hypoxemic respiratory failure; ECMO: extracorporeal membrane oxygenation; ICU: intensive care unit; H1N1: influenza-A.

Table 10. Summary of Key Nonrandomized OR Observational Comparative Study Results

Study	Mortality	Adverse events	Length of mechanical ventilation; ICU stay (days)
Pham et al (2013)14,	Matched: N=52 ECMO; N=52		N
ECMO in 1st week of mechanical ventilation	40%	NR	n (%)
No ECMO	50%	NR	n (%)
OR; 95% CI; P	1.48; 0.68-3.23; P=32	NR	HR/Diff/OR/RR (95% CI)
Noah et al (2011)13,	N: 80; matched pairs: 3
Relative risk -depending on matching method- RR, CI, P	RR 1: 0.51; 0.31 to 0.84; P=.008 RR 2: 0.47; 0.31-0.72;.001 RR 3: 0.45; 0.26 to 0.79; p=0.006	NR	n (%)
Roch et al (2010)17,		Shock requiring vasopressors
ECMO(n=9)	NR	7(77.77%)
No ECMO (n=9)	NR	2 (22.22%)
P	NR	P=0.05
Davies et al (2009)18,	ICU-mortality rate
ECMO (n=68)	9%		Median 8 ; Median 12
No ECMO (n=133)	23%		Median 18 ; Median = 22
P value	P=0.01		P=0.001 ; P=0.001
	Adjusted survival		Length of ECMO (days)
Guirand et al (2014)19,
VV ECMO	(n=26)		Median 11
Mechanical Ventilation	(n=76)
Adjusted OR; 95% CI; P	0.193; 0.042 to 0.884; p=0.034

CI: confidence interval; Diff: difference; HR: hazard ratio; OR: odds ratio; RR: relative risk; NR: not reported; ICU: intensive care unit; VV ECMO: venovenous extracorporeal membrane oxygenation.

Noncomparative Studies

A large number of noncomparative cohort studies and case series have reported on outcomes after use of ECMO for acute respiratory failure. The largest of these noncomparative studies of ECMO for acute respiratory failure, published by Brogan et al (2009), is a retrospective case review of patients included in the Extracorporeal Life Support Organization registry from 1986 to 2006.²² The Extracorporeal Life Support Organization registry is voluntary and 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 2006. 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 2002-2006 period were the need for inotropic medications (52% of survivors vs 67% of nonsurvivors), need for renal replacement therapy (42% of survivors vs 55% of nonsurvivors), surgical hemorrhage (29% of survivors vs 35% of nonsurvivors), and mechanical circuit complications (25% of survivors vs 36% of nonsurvivors). In multivariable modeling, during the same period, independent predictors of mortality included increasing age, pre-ECMO arterial Paco₂ of 70 mm Hg or greater, VA ECMO, the need for extracorporeal membrane oxygenation-assisted cardiopulmonary resuscitation (ECPR), radiographic evidence of central nervous system infarction or hemorrhage, renal insufficiency, gastrointestinal or pulmonary hemorrhage, and abnormal arterial pH (>7.6 or <7.2).

Section Summary: Extracorporeal Membrane Oxygenation for Adults With Acute Respiratory Failure

The evidence for the use of ECMO in adults with acute respiratory failure consists of a pragmatic RCT, several other RCTs, several nonrandomized comparative studies, and numerous case series.). The most direct evidence on 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 trial's primary outcome (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%). Nonrandomized comparative studies have generally reported improvements in outcomes with ECMO, but might be subject to bias.

Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplantation
Clinical Context and Therapy Purpose

The purpose of ECMO as a bridge to lung transplantation is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as medical management and standard ventilator management, in patients who are adult lung transplant candidates.

The question addressed in this policy is: Does the use of ECMO improve the net health outcome in adults who are lung transplant candidates?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals who are adult lung transplant candidates.

Interventions

The therapy being considered is ECMO as a bridge to lung transplantation.

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 long enough that normal reparative processes or treatment can occur (eg, resolution of acute respiratory distress syndrome, treatment of infection) or other life-saving intervention can be delivered (eg, provision of a lung transplant).

Patients who are adult lung transplant candidates are actively managed by pulmonologists and intensivists in a tertiary clinical setting.

Comparators

Comparators of interest include medical management and standard ventilator management. Treatment includes portable oxygen, the use of ventilator support, and artificial airway insertion by tracheostomy. These treatments are administered by pulmonologists and primary care providers in an inpatient clinical setting.

Outcomes

The general outcomes of interest are OS, change in disease status, morbid events, treatment-related mortality, and treatment-related morbidity.

Outcomes should include short- and long-term mortality, along with measures of significant morbidity (eg, intracranial hemorrhage, thrombosis, vascular access site hemorrhage, limb ischemia) and short- and long-term disability and quality-of-life measures.

Table 11. Outcomes of Interest for Individuals who are adult lung transplant candidates

Outcomes	Details	Timing
Change in disease status	Evaluated using outcomes such as transfer to treatment centers and ventilator-free days	≥2 days
Morbid events	Evaluated using outcomes such as length of ICU stay	≥2 days
Treatment-related morbidity	Evaluated using outcomes such as severe disability or receiving steroids	≥2 days

ICU: intensive care unit.
Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Nonrandomized comparative studies

Schechter et al (2016) published a survival analysis comparing types of preoperative support prior to lung transplantation, using data from the United Network for Organ Sharing (Table 12).^20, Included in the analysis were 12403 adult lung transplantations from 2005 through 2013: 11607 (94.6%) did not receive invasive support prior to transplantation, 612 (4.9%) received invasive mechanical ventilation only, 119 (1%) received invasive mechanical ventilation plus ECMO, and 65 (0.5%) received ECMO only. Table 13 shows the cumulative survival rates for patients at six months, one year, and three years, by support before transplantation. Compared with patients with no invasive support, patients receiving invasive mechanical ventilation with or without ECMO had an increased mortality risk. Patients receiving ECMO alone had mortality rates comparable to patients receiving no support at three years. A limitation of the study relates to its use of registry data, in that complications due to the bridge strategy and certain details (eg, equipment, the technique of ECMO) were not available.

Table 12. Cumulative Survival Among Patients Undergoing Lung Transplantation by Support Type

Support Type	N	6 Months, %	1 Year, %	3 Years, %
No support	11,607	89.4	84.2	67.0
Invasive mechanical ventilation only	612	79.9	72.0	57.0
Invasive mechanical ventilation plus ECMO	119	68.1	61.0	45.1
ECMO only	65	75.2	70.4	64.5

Adapted from Schechter et al (2016).^20,
ECMO: extracorporeal membrane oxygenation.

In an earlier retrospective analysis of United Network for Organ Sharing data, Hayes et al (2014) evaluated the impact of pretransplant ECMO on outcomes after lung transplantation.^21, Of 15772 lung transplants identified from 2001 to 2012, 189 were receiving ECMO at the time of transplantation. In Kaplan-Meier analysis, patients who required ECMO pretransplant had worse survival than non-ECMO patients (p<0.001). In a multivariable Cox proportional hazards analysis, a requirement for ECMO pretransplant was associated with high-risk of death (HR, 2.23; 95% CI, 1.79 to 2.78; p<0.001).

Representative case series describing outcomes for patients who received ECMO before transplant are outlined in Table 13. 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 have included "awake ECMO" patients (Nosotti et al [2013],^22, Rehder et al [2013]^23,).

Table 13. Case Series of ECMO as Bridge to Lung Transplantation

Study	N	Indications for Lung Transplant	ECMO Technique	Summary of Outcomes
Inci et al (2015)24,	30	Not reported	VV (n=10) VA (n=4) iLA (n=5) Combination (n=7)	Bridge to transplant success: 86.6% Compared with 160 patients who underwent lung transplant without ECMO during same period, more ECMO patients required tracheostomy (73% vs 27.5%, p=0.001) and had longer ICU stays (18 d vs 3 d, p=0.001), but 30-d mortality did not differ
Hoopes et al (2013)25,	31	PF (n=9) CF (n=7; 2 with prior transplant) ARDS (n=3) ILD (n=3) PVOD (n=3) PAH (n=2) Other diagnoses (n=4)	VV (n=13) VA (n=17) "hybrid" (n=1)	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 et al (2013)26,	36	CF (n=20) PF (n=11) Other diagnoses (n=5)	VV (n=27) VA (n=9)	For all patients: success for bridge to transplant, 83%; 1-y survival, 75% For transplant recipients: 75% survived transplant; 56% survived to hospital discharge; 60.5% survived to 2 y

ARDS: acute respiratory distress syndrome; CF: cystic fibrosis; COPD: chronic obstructive pulmonary disease; ECMO: extracorporeal membrane oxygenation; ICU: intensive care unit; iLA: interventional lung assist; 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: Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplantation

The evidence on the use of ECMO as a bridge to lung transplantation includes two large nonrandomized comparator studies and many small case series. One of the large comparator studies showed that after a three-year follow-up, patients receiving ECMO as a bridge to transplant had comparable survival to patients receiving no support. Patients receiving invasive mechanical ventilation (with and without ECMO) had significantly lower three year survival. The other large comparator study found that patients on ECMO before both transplantation and retransplantation had a significantly higher risk for mortality. The small case series generally reported high positive rates of success for ECMO as a bridge to transplant.

Extracorporeal Membrane Oxygenation for Acute Cardiac Failure
Clinical Context and Therapy Purpose

The purpose of ECMO is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as medical management and other cardiac devices (eg, ventricular assist devices), in patients who are adults with acute cardiac failure. In adults, VA ECMO might be used for cardiorespiratory support where there is a potentially reversible cardiac condition, pulmonary blood flow disorder, or parenchymal disease severe enough to compromise right heart function. Predominant uses of ECMO in this category include postcardiotomy syndrome (failure to wean off bypass) and refractory cardiogenic shock due to acute myocarditis.

The question addressed in this policy is: Does the use of ECMO improve the net health outcome in adults with acute cardiac failure?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals who are adults with acute cardiac failure.

Interventions

The therapy being considered is ECMO.

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 long enough that normal reparative processes or treatment can occur (eg, resolution of acute respiratory distress syndrome, treatment of infection) or other life-saving intervention can be delivered (eg, provision of a lung transplant).

Patients who are adults with acute cardiac failure are actively managed by cardiologists and intensivists in a tertiary clinical setting.

Comparators

Comparators of interest include medical management and other cardiac devices (eg, ventricular assist devices). Treatment includes self-care (physical exercise and a low sodium diet), medications that include diuretics, beta blockers, ACE inhibitors, antihypertensive drugs, blood pressure support, vasodilators, and heart medication, and cardiac resynchronization therapy. These treatments are managed by cardiologists and primary care providers in an outpatient clinical setting.

Outcomes

The general outcomes of interest are OS, change in disease status, morbid events, treatment-related mortality, and treatment-related morbidity.

Outcomes should include short- and long-term mortality, along with measures of significant morbidity (eg, intracranial hemorrhage, thrombosis, vascular access site hemorrhage, limb ischemia) and short- and long-term disability and quality-of-life measures.

Table 14. Outcomes of Interest for Individuals who are adults with acute cardiac failure

Outcomes	Details	Timing
Change in disease status	Evaluated using outcomes such as transfer to treatment centers and ventilator-free days	≥2 days
Morbid events	Evaluated using outcomes such as length of ICU stay	≥2 days
Treatment-related morbidity	Evaluated using outcomes such as acute kidney injury, renal dialysis, neurologic events, and reoperation for bleeding	≥2 days

ICU: intensive care unit.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Utilizing a systematic review and meta-analysis of 20 observational studies, Wang et al (2018) investigated the clinical outcomes for adults with postcardiotomy cardiogenic shock (PCS) who receive ECMO.^27, The primary outcome of interest was the rate of survival to hospital discharge for PCS patients who received ECMO. Secondary outcomes included one-year and mid-term survival rates (defined as three-five years), several comorbidities, and select adverse effects, as well as PCS-related and ECMO-related survival rates. Studies included in the meta-analysis were published from 1996 to 2017 and include a total pooled population of 2877 participants. Of the 20 studies included, survival rate (or mortality) was reported as follows: All (20) studies reported on in-hospital mortalities, 4 reported on midterm survival rate, and 1 reported on the 1-year survival rate. Regarding the secondary outcomes, reporting is as follows: 11 reported on leg ischemia, 10 reported on redo surgery, 12 reported on renal failure, 12 reported on the incidence of neurological complications, and 9 reported the incidence of infection. Regarding the primary outcome (survival rate to discharge, of the total population in all studies (n=2877), 964 (32.85%) of patients survived to discharge. The pooled rate of survival to discharge was 34.0% (95% CI, 30.0%-38.0%, I²=71.8%) in PCS patients that underwent ECMO. Pooled results of the incidence of secondary outcomes are reported in Table 15, below. One limitation of this study is due to the retrospective nature of the analysis, the quality of most of the studies was low. The limited number of patients per study may result in small-sample bias in individual studies and carryover into the data reported as only 5/20 studies included >100 patients. Almost 66% of the patients in the meta-analysis were from those 5 studies with the populations >100.

Table 15. Meta-analysis for secondary outcomes and publication bias from Wang (2018)

Outcomes	Proportion 95% CI	I2 (%)	Egger's p
1-y survival rate	0.24 (0.19-0.30)	75.6	NR
Midterm survival rate	0.18 (0.11-0.27)	77.3	NR
Leg ischemia	0.14 (0.10-0.20)	74.8	0.45
Redo surgery	0.50 (0.32-0.68)	96.6	0.17
Renal failure	0.57 (0.47-0.66)	87.1	0.65
Neurologic complication	0.16 (0.13-0.20)	60.5	0.37
Infection	0.31 (0.22-0.41)	78.9	NR

Adapted from Wang et al (2018)
CI: confidence interval; I² : heterogeneity, refers to the variation in outcomes between studies; NR: not reported.

Other smaller cases series have reported similarly high morbidity and mortality rates after ECMO for postcardiotomy cardiac shock. In a study of 77 patients who underwent ECMO support after surgery for acquired heart disease, Slottosch et al (2013) reported that 62% of patients were weaned from ECMO (after a mean 79 hours of ECMO support) and 30-day mortality was 70%.^29, Bakhtiary et al (2008) reported on outcomes for a cohort of 45 patients treated with ECMO for postcardiotomy cardiac shock, with a 30-day and in-hospital mortality rates of 53% and 71%, respectively, and an average ECMO duration of 6.4 days.^30,

Extracorporeal Membrane Oxygenation for Refractory Cardiogenic Shock Due to Other Causes

The literature on the use of ECMO for refractory cardiogenic shock outside of the postcardiotomy setting includes a meta-analysis and multiple case series, the largest of which includes 147 patients (most have <50 patients), and case reports, and addresses a range of underlying etiologies for cardiogenic shock (Tables 16 and 17).

Xie et al (2015) conducted a meta-analysis evaluating VA ECMO for cardiogenic shock and cardiac arrest that included observational studies and clinical trials with at least 10 adults.^31, Twenty-two studies, all observational, with a total of 1199 patients (12 studies [n=659 patients] with cardiogenic shock; 5 studies [n=277 patients] with cardiac arrest; 5 studies [n=263 patients] with both patient types) met inclusion criteria. Across the 16 studies (n=841 patients) that reported survival to discharge, the weighted average survival was 40.2% (95% CI, 33.9% to 46.7%). Across the 14 studies that reported 30-day survival, the weighted average survival was 52.8% (95% CI, 43.9% to 61.6%), with similar survival rates at 3, 6, and 12 months across studies that reported those outcomes. Across studies that reported on cardiogenic shock only, the weighted average survival rate to discharge was 42.1% (95% CI, 32.2% to 52.4%; I²=79%). Across all studies, complications were common, most frequently acute kidney injury (pooled incidence, 47.4%; 95% CI, 30.2% to 64.9%; I²=92%), followed by renal dialysis (pooled incidence, 35.2%; 95% CI, 23% to 47.4%; I²=95%) and reoperation for bleeding (pooled incidence, 30.3%; 95% CI, 1.8% to 72.2%; I²=98%). However, reviewers expressed uncertainty that the complications were entirely due to ECMO, given the underlying illness in patients who receive ECMO.

Several studies, published after the Xie et al (2015) meta-analysis, are described next. For example, Dobrilovic et al (2017) retrospectively evaluated the preoperative use of VA ECMO as a bridge to prepare 12 patients deemed inoperable for cardiac surgery.^32,Definitive cardiac surgical procedures included complex valve (n=5), left ventricular assist device implantation (n=3), coronary artery bypass grafting; n=2), coronary artery bypass grafting/ventricular septal defect repair (n=1), and mitral valve replacement/coronary artery bypass grafting (n=1). The average ECMO support time was 200 hours. The 30-day mortality rate was 25% (3/12), and the hospital mortality rate was 33% (4/12). No patient died of a primary cardiac complication, but four patients died of recognized complications from ECMO, gastrointestinal bleeding, or liver failure.

Aso et al (2016) analyzed 5263 patients from the Japanese Diagnosis Procedure Combination database who received VA ECMO during hospitalization.^33, Reasons for receiving VA ECMO included: cardiogenic shock (88%), pulmonary embolism (7%), hypothermia (2%), trauma (2%), and poisoning (1%). Among patients in the cardiogenic shock group, 33% died during VA ECMO, 40% died after weaning from VA ECMO, and 25% were discharged following weaning from VA ECMO. Multivariate logistic regression for in-hospital mortality showed an increased risk among patients 60 years of age and older, a body mass index less than 18.5 kg, a body mass index of 25 kg or more, ischemic heart disease, myocarditis, use of intra-aortic balloon pumping, use of continuous serial replacement therapy, and cardiac arrest.

Diddle et al (2015) reported on 147 patients, treated with ECMO for acute myocarditis, and identified from the Extracorporeal Life Support Organization database.^34, Patients in this group were relatively young (median age, 31 years) and were most often treated with VA ECMO (91%). Of the cohort, 101 (69%) were decannulated from ECMO and 90 (61%) survived to discharge. In multivariable analysis, the occurrence of pre-ECMO cardiac arrest and the need for higher ECMO support at 4 hours were significantly associated with in-hospital mortality (OR=2.4; 95% CI, 1.1 to 5.0; p=0.02 for pre-ECMO arrest; OR=2.8; 95% CI, 1.1 to 7.3; p=0.03 for increased ECMO support at 4 hours).

A retrospective study by Sibai et al (2018) utilized data within the 2013 Nationwide Emergency Department Sample (NEDS) to identify variables associated with increased mortality in ECMO. The NEDS database is the largest, all-payer US emergency department database and is a product of the Agency for Healthcare Research and Quality For this study, the 2013 NEDS database version was utilized; the 2013 database reflects 20% of all hospital-based emergency departments (EDs) in the US; with information from 945 hospital-based EDs that reported 134869015 weighted ED visits across 30 states and the District of Columbia. For the population of interest (adult patient visits that included ECMO and an admission to the ED with cardiogenic shock), 8605807 weighted adult visits involved ED admission and cardiogenic shock; of these, 992 visits included ECMO (0.1 per 1000 ED visits) and represent the study population. The mean age of the group was 50.8 years (95% CI, 48.8-57.7) and the majority were males (66.3%; 95% CI, 60.3-71.8). Linear regression models were used to identify associations between ECMO as a treatment and any variable that was statistically significant between the groups of patients who survived to discharge and those who did not. Lower mortality was associated with a younger age [(mean 49.5 vs 52.1 years) 1 year: OR, 95% CI, 1.01-1.04 p=0.239], injury and poising (OR, 0.47) significantly greater total hospital charge (per $10,000: OR, 1.01; 95% CI, 1.00-1.02; P=.069), and a longer length of hospital stay (1 day: OR, 0.94; 95% CI, 0.90-0.98; P=.003). Increased mortality was associated with a presence of respiratory diseases (OR, 3.83), genitourinary diseases (OR, 4.97), and undergoing and EKG (OR, 4.63). The study was limited due to the structural features of the NEDS database as ICD-9 CM codes do not differentiate between types of ECMO. Further, information on the duration of ECMO use of timing is not available.

Table 16. Summary of Key Retrospective Study Characteristics

Study	Study Type	Country	Dates	Participants	ECMO	Wean from ECMO	Follow-Up
Dobrilovic et al (2017) 32,	Retrospective	US	Dec 2011 to Aug 2017	Patients deemed inoperable for cardiac surgery who used ECMO preoperatively (n=12)	N=12	-	30 days
Aso et al (2016)33,	Retrospective	Japan	Jul 2010 to March 2013	Patients given VA ECMO during hospitalization (N=5263) and at least 19 years	N=5263	3389 (64.4%)	NR
Diddle et al (2015)34,	Retrospective	US	1995-2011	Patients with acute myocarditis treated by ECMO (median age, 31 years)	N=147	--	-

ECMO: extracorporeal membrane oxygenation; NR: not reported; VA: venoarterial.

Table 17. Summary of Key Nonrandomized Trials OR Observational Comparative Study Results

Study	Morality	Hospital mortality rate	ECMO Support time (hours)	Complications leading to ECMO-related mortality
	30-day
Dobrilovic et al (2017)32,	N=12	N=12	N=12	N=12
ECMO	3(25%)	4(33%)	N=200	4 (33.33%)
Aso et al (2016)33, N=5263	-
Total	-	3817(72.5%)	-	-
Under VA ECMO	-	1823 (34.6%)	-	-
Diddle et al (2015)34, N=147	Survival to discharge	-	-	-
ECMO	90 (61%)	-	-	-

ECMO: extracorporeal membrane oxygenation; VA: venoarterial.
1 Include number analyzed, association in each group and measure of association (absolute or relative) with CI.

Lorusso et al (2016) reported on a series of 57 adults with acute fulminant myocarditis treated with VA ECMO identified from institutional databases from 13 centers.^35, Primary inclusion criteria were the presence of sudden and refractory cardiogenic shock, cardiac arrest, or severe hemodynamic instability despite aggressive inotropic drugs with or without intra-aortic balloon pump, demonstration of normal coronary artery anatomy, and echocardiographic signs of myocardial tissue swelling and biventricular involvement. The series excluded patients with organic valvular or coronary artery disease, chronic dilated cardiomyopathy, toxic myocarditis, mediastinal radiotherapy, or other mechanical circulatory support, other than intra-aortic balloon pump. Mean VA ECMO time was 9.9 days (range, 2-24 days), and 43 (75.5%) patients had cardiac recovery. Complications were common (40 [70.1%] patients), most frequently acute kidney injury (10 [17.5%] patients) and neurologic events (10 [17.5%] patients). Sixteen (28.1%) patients died before hospital discharge.

Section Summary: Extracorporeal Membrane Oxygenation for Adults With Acute Cardiac Failure

The evidence on ECMO for adults with cardiorespiratory failure (for postcardiotomy failure to wean off bypass and refractory cardiogenic shock) includes meta-analyses, case series, case reports, and several observational studies. For the use of ECMO in the failure to wean from bypass population, case series found some successful cases of weaning patients from ECMO in the setting of very high expected morbidity and mortality rates. However, without comparative studies, it is difficult to assess whether rates of weaning from bypass are better with ECMO than with standard care. ECMO for refractory cardiogenic shock is accompanied by high mortality and complication rates. Without comparative studies, there is uncertainty about the effect of ECMO on patients with cardiorespiratory failure. While a potential benefit exists, the lack of comparators makes it difficult to determine the effects this technology has on health outcomes.

Extracorporeal Membrane Oxygenation-Assisted Cardiopulmonary Resuscitation for Adults with Cardiac Arrest
Clinical Context and Therapy Purpose

The purpose of ECMO-assisted CPR is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as standard CPR, in patients who are adults in cardiac arrest.

The question addressed in this policy is: Does the use of ECMO improve the net health outcome in adults with cardiac arrest?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals who are adults in cardiac arrest.

Interventions

The therapy being considered is ECMO-assisted CPR.

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 long enough that normal reparative processes or treatment can occur (eg, resolution of acute respiratory distress syndrome, treatment of infection) or other life-saving intervention can be delivered (eg, provision of a lung transplant).

Patients who are adults in cardiac arrest are actively managed by cardiologists and intensivists in a tertiary clinical setting.

Comparators

Comparators of interest include standard CPR. This is managed by emergency medical technicians, cardiologists, and primary care providers in an inpatient clinical setting.

Outcomes

The general outcomes of interest are OS, change in disease status, morbid events, treatment-related mortality, and treatment-related morbidity.

Table 18. Outcomes of Interest for Individuals who are adults in cardiac arrest

Outcomes	Details	Timing
Change in disease status	Evaluated using outcomes such as transfer to treatment centers and ventilator-free days	≥2 days
Morbid events	Evaluated using outcomes such as length of ICU stay	≥2 days
Treatment-related morbidity	Evaluated using outcomes such as acute kidney injury, renal dialysis, neurologic events, and reoperation for bleeding	≥2 days

ICU: intensive care unit.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought. Studies with duplicative or overlapping populations were excluded.
• Some centers have evaluated relatively portable ECMO systems to manage in- or out-of-hospital cardiac arrest, referred to as ECPR. The evidence for the use of ECPR consists of systematic reviews, nonrandomized comparative studies, and noncomparative studies.

Meta-Analyses Characteristics and Results are described in Tables 19 and 20.

Debaty et al (2017) published a systematic review and meta-analysis on prognostic factors for patients receiving ECPR following out-of-hospital refractory cardiac arrest, to inform the decision of which patients benefit most from ECPR.^36, The search included literature through September 2016. Fifteen retrospective and prospective cohort studies were included (total n=841 patients). The overall rate of a favorable outcome following ECPR was 15%, though the range among the studies was wide (0%-50%) due to the heterogeneity of inclusion criteria, outcome definitions, and compliance with protocols. Favorable outcomes occurred more frequently among patients with initial shockable cardiac rhythms, shorter low-flow duration, higher arterial pH, and lower serum lactate concentration on hospital admission. No significant differences were found when age, sex, and bystander CPR attempt were evaluated.

Twohig et al (2019) reported a systematic review and meta-analysis of the effectiveness of ECPR versus conventional CPR in patients in cardiac arrest.^37, Seventeen papers were included, 6 papers compared ECPR to CPR, 3 papers evaluated parameters of patients that survived ECPR, and 3 papers evaluated both. Eleven papers were graded as being at moderate risk of bias and the remainder were considered to be at either serious or critical risk of bias. One comparative study was prospective and 6 used propensity scoring. ECPR showed a survival benefit (odds ratio [OR] 0.40, p < 0.001, and a greater likelihood of being neurologically intact (OR: 0.10, p < 0.001) compared to conventional CPR. Having an initial shockable rhythm was associated with survival (OR 0.38) as was the arrest to ECPR time (mean difference of -10.17 min, 95% CI -19.22 to -1.13), but high heterogeneity limits confidence in this finding.

Table 19. Meta-Analyses Characteristics

Study	Dates	Trials	Participants	N (Range)	Design	Duration
Debaty et al (2017)36,	2016	15	Patients with out of hospital cardiac arrest	841	Prospective and retrospective observational studies
Twohig et al (2019)37,	2011 - 2017	17	Patients with cardiac arrest undergoing ECPR or conventional CPR	ECPR 915 (20 to 320) vs CPR 37,938 (23 to 36,227)	Prospective and retrospective observational studies	Hospital discharge or 30 days

CPR: cardiopulmonary resuscitation; ECPR: Extracorporeal membrane oxygenation with cardiopulmonary resuscitation

Table 20. Meta-Analyses Results

Study	Survival	Neurologic Outcome	Factors for Survival
Debaty et al (2017)36,			Shorter Low-Flow Duration	Bystander CPR	Initial Shockable Cardiac Rhythm
Total N
OR (95% CI)			0.90 (0.03 to 0.22)	2.81 (0.95 to 8.32)	2.20 (1.30 to 3.72)
P			<.001	.06	.003
I2 (p)					0% (.967)
Twohig et al (2019) 37,			Witnessed Arrest	Bystander CPR	Initial Shockable Cardiac Rhythm
Total N	38,853	37,784	374	184	241
OR (95% CI)	0.40 (0.27 to 0.60)	0.10 (0.04 to 0.27)	0.47 (0.11 to 1.95)	0.19 (0.01 to 2.48)	0.38 (0.26 to 0.57)
I2 (p)	59% (.01)	76% (<.001)	11% (.32)	75% (.02)	0% (.94)

CI: confidence interval; CPR: cardiopulmonary resuscitation; OR: odds ratio.

The American Heart Association (2015) updated its guidelines on CPR and emergency cardiovascular care.^38, These guidelines were based on a systematic review by the International Liaison Committee on Resuscitation and included a comparison of ECPR with conventional CPR for adults with in- or out-of-hospital cardiac arrest. The systematic review did not identify any RCTs evaluating ECPR for cardiac arrest. Reviewers concluded: "The low-quality evidence suggests a benefit in regard to survival and favorable neurologic outcome with the use of ECPR when compared with conventional CPR." However, variability in the inclusion and exclusion criteria of the studies was noted, which affects generalizability.

Nonrandomized Comparative Studies

Shin et al (2011) compared ECPR with conventional CPR in adults who had undergone CPR for more than 10 minutes after in-hospital cardiac arrest.^39, Four hundred six patients were included, 85 who underwent ECPR and 321 who underwent conventional CPR. The cause of arrest was considered cardiac in most cases (n=340 [83.7%]) and noncardiac (secondary to respiratory failure or hypovolemia) in the remainder (n=66 [16.3%]). The decision to initiate ECPR was made by the CPR team leader. Typically, the ECMO device was available in the catheterization laboratory, coronary care unit, and operating room and an ECMO cart was transported to the CPR site within 5 to 10 minutes during the day and within 10 to 20 minutes at night. After propensity score matching, 120 patient pairs were included; in the matched group, ECPR was associated with significantly higher rates of survival to discharge with minimal neurologic impairment (OR for mortality or significant neurologic deficit, 0.17; 95% CI, 0.04 to 0.68; p=0.012) and survival at 6 months with minimal neurologic impairment (HR=0.48; 95% CI, 0.29 to 0.77; p=0.003).

In an earlier prospective study, Chen et al (2008) compared ECPR with conventional CPR in adults who had undergone prolonged (>10 minutes) conventional CPR after in-hospital cardiac arrest of cardiac origin.^40, One hundred seventy-two patients were included, 59 in the ECPR group and 113 in the conventional CPR group. The decision to call for extracorporeal life support was made by the physician in charge. The average duration of the call to team arrival was 5 to 7 minutes during the day and 15 to 30 minutes overnight. Survival to discharge occurred in 17 (28.8%) patients in the ECPR group and 14 (12.3%) patients in the conventional CPR group. In a multivariable logistic regression model to predict survival at discharge, use of ECPR was associated with reduced risk of death before discharge (adjusted HR=0.50; 95% CI, 0.33 to 0.74; p=0.001).

Section Summary: Extracorporeal Membrane Oxygenation-Assisted CPR for Adults with Cardiac Arrest

Evidence for the use of ECPR in cardiac arrest consists of meta-analyses of nonrandomized comparative studies, most of which demonstrated a survival benefit with ECPR. However, nearly all of the studies were retrospective and at risk of bias, limiting conclusions. Selection for ECMO in these studies was at the discretion of the treating physicians, and although propensity matching was used in some studies, selection bias in the small studies may remain. Multiple unanswered questions remain about the role of ECPR in refractory cardiac arrest, including appropriate patient populations, duration of conventional CPR, and assessment of futility. Studies have begun to address the question of appropriate patient population, with results indicating that patients with an initial shockable cardiac rhythm, shorter low-flow duration, higher arterial pH, and lower serum lactate concentrations on hospital admission experienced favorable outcomes. Further study is needed to evaluate efficacy and define the population that may benefit from this treatment.

Predictors of outcomes

Studies that include mixed populations of ECMO patients have reported factors associated with outcomes. In the largest study identified, Gray et al (2015) reported on 2000 patients treated with ECMO at a single-center from 1973 to 2010.^41, Most patients in this series were pediatric, but 353 adults were included. Survival for adults treated with ECMO for respiratory failure (n=207) in the period after 1998 was 52%, and for cardiac failure (n=88) it was 40%. Overall, need for dialysis or hemofiltration and nonintracranial bleeding were the most common adverse events.

Guttendorf et al (2014) reported on factors associated with discharge outcomes in ECMO-treated patients in a single-center retrospective cohort.^42, The cohort included 212 patients, of whom 126 had a primary cardiac indication and 86 had a primary respiratory indication. Overall, 57% of patients were weaned from ECMO, and 33% lived to hospital discharge ("good outcome"). Compared with "good outcome" patients, patients with a "poor outcome" (death before hospital discharge) were more likely to have had a primary cardiac indication (69.7% of poor outcome patients vs 38.6% of good outcome patients, p<0.001), and be older (53.1 years vs 47.4 years, p=0.007), and sicker (Murray Lung Injury Score, 2.74 vs 3.04, p=0.02) at baseline. Complication rates were more frequent among "poor outcome" patients.

In a series of 171 patients treated with ECMO at a single institution from 2007 to 2014, Omar et al (2016) reported on predictors of ischemic stroke.^43, The most common indication for ECMO was cardiogenic shock (42.4%), followed by post cardiac surgery (13.3%). Overall, 10 (5.8%) subjects had a radiologically confirmed ischemic stroke. In univariate analysis, patients with ischemic stroke had higher lactic acid levels at baseline (10.6 mmol/L vs 6.3 mmol/L, p=0.039) and were more likely to require ECMO for a cardiac indication (100% vs 73.3%, p=0.05). In multivariable analysis, only an elevated pre-ECMO lactic acid level remained associated with ischemic stroke risk.

Aubron et al (2013) reported on outcomes from a prospective cohort of 151 patients treated with ECMO over a 5-year period, 99 with VA ECMO and 52 with VV ECMO.^44, The most common indication for VA ECMO was post-heart transplant, while the most common indication for VV ECMO was ARDS. The overall mortality rate was 37.3% (37.1% of patients who had VA ECMO vs 37.7% of patients who had VV ECMO, p=NS). In multivariable analyses, the number of red blood cell units transfused was independently associated with increased mortality for VA ECMO (OR=1.057; 95% CI, 1.016 to 1.102; p=0.007), while the number of bags of platelets transfused was independently associated with increased mortality for VV ECMO (OR=1.572; 95% CI, 1.125 to 2.197; p=0.008).

Summary of Evidence

For individuals who are adults with acute respiratory failure who receive ECMO, the evidence includes RCTs, systematic reviews, nonrandomized comparative studies, and case series. Relevant outcomes are overall survival (OS), change in disease status, morbid events, and treatment-related mortality and morbidity. The most direct evidence on the efficacy of ECMO in adult respiratory failure comes from the CESAR trial. Although this trial had limitations, including nonstandardized management of the control group and unequal intensity of treatment between treatment and control groups, for the trial's primary outcome (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 have generally reported improvements in outcomes with ECMO. The available evidence supports the conclusion that outcomes are improved for adults with acute respiratory failure, particularly those who meet the patient selection criteria outlined in the CESAR trial. However, questions remain about the generalizability of findings to other patient populations, and additional clinical trials in more specific patient populations are needed. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are adult lung transplant candidates who receive ECMO as a bridge to lung transplantation, the evidence includes two large nonrandomized comparator studies and small case series. Relevant outcomes are OS, change in disease status, morbid events, and treatment-related mortality and morbidity. One of the large comparator studies found that patients receiving ECMO had three-year survival rates similar to patients receiving no support and significantly better survival rates than patients receiving invasive mechanical support. Single-arm series have reported rates of the successful bridge to transplant on the order of 70% to 80%. Given the lack of other treatment options for this population and the suggestive clinical evidence ECMO may be an appropriate therapy for this patient population. The evidence is sufficient to determine the effects of the technology on health outcomes.

For individuals who are adults with acute cardiac failure who receive ECMO, the evidence includes meta-analyses, observational studies, case series, and case reports. Relevant outcomes are OS, change in disease status, morbid events, and treatment-related mortality and morbidity. Case series in patients with postcardiotomy failure to wean off bypass have reported rates of successful decannulation from ECMO on the order of 60%. Case series in populations affected by other causes of acute cardiac failure have reported rates of survival to discharge of 40% to 60%. Complication rates are high. Evidence comparing ECMO with other medical therapy options is lacking. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who are adults in cardiac arrest who receive ECMO with cardiopulmonary resuscitation (ECPR), the evidence includes meta-analyses of nonrandomized comparative studies and case series. Relevant outcomes are OS, change in disease status, morbid events, and treatment-related mortality and morbidity. A meta-analysis of non-randomized comparative studies found an increased odds of survival and odds of remaining neurologically intact with ECPR. However, the benefit associated with using ECPR is uncertain given the potential for bias in nonrandomized studies. Additionally, factors related to the implementation of ECPR procedures in practice need better delineation. Multiple unanswered questions remain about the role of ECPR in refractory cardiac arrest, including appropriate patient populations, duration of conventional CPR, and assessment of futility. Studies have begun to address these questions, with results indicating that patients with an initial shockable cardiac rhythm, shorter low-flow duration, higher arterial pH, and lower serum lactate concentrations on hospital admission experienced favorable outcomes. Further study is needed to evaluate efficacy and define the population that may benefit from this treatment. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION
Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 3 physician specialty societies, 1 of which provided 2 responses and 1 of which provided 2 responses and a consensus letter, and 2 academic medical centers, 1 of which provided 3 responses, while this policy was under review in 2015. There was a consensus that extracorporeal membrane oxygenation (ECMO) is medically necessary for adults with respiratory failure that is severe and potentially reversible. There was a consensus that ECMO is medically necessary for adults as a bridge to heart, lung, or heart-lung transplant. There was no consensus that ECMO is medically necessary for adults with refractory cardiac failure. There was a consensus that ECMO is investigational as an adjunct to cardiopulmonary resuscitation.

Practice Guidelines and Position Statements
Extracorporeal Life Support Organization

The Extracorporeal Life Support Organization (ECLO) provides education, training, and guidelines related to the use of ECMO, along with supporting research and an ECMO patient registry. In addition to general guidelines that describe ECMO, ECLO published specific recommendations on use of ECMO in adult respiratory failure, adult cardiac failure, in adult ECMO-assisted cardiopulmonary resuscitation (ECPR), which are outlined in Table 21.

Table 21. Guidelines for Use of ECMO in Adults

Condition	Indications	Contraindications
Adult respiratory failure v1.4	In hypoxic respiratory failure due to any cause (primary or secondary) ECLS should be considered when the risk of mortality is ≥50%, and is indicated when the risk of mortality is≥80%. 50% mortality risk is associated with a Pao2/Fio2<150 on Fio2 >90% and/or Murray score 2-3 80% mortality risk is associated with a Pao2/Fio2<100 on Fio2 >90% and/or Murray score 3-4, despite optimal care for ³6 h CO2 retention on mechanical ventilation, despite high Pplat (>30 cm H2O) Severe air leak syndromes Need for intubation in a patient on lung transplant list Immediate cardiac or respiratory collapse (PE, blocked airway, unresponsive to optimal care)	Relative contraindications: Mechanical ventilation at high settings (Fio2 >0.9, Pplat >30) for > 7 d Major pharmacologic immunosuppression (absolute neutrophil count <400/mm3) CNS hemorrhage that is recent or expanding Nonrecoverable comorbidity such as major CNS damage or terminal malignancy Age: no specific age contraindication but consider increasing risk with increasing age
Adult cardiac failure v1.3	Indications for ECLS in adult cardiac failure is cardiogenic shock, defined by the following: Inadequate tissue perfusion manifested as hypotension and low cardiac output, despite adequate intravascular volume. Shock persists despite volume administration, inotropes and vasoconstrictors, and intra-aortic balloon counterpulsation, if appropriate. Typical causes: acute myocardial infarction, myocarditis, peripartum cardiomyopathy, decompensated chronic heart failure, postcardiotomy shock. Septic shock is an indication in some centers.	Absolute contraindications Unrecoverable heart and not a candidate for transplant or VAD. Advanced age Chronic organ dysfunction (emphysema, cirrhosis, renal failure). Compliance (financial, cognitive, psychiatric, or social limitations) Prolonged CPR without adequate tissue perfusion Relative contraindications: Contraindication for anticoagulation. Advanced age (Note: advanced age appears in both relative and absolute contraindication lists). Obesity.
Adult ECPR v1.3	AHA guidelines for CPR recommend consideration of ECMO to aid CPR in patients who have an easily reversible event, have had excellent CPR	All contraindications to ECMO use (eg, gestational age <34 wk) should apply to ECPR Do-not-resuscitate orders
COVID-19 (interim)	During the pandemic, COVID-19 and non-COVID-19 patients should receive ECMO in established ECMO centers using available resources to maximize benefits.	Conventional capacity: Offer ECMO in selected COVID-19 patients based on usual criteria. Capacity Tier 1: VV, VA ECMO in younger COVID-19 patients with single organ failure. Capacity Tier 2: VV ECMO in younger, single organ failure COVID-19 patients. VA ECMO not offered. Crisis Capacity: ECMO not feasible in both COVID-19 and non-COVID-19 patients.

AHA: American Hospital Association; CNS: central nervous system; CPR: cardiopulmonary resuscitation; ECLS: extracorporeal lung support; ECMO: extracorporeal membrane oxygenation; ECPR: extracorporeal membrane oxygenation- assisted cardiopulmonary resuscitation; Fio₂: fraction of inspired oxygen; Pao₂: partial pressure of oxygen in arterial blood; PE: pulmonary embolus; Pplat: airway plateau pressure; VA: Veno-arterial; VAD: ventricular assist device; VV: veno-venous.

International Extracorporeal Membrane Oxygenation Network

In 2014, the International ECMO Network with endorsement by Extracorporeal Life Support Organization published a position paper detailing institutional, staffing, and reporting requirements for facilities providing ECMO.^45,

National Institute for Health and Care Excellence

In 2014, the National Institute for Health and Care Excellence issued guidance on the use of ECMO for acute heart failure in adults, which made the following recommendations^46,:

"The evidence on the efficacy of extracorporeal membrane oxygenation (ECMO) for acute heart failure in adults is adequate but there is uncertainty about which patients are likely to benefit from this procedure, and the evidence on safety shows a high incidence of serious complications."

"Evidence on the safety of extracorporeal membrane oxygenation (ECMO) for severe acute respiratory failure in adults is adequate but shows that there is a risk of serious side effects. Evidence on its efficacy is inadequate to draw firm conclusions: data from the recent CESAR (Conventional ventilation or extracorporeal membrane oxygenation for severe adult respiratory failure) trial were difficult to interpret because different management strategies were applied among many different hospitals in the control group and a single centre was used for the ECMO treatment group."

In 2015, the American Heart Association updated its guidelines on cardiopulmonary resuscitation and emergency cardiovascular care, which included a new systematic review of the evidence for ECPR and recommendations on the use of ECPR for adults with in- or out-of-hospital cardiac arrest.^38, The findings of the systematic review are discussed in the Rationale. The guidelines made the following recommendations related to ECPR:

"There is insufficient evidence to recommend the routine use of ECPR for patients with cardiac arrest. In settings where it can be rapidly implemented, ECPR may be considered for select cardiac arrest patients for whom the suspected etiology of the cardiac arrest is potentially reversible during a limited period of mechanical cardiorespiratory support" (Class IIb, level of evidence C-limited data).

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Current ongoing and unpublished trials that might influence this policy are listed in Table 21.

Table 21. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT02301819	ExtraCorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock	120	Dec 2020
NCT03101787	Early Initiation of Extracorporeal Life Support in Refractory OHCA (INCEPTION)	110	Jul 2021
NCT02654327	pRotective vEntilation With Veno-venouS Lung assisT in Respiratory Failure	1120	Aug 2021
NCT03880565	Advanced REperfusion STrategies for Refractory Cardiac Arrest (The ARREST Trial)	180	Jan 2023
Unpublished
NCT02527031	A Comparative Study Between a Pre-hospital and an In-hospital Circulatory Support Strategy (Extracorporeal Membrane Oxygenation) in Refractory Cardiac Arrest (APACAR2)	210	Mar 2020

NCT: national clinical trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Extracorporeal Membrane Oxygenation for Adult Conditions
ECMO for Adult Conditions

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46. National Institute for Health and Care Excellence (NICE). Extracorporeal membrane oxygenation (ECMO) for acute heart failure in adults [IPG482]. 2014; https://www.nice.org.uk/Guidance/ipg482. Accessed April 28, 2020.

47. National Institute for Health and Care Excellence (NICE). Extracorporeal membrane oxygenation for severe acute respiratory failure in adults [IPG391]. 2011; https://www.nice.org.uk/guidance/IPG391/chapter/1-guidance. Accessed April 28, 2020.

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