Accepted Manuscript Extracorporeal Life Support for Adult Cardiopulmonary Failure Basil W. Schaheen, MD, Robert H. Thiele, MD, Assistant Professor of Anesthesiology and Biomedical Engineering, James M. Isbell, MD, MSCI, Assistant Professor of Surgery PII:

S1521-6896(15)00035-X

DOI:

10.1016/j.bpa.2015.04.004

Reference:

YBEAN 855

To appear in:

Best Practice & Research Clinical Anaesthesiology

Received Date: 2 April 2015 Revised Date:

11 April 2015

Accepted Date: 14 April 2015

Please cite this article as: Schaheen BW, Thiele RH, Isbell JM, Extracorporeal Life Support for Adult Cardiopulmonary Failure, Best Practice & Research Clinical Anaesthesiology (2015), doi: 10.1016/ j.bpa.2015.04.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Extracorporeal Life Support for Adult Cardiopulmonary Failure

Basil W. Schaheen, MD

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Resident, General Surgery University of Virginia P.O. Box 800681 Charlottesville, VA 22908

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[email protected]

Robert H. Thiele, MD

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Assistant Professor of Anesthesiology and Biomedical Engineering Director, Technology in Anesthesia and Critical Care Group

Co-Director, Enhanced Recovery after Surgery (ERAS) Program Department of Anesthesiology University of Virginia Health System

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PO Box 800710 Charlottesville, VA 22908-0710 Email: [email protected]

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Office: (434) 243-9412

James M. Isbell, MD, MSCI, Corresponding author

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Assistant Professor of Surgery

Director, Adult Extracorporeal Life Support Program Co-Director, Thoracic & Cardiovascular Critical Care Department of Surgery, Division of Thoracic and Cardiovascular Surgery University of Virginia Health System P.O. Box 800679 Charlottesville, VA 22908 [email protected] Office: (434) 243-6443

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Fax: (434) 244-9429 Key terms Extracorporeal life support/extracorporeal membrane oxygenation Acute respiratory distress syndrome/acute lung injury

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Cardiogenic shock/postcardiotomy shock

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Pumpless extracorporeal lung assist

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Abstract The use of extracorporeal life support (ECLS) or extracorporeal membrane oxygenation (ECMO), as it is also known, has rapidly expanded over the past decade. The increase in ECMO use is a

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consequence of multiple factors including significant advancements in extracorporeal technology, the emergence of data supporting its use and a growing number of potential clinical applications. This

review focuses on the various modes of ECLS as well as the clinical indications and available evidence

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for the use of extracorporeal support.

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Introduction

Extracorporeal life support (ECLS), also known as extracorporeal membrane oxygenation (ECMO), is a lifesaving technology that employs a modified form of cardiopulmonary bypass for

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patients with severe cardiac and/or pulmonary failure. The report of the first ECMO survivor in

1972 generated significant excitement for the use of this technology. [1] However, this enthusiasm was tempered after the U.S. National Institutes of Health (NIH) sponsored a randomized trial

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comparing ECMO to conventional mechanical ventilation in the 1970s that demonstrated 90%

mortality in both treatment groups. [2] Although multiple studies have since established ECMO as an effective rescue strategy for circulatory and pulmonary failure in the neonatal and pediatric

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populations, until recently, application of ECMO in adults had been slow to gather broad support. Advancements in ECMO technology along with multiple reports of its successful use in patients with recalcitrant respiratory failure during the 2009-2010 H1N1 influenza pandemic have led to a significant rise in its use. The adult patient populations treated with ECLS and their overall outcomes as reported in the International Registry for the Extracorporeal Life Support Organization (ELSO) are

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provided in Table 1. Additionally, with modern ECMO technology’s improved safety profile, the potential clinical applications for extracorporeal support are rapidly expanding. In this review, we will discuss the indications and potential cannulation sites available for each of the more common

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modes of ECLS in adults. We will also highlight the evidence for ECLS and briefly discuss newer applications for the technology. Insert Table 1 here

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Basic Circuit Configuration

ECLS involves the removal of circulating venous blood that is then delivered by a pump to a

membrane oxygenator, which introduces oxygen and removes carbon dioxide from the blood. Oxygenated blood can then be brought to the desired temperature and returned to the patient’s systemic circulation. In patients with primary respiratory failure with adequate cardiac function, a venovenous approach is preferred. With the venovenous (VV) technique, blood is both withdrawn and returned to the patient via the venous circulation. A venoarterial (VA) approach is typically

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employed in patients with primary circulatory failure or in patients with both circulatory and pulmonary failure. With this arrangement, blood is withdrawn from the venous circulation and returned to the arterial circulation, thereby bypassing the heart and lungs. Specific cannulation

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strategies for each form of ECLS will be discussed in more detail below.

Centrifugal Pump

Most adult ECMO centers have transitioned to centrifugal pumps and away from older roller

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pumps. The newest centrifugal pump design employs a magnetically suspended, rotating impeller

that propels blood to the oxygenator while also minimizing blood stasis, thrombosis and hemolysis.

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Another benefit of centrifugal pumps is the low priming volume, decreasing the need for red cell transfusion.

Membrane Oxygenator

Contemporary ECLS circuits designed for longer term support (i.e., greater than a few hours)

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typically incorporate hollow core fiber membrane oxygenators. Although most are only approved by the U.S. Food and Drug Administration for up to 6 hours of use, the newer oxygenators can often last for days to weeks (“off label” use) when anticoagulation is managed appropriately. These

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oxygenators work by allowing so called “sweep” gas to flow through the hollow fibers while blood flows external to the fibers. The composition of the sweep gas is regulated by using an air-oxygen

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blender, which mixes ambient air with oxygen to control the fraction of oxygen delivered to the oxygenator. Despite their name, oxygenators are far less efficient at oxygenating blood than removing carbon dioxide (CO2) due to the increased solubility of the latter. The central determinant of PaCO2 clearance in patients on ECMO is sweep gas flow, while the main driver of PaO2 is circuit flow. ECMO flow rates are typically set based on the patient’s cardiac output and overall oxygen consumption. It should be noted that flow rates are more often limited by the size of the venous (inflow) drainage cannula than the arterial (outflow) cannula.

Anticoagulation

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Most modern ECMO circuit components are coated with heparin or biocompatible materials, which has markedly reduced the level of anticoagulation required. Nonetheless, some anticoagulation is still necessary in most circumstances. Unfractionated heparin is most commonly

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used. In patients who are not bleeding, heparin is dosed to achieve an anti-Xa activity level in the range of 0.3-0.5 IU/mL, although it should be noted that there is wide variation across centers in target goals for anticoagulation. Relatively recent innovations in circuit components have made

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ECMO safer and easier to implement with far fewer bleeding complications.

The clinical applications of ECMO have expanded considerably over the past decade and are

indications and cannulation strategies.

Indications and Clinical Evidence

ECMO for Adult Respiratory Failure

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listed in Table 2. The remainder of this review will detail many of these applications along with their

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In general, venovenous ECMO should be considered for patients with reversible hypoxemic or uncompensated hypercarbic respiratory failure that is refractory to optimal mechanical ventilation strategies. Insert table 2 here

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Hypoxemic Respiratory Failure. The first successful use of ECMO was for the treatment of severe acute respiratory failure in a 24 year-old trauma victim in 1971. [1] This early success in the

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treatment of severe respiratory failure led to a NIH-sponsored randomized trial in the 1970s, which demonstrated no survival benefit in those patients receiving ECMO support. [2] However, the trial design was flawed in many ways. The study used only the venoarterial mode of support along with first-generation ECMO technology requiring high levels of anticoagulation, which led to excessive bleeding complications. In addition, both the treatment and control arms used what would be considered today injurious mechanical ventilator settings with high tidal volumes and pressures. Ultimately, survival in each group was less than 10%. Despite these abysmal results, several centers

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continued to use ECMO for the treatment of refractory respiratory failure and have reported generally favorable outcomes. [3-7]

The true tipping point for the use of ECMO in the setting of severe adult respiratory failure

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came in 2009 in the midst of the worldwide H1N1 influenza pandemic, which disproportionately affected younger rather than older adults in contrast to typical seasonal influenza patterns. A

significant proportion of these younger H1N1 patients failed to improve with advanced mechanical

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ventilation strategies, prompting the rapid expansion of ECMO utilization in many intensive care units across the world. Several retrospective cohorts from the 2009-2010 H1N1 influenza

experience demonstrated outcomes favoring the use of ECMO in patients with severe ARDS (median

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PaO2 to FiO2 ratio < 60). [8-11] However, the efficacy of ECMO in H1N1-related ARDS remains uncertain as patients with similar disease severity managed without ECMO had comparable outcomes in some studies. [12-14] Even after the H1N1 pandemic subsided, the use of ECMO support continued to rise, possibly spurred by the availability of a new dual lumen cannula (Avalon Elite®, Maquet, Wayne, NJ) as well as the results of the multicenter, randomized controlled trial

(CESAR). [15, 16]

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comparing conventional ventilatory support versus ECMO for severe adult respiratory failure

The CESAR trial randomized 180 adults with severe respiratory failure to either continued

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conventional management or referral to a specialized center where patients were managed under a standardized ARDS treatment protocol, which included consideration for treatment with VV ECMO.

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The primary outcome measure was death or severe disability at 6 months, which occurred in 37% of the patients referred for ECMO consideration and 53% of the patients in the conventional treatment group (RR 0.96, 95% CI 0.05-0.97; P=0.03). [16] Of note, among the 90 patients randomly assigned for transfer to an ECMO center, only 68 (76%) actually received ECMO support. The trial had two principal limitations that should be considered. Of the 22 patients who were randomized to the ECMO group but did not receive ECMO, 3 died before transfer and 2 died in transit while the others either improved with conventional management or had a contraindication to anticoagulation. The

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vast majority of patients (93%) cared for at the specialized ECMO center were managed with lung protective ventilation, whereas only 70% of those in the conventional management group received protective ventilation. Despite the methodological issues with the CESAR trial, its results support the

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development of specialized treatment centers with expertise in the care of patients with severe ARDS, including the use of ECMO.

Due to the limitations of the CESAR trial, additional randomized trials are needed to

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evaluate the efficacy of ECMO in severe respiratory failure. Toward this goal, there is an ongoing international, multicenter, randomized Extracorporeal Membrane Oxygenation for Severe Acute

Respiratory Distress Syndrome (EOLIA) trial, which will compare early VV ECMO in ARDS to a control

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(non-ECMO) group managed under a strict, protocol-driven protective lung ventilation strategy. [17, 18] Unlike the CESAR trial, all patients assigned to the ECMO treatment arm will be placed on ECMO before being transported to specialized centers. If this trial design proves successful in achieving early implementation of ECMO as intended (within 3 to 6 hours of worsening ARDS), it should lend important insights into the utility of early ECMO, which is thought to be superior to later or rescue

early 2016.

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implementation. The EOLIA trial is approaching completion of enrollment with results expected in

In the meantime, according to the ELSO guidelines for the management of adult respiratory

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failure, ECMO should be considered when the risk of mortality is 50% or greater, and it is indicated when the risk of mortality is 80% or greater. [19] A PaO2/FiO2 less than 150 mmHg on a FiO2 of

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90% or greater or a Murray score [Table 3] of 2-3 is associated with a 50% mortality risk; whereas a PaO2/FiO2 less than 100 mmHg on a FiO2 of 90% or greater or a Murray score of 3-4 despite optimal management of the mechanical ventilator is associated with 80% mortality.

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Hypercarbic respiratory failure. Extracorporeal support should also be considered in patients with uncompensated hypercarbia with acidemia (pH < 7.15) or those with end-inspiratory plateau pressures above 30 cm of water. [20] The extracorporeal removal of CO2 in this setting permits the use of low tidal volume ventilation, and in turn, minimizes barotrauma and atelectrauma. [4, 21-23]

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Extracorporeal CO2 removal (ECCO2R) has been successfully deployed to wean patients with hypercarbic respiratory failure from mechanical ventilation. [24-26] Aside from traditional VV ECMO, there are now several devices available in Europe and Canada (but none yet approved by the

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U.S. Food and Drug Administration) for ECCO2R. One such device is the Novalung iLA® Membrane Ventilator (Hechingen, Germany), the only pumpless extracorporeal lung assist (PECLA) system

available. It uses the patient’s own systemic blood pressure via arteriovenous cannulation to propel blood through a low-resistance hollow fiber membrane lung. Other systems including Hemolung®

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(ALung, Pittsburgh, PA, USA) and Decap® (Hemodec, Salerno, Italy) use a pump but are more similar to continuous venovenous hemofiltration devices than to traditional VV ECMO. Although these

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systems are very efficient at removing CO2, they are poor at oxygenating the blood given their relatively low flow rates (2.5 severe injury

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Table 3. Lung Injury Score- Murray Score

Adapted from Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult

3.

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respiratory distress syndrome. The American review of respiratory disease. 988;138(3):720-