Listen to this manuscript’s

audio summary by

JACC Editor-in-Chief

Dr. Valentin Fuster.

J O U R N A L O F T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 7 2 , N O . 1 4 , 2 0 1 8

ª 2 0 1 8 B Y T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N

P U B L I S H E D B Y E L S E V I E R

THE PRESENT AND FUTURE

JACC TECHNOLOGY CORNER

Artificial Lungs for Lung Failure

JACC Technology Corner

Noritsugu Naito, MD, PHD,a Keith Cook, PHD,a Yoshiya Toyoda, MD, PHD,b Norihisa Shigemura, MD, PHDb

JACC JOURNAL CME/MOC/ECME

This article has been selected as the month’s JACC CME/MOC/ECME

activity, available online at http://www.acc.org/jacc-journals-cme by

selecting the JACC Journals CME/MOC/ECME tab.

Accreditation and Designation Statement

The American College of Cardiology Foundation (ACCF) is accredited by

the Accreditation Council for Continuing Medical Education to provide

continuing medical education for physicians.

The ACCF designates this Journal-based CME activity for a maximum

of 1 AMA PRA Category 1 Credit(s)�. Physicians should claim only the

credit commensurate with the extent of their participation in the

activity.

Successful completion of this CME activity, which includes participa-

tion in the evaluation component, enables the participant to earn up to

1 Medical Knowledge MOC point in the American Board of Internal

Medicine’s (ABIM) Maintenance of Certification (MOC) program. Par-

ticipants will earn MOC points equivalent to the amount of CME credits

claimed for the activity. It is the CME activity provider’s responsibility

to submit participant completion information to ACCME for the pur-

pose of granting ABIM MOC credit.

Artificial Lungs for Lung Failure: JACC Scientific Expert Panel will be

accredited by the European Board for Accreditation in Cardiology

(EBAC) for 1 hour of External CME credits. Each participant should

claim only those hours of credit that have actually been spent in the

educational activity. The Accreditation Council for Continuing Medi-

cal Education (ACCME) and the European Board for Accreditation in

Cardiology (EBAC) have recognized each other’s accreditation sys-

tems as substantially equivalent. Apply for credit through the post-

course evaluation. While offering the credits noted above, this pro-

gram is not intended to provide extensive training or certification in

the field.

ISSN 0735-1097/$36.00

From the aDepartment of Biomedical Engineering, Carnegie Mellon Univer

Cardiovascular Surgery, Lewis Katz School of Medicine, Temple University H

the co-owner of Advanced Respiratory Technologies (ART); and has served

authors have reported that they have no relationships relevant to the conte

Manuscript received April 18, 2018; revised manuscript received June 13, 20

Method of Participation and Receipt of CME/MOC/ECME Certificate

To obtain credit for JACC CME/MOC/ECME, you must:

1. Be an ACC member or JACC subscriber.

2. Carefully read the CME/MOC/ECME-designated article available on-

line and in this issue of the Journal.

3. Answer the post-test questions. A passing score of at least 70% must be

achieved to obtain credit.

4. Complete a brief evaluation.

5. Claim your CME/MOC/ECME credit and receive your certificate

electronically by following the instructions given at the conclusion of the

activity.

CME/MOC/ECME Objective for This Article: Upon completion of this

activity, the learner should be able to: 1) discuss the current practice and

limitations of treatment for patients with end-stage lung failure, by

comparing with the treatment of heart failure; 2) recognize the charac-

teristics of each mode of artificial lung support; 3) summarize the history

and current status of artificial lung support; and 4) discuss the evolving

technology of artificial lungs and future prospect of long-term artificial

lungs that can be used as a destination therapy.

CME/MOC/ECME Editor Disclosure: JACC CME/MOC/ECME Editor Raga-

vendra R. Baliga, MD, FACC, has reported that he has no financial re-

lationships or interests to disclose.

Author Disclosures: Dr. Cook is the co-owner of Advanced Respiratory

Technologies (ART); and has served as a consultant for ALung

Technologies. All other authors have reported that they have no

relationships relevant to the contents of this paper to disclose.

Medium of Participation: Print (article only); online (article and quiz).

CME/MOC/ECME Term of Approval

Issue Date: October 2, 2018

Expiration Date: October 1, 2019

https://doi.org/10.1016/j.jacc.2018.07.049

sity, Pittsburgh, Pennsylvania; and the bDivision of

ealth System, Philadelphia, Pennsylvania. Dr. Cook is

as a consultant for ALung Technologies. All other

nts of this paper to disclose.

18, accepted July 3, 2018.

J A C C V O L . 7 2 , N O . 1 4 , 2 0 1 8 Naito et al.O C T O B E R 2 , 2 0 1 8 : 1 6 4 0 – 5 2 Artificial Lungs for Lung Failure

1641

Artificial Lungs for Lung Failure

JACC Technology Corner

Noritsugu Naito, MD, PHD,a Keith Cook, PHD,a Yoshiya Toyoda, MD, PHD,b Norihisa Shigemura, MD, PHDb

ABSTRACT

Although lung transplantation is an effective treatment for end-stage lung failure, its limitations have led to renewed

interest in artificial lung support for patients with lung failure. The use of ventricular assist devices has significantly

improved the quality of life and survival of patientswith end-stage heart failure. In contrast, there are no devices that can be

used long term as destination therapy for end-stage lung failure, and there is a strong need for them. Extracorporeal

membrane oxygenation is widely used as a temporary treatment for acute lung failure and as a bridge to lung transplant.

Many patients with advanced lung failure cannot return home with good quality of life once they are hospitalized. In this

review, the authors discuss the history, status, and future of artificial lungs, focusing on long-term artificial respiratory

support as a destination therapy. Respiratory assist devices, such as artificial lungs, could eventually become analogous to

ventricular assist devices. (J AmColl Cardiol 2018;72:1640–52) © 2018 by the American College of Cardiology Foundation.

M ore than 150,000 Americans die fromlung failure annually (1). Although lungtransplantation remains the most effec-

tive treatment for end-stage lung failure, there isan urgent need for robust, durable, and safe artifi-cial respiratory support for patients with progres-sively decompensating lung failure, particularly inlight of the scarcity of donated lungs suitable fortransplantation. Accumulating evidence supportsusing extracorporeal membrane oxygenation(ECMO) to treat lung failure and support patientsbefore lung transplant. The success of ECMO hasled to increased interest in the development of anentirely artificial lung (AL). Recent progress in ALtechnologies has been outstanding, leading togrowing expectations for ALs as a bridge to lungtransplant (BTT) and as a destination therapy (DT).AL devices could become analogous to ventricularassist devices (VADs), which have significantlyimproved outcomes and quality of life (QOL) for pa-tients with severe heart failure (Figure 1). Over thepast 3 decades, there has been expansive growthand development in the treatment of heart failure,with the introduction of cardiac transplantationand VADs. Advancing the role of ALs in pulmonarymedicine will ultimately lead to improve patientcare and human life. In this review, we discussthe history, status, and the future of AL supportfor advanced lung failure.

EVOLVING THERAPEUTIC STRATEGIES

FOR ADVANCED LUNG FAILURE

AND THE LIMITATIONS OF

CONVENTIONAL STRATEGIES

In current clinical practice, end-stage lung failureultimately requires lung transplant as a definitivetherapy (Central Illustration). Patients with advancedlung failure that is refractory to noninvasive thera-pies are supported with mechanical ventilation (MV)initially. Eventually, some of these patients willrequire complete lung support, which conventionallyconsists of ECMO. These patients generally havebecome too deconditioned and sick to expect recov-ery, and lung transplant becomes their last resort forlife. Because of the progressive complications to thepatients and the lack of commercially available ALsthat can be used for months without device exchange,patients with end-stage lung failure need to undergolung transplant within a few weeks once AL support isinstalled.

The concept of allowing injured lungs to “rest andrecover” by reducing airway pressure and tidal vol-ume is supported by many clinical studies (2). Therehas been increased interest in the use of extracorpo-real AL for acute respiratory distress syndrome, tooptimize gas exchange and decrease MV support, andits associated complications (3,4). Using AL, insteadof MV, at an early stage in the disease progression of

ABBR EV I A T I ON S

AND ACRONYMS

AL = artificial lung

APL = artificial pump-lung

BTR = bridge to recovery

BTT = bridge to lung transplant

cTAL = compliant thoracic

artificial lung

DT = destination therapy

ECMO = extracorporeal

membrane oxygenation

ICU = intensive care unit

iLA = interventional lung assist

device

MV = mechanical ventilation

QOL = quality of life

VAD = ventricular assist device

Naito et al. J A C C V O L . 7 2 , N O . 1 4 , 2 0 1 8

Artificial Lungs for Lung Failure O C T O B E R 2 , 2 0 1 8 : 1 6 4 0 – 5 2

1642

advanced lung failure should become a morefrequent treatment strategy, given thepromising results thus far (CentralIllustration). Avoiding MV or reducing MVsupport may prevent patients from beingsedated and could allow them to eat, drink,sit, stand, and even walk. This, in turn, willimprove their physical status and organfunction, resulting in better QOL and sur-vival, regardless of the patient’s candidacyfor lung transplant.

MECHANICAL VENTILATION

Outcomes after MV support for acute respi-ratory distress syndrome have improved dueto advances in lung-protective MV strategies(2). Although oxygen is essential to maintainhomeostasis, excessive oxygen and high

pressure in the airway can cause tissue damage andinflammation—commonly known as oxygen toxicityand barotrauma. Endotracheal intubation or trache-ostomy for MV causes some patients to be sedatedand bedridden, resulting in decreased QOL. Addi-tionally, MV can lead to ventilation-associatedpneumonia, one of the most significant complica-tions of MV, due to aspiration and inadequate clear-ance of secretions, especially in patients withendotracheal intubation.

LUNG TRANSPLANTATION

Lung transplant is currently the only definitivetreatment for the patients with end-stage lung fail-ure. However, there are several concerns associatedwith lung transplant. The number of lung transplantsperformed annually is reaching a plateau (5). Lungallocation score distribution on the waiting list istrending to higher scores, which indicate patients inpoorer clinical condition. The waiting time for pa-tients with high lung allocation score is likely to getlonger, which will lead to increased waitlist mortality.Moreover, only 15% to 20% of donated lungs aretransplantable (3,6). Although median post–lungtransplant survival increased from 3.9 years to 5.8years during the last decade, the 5-year survival rateis only 55%, and 10-year survival is only w45%, whichare both worse than survival after transplantation ofany other solid organ (5).

AL SUPPORT

When MV fails to improve gas exchange, continuoussevere hypoxia and hypercapnia may cause irrevers-ible organ failure or death. AL support can improve

both oxygenation and carbon dioxide removal. Sup-porting a patient temporarily with an AL whileallowing him or her to recover from a critically illstatus can be defined as bridge to recovery (BTR).Those who cannot be weaned from respiratory sup-port need a BTT or DT. As the technology advances,using ALs as BTR, BTT, or DT in patients withadvanced lung failure should become analogous tousing ECMO or a VAD as a BTR, BTT, or DT in patientswith advanced heart failure (Central Illustration,Figure 1). AL circuit preferences differ between indi-vidual physicians and institutes. However, cliniciansshould become familiar with the devices currentlyavailable for AL support (Tables 1 and 2). In theory, ALsupport can be extracorporeal, paracorporeal, orimplantable, but an implantable AL suitable for clin-ical use has not been developed yet.

BTT USING ALS

Treatment choices for patients with acute or acute-on-chronic advanced lung failure include ECMO andparacorporeal AL support (Figure 2). ECMO is widelyused as a BTT, and the outcomes following ECMObridging to lung transplant are improving, with manypublished series demonstrating good tolerance, effi-cacy, and safety (7–12). Hayanga et al. (10) examinedthe UNOS (United Network for Organ Sharing) data-base and reported that the 1-year survival rate ofpatients bridged to lung transplant with ECMOincreased from 25% in the period between 2000 and2002 to 75% between 2009 to 2011.

Physical strength before transplant is important forsuccessful post-transplant outcomes (13). Patientssupported by ambulatory ECMO can undergo intensephysical therapy in the hospital. However, itcurrently impossible for them to be discharged fromthe intensive care unit (ICU), go home, and be fol-lowed as an outpatient due to the large size of ECMOsupport devices, long circuits, the requirement forfrequent device exchange, and the potential forcomplications. There are significant limitations of ALtechnologies as a BTT, as compared with the VADsused to bridge to heart transplantation.

ECMO INSTALLATION

ECMO perfusion can be venoarterial (VA) or venove-nous (VV), depending on the patient’s needs(Figure 3). Usually, VV ECMO is placed in patientswithout heart dysfunction, and MV can be weaned inthese patients, freeing them from sedative drugs. VAECMO is typically placed in patients with severepulmonary hypertension or heart failure (9). VA

FIGURE 1 Device Options for Supporting Patients With Advanced Heart or Lung Failure

Device options for advanced heart failure

Device options for advanced lung failure

ECMOPercutaneous VAD

BTR, BTT

Paracorporeal VAD

BTR, BTT

Implantable VAD

BTT, DT

Extracorporeal AL(ECMO, iLA)

BTR, BTT

Paracorporeal AL(iLA or other devices)

BTR, BTT

Paracorporeal ALImplantable AL

BTT, DTStill under

development

Ideal duration of use of support devices

Day YearMonthWeek

There are still unmet needs in the field of advanced lung failure. Development of treatment options that can be analogues of ventricular assist

devices in the field of heart failure are required. AL ¼ artificial lung; BTR ¼ bridge to recovery; BTT ¼ bridge to transplantation;

DT ¼ destination therapy; ECMO ¼ extracorporeal membrane oxygenator; iLA ¼ interventional lung assist device; VAD ¼ ventricular assist

device.

J A C C V O L . 7 2 , N O . 1 4 , 2 0 1 8 Naito et al.O C T O B E R 2 , 2 0 1 8 : 1 6 4 0 – 5 2 Artificial Lungs for Lung Failure

1643

ECMO can be installed with either peripheral or cen-tral cannulation. Peripheral cannulation is preferred,because it does not require sternotomy, is much lessinvasive, and can be placed faster than centralcannulation.

Peripheral cannulation for femoral VA ECMO isinstalled via the femoral artery and femoral vein.Patients supported by femoral VA ECMO sometimesface complications, notably cannulation site in-fections, central hypoxia (hypoxia in the heart andbrain), and increased left ventricular afterload. Con-version to central cannulation is considered whenthese problems are a concern. Installation of centralVA ECMO through right atrial drainage and ascendingaortic perfusion eliminates concerns of increased leftventricular afterload and central hypoxia and unloadsthe right heart system.

Peripheral VA ECMO with subclavian or axillaryartery placement can also be managed safely andeffectively (14–18). Subclavian or axillary cannulationis preferred in patients who are stable enough to betransferred to the operating room for ECMO installa-tion. VA ECMO with subclavian or axillary arterycannulation provides antegrade blood flow from theECMO circuit and reduces the risk of central hypoxia,distal limb ischemia, and thromboembolic events (17).Moreover, patients supported by VA ECMO with

subclavian or axillary artery cannulation can sit andwalk.

All VV ECMO cannulation is peripheral and can beplaced either in the internal jugular vein or in thefemoral vein. The PROTEK Duo VV cannula (Cardia-cAssist, Pittsburgh, Pennsylvania) is a dual-lumencatheter that can be placed through the internaljugular vein for VV ECMO. The cannula enables rightheart system support by draining blood from the rightatrium and reperfusing it through the tip of thecannula placed in the pulmonary artery, and mayincrease the number of single-site cannulations forVV ECMO (19,20). As with VA ECMO, there are meritsof avoiding cannulation of the groin for VV ECMO (8).

VV or VA ECMO without MV can often be admin-istered as “awake” or “ambulatory” ECMO. Fuehneret al. (9) reported well-tolerated and successful BTTusing awake ECMO with a better 6-month post-transplantation survival than BTT with MV. Patientssupported using awake ECMO can breathe spontane-ously without complications associated with MV, eat,drink, and be involved in active physical therapy.

INSTALLATION OF OTHER AL DEVICES

Some patients without decreased heart function canbe supported with low-resistance ALs, including

CENTRAL ILLUSTRATION Conventional and Evolving Strategies for Treating Artificial Lung Failure

Initiation of AL supportEvolving strategy

Advanced lung failure progression over time

Initiation of AL supportConventional strategy

No support of AL

BTRBTT, DT

Pulmonaryreserve

Evolving strategy

MV Artificial Lung (AL)

Recovery (BTR)

Life-long support (DT)

Death

LTx (BTT)

Conventional strategy

Mechanical ventilation (MV) AL LTx (BTT)

Recovery

Death

Naito, N. et al. J Am Coll Cardiol. 2018;72(14):1640–52.

Using conventional strategies (upper bar), artificial lung (AL) support is initiated when the other treatment options, including mechanical ventilation (MV), fail to

improve the patient’s status. In the evolving strategy (lower bar), AL support is initiated at an early stage to allow the lungs to rest and recover. AL can be weaned off

in some patients because of improvement of patients’ conditions (bridge to recovery [BTR]), whereas prolonged support of an AL is needed in the other patients (bridge

to transplantation [BTT] or destination therapy [DT]). LTx ¼ lung transplantation.

Naito et al. J A C C V O L . 7 2 , N O . 1 4 , 2 0 1 8

Artificial Lungs for Lung Failure O C T O B E R 2 , 2 0 1 8 : 1 6 4 0 – 5 2

1644

interventional lung assist devices (iLAs), without us-ing a centrifugal pump (Table 2). The heart itselfpumps the blood, and AL support can be installedwith arterial drainage and venous perfusion. Patientswho suffer from CO2 retention (hypercapnia) canundergo extracorporeal CO2 removal using low-resistance ALs without a centrifugal pump, becauseCO2 exchange requires less blood flow than O2 ex-change. There are several reports of successful BTTusing a Novalung (XENIOS AG, Heilbronn, Germany)in patients with hypercapnic lung failure (21).Changing the sweep gas flow allows complete CO2

removal even under low blood flow through the cir-cuit. Without centrifugal pumps, maintenance is lessdemanding. The Hemolung (ALung Technologies,Pittsburgh, Pennsylvania) is another AL that is usedfor extracorporeal CO2 removal. A centrifugal pump iscombined with AL in the device. A clinical case series

showed successful VV extracorporeal CO2 removalwith low blood flow (22).

There are mainly 2 ways of placing paracorporealAL support: in series (pulmonary artery to pulmonaryartery) and in parallel (pulmonary artery to leftatrium) (Table 1). Although these ALs can be eitherpump-driven or pumpless, pumpless AL placementmakes mobilization of the patient and managementof the circuits easier due to the shorter and simplercircuit. Central cannulation may allow longer supporttime as compared with peripheral cannulation.However, placement of these circuits requires mediansternotomy or thoracotomy resulting in higher inva-siveness to those who are already critically ill.Circuits placed in series increase the risk of the right-sided heart failure and should be avoided in thepatients with pulmonary hypertension (23,24). Onthe other hand, in-parallel placement is beneficial to

TABLE 1 Characteristics of Each Mode of AL Support

Extracorporeal Paracorporeal Implantable

Device ECMO circuit Low resistanceoxygenator

Low resistanceoxygenator,IVOX

Configuration Peripheral ECMO(VV or VA)

Central ECMOArteriovenous iLA

PA-LAPA-PA

PA-LAPA-PAIntravascular

Duration ofsupport

Days to a few weeksBTR, BTT

Weeks to monthsBTR, BTT, DT

Months to yearsBTT, DT

Time to oxygenatorexchange

Days to a few weeks Days to a few weeks Months to years

Portability Large circuit - lowmobility

Patients with DLCcannulation throughthe neck can walk,but still require theassistance of medicalstaff

Small circuit device isplaced on thepatient’s body

Patients can walkunassisted

Device is implantedinside thepatient’s body

Patients can walkunassisted

QOL Patients need to bebedridden or to stayin ICU

Requires hospital stayPatients may be able to

be discharged, butwill require admissionfor device exchange

Patients are able togo back home

Management Requires highly skilledtechnicians

Care by patient, family,and health care staff

Care by patient andfamily

Clinical use Widely used Used at some institutes In development/preclinicalresearch

Rates of complications

Infection High High Low

Bleeding High Low (after stabilization) Low (afterstabilization)

Thrombosis High High Low

Invasiveness ofplacement

Relatively low High—requiressternotomy

Likely high—willlikely requiresternotomy

BTR ¼ bridge to recovery; BTT ¼ bridge to transplantation; DLC ¼ double lumen catheter; DT ¼ destinationtherapy; ECMO ¼ extracorporeal membrane oxygenation; ICU ¼ intensive care unit; iLA ¼ interventional lungassist device; IVOX ¼ intravascular oxygenator; LA ¼ left atrium; PA ¼ pulmonary artery; QOL ¼ quality of life;VA ¼ venoarterial; VV ¼ venovenous.

J A C C V O L . 7 2 , N O . 1 4 , 2 0 1 8 Naito et al.O C T O B E R 2 , 2 0 1 8 : 1 6 4 0 – 5 2 Artificial Lungs for Lung Failure

1645

the right ventricular function. In-parallel placementsignificantly reduces systolic right ventricular andpulmonary arterial pressure by creating a parallelpathway around the diseased native lungs to the leftatrium. Reduced right ventricular afterload increasescardiac output and systemic blood pressure especiallyin the patients with pulmonary hypertension, leadingto improved coronary arterial perfusion. Unlikedrainage from the vena cava or the right atrium,in-parallel placement can maintain the right ventric-ular preload, which may duly restore the rightventricular function and geometry. Moreover, opti-mization of the right ventricular geometry mayimprove interventricular interaction. However, themain disadvantage of in-parallel placement is the riskof systemic embolism in a fashion similar to VAECMO. There is also a concern about long-termreductions in the pulmonary circulation with thein-parallel configuration. The total cessation of pul-monary arterial flow should be avoided. Takewa et al.(25) demonstrated that the critical level to maintainmetabolic function was w10% of normal blood flow.

LIMITATIONS OF ECMO AND AL SUPPORT

There are some concerns associated with ECMO as aBTT. Although patients can tolerate ECMO, shorterdurations of support are associated with better out-comes. Prolonged ECMO can lead to muscular decon-ditioning, blood loss or hemolysis, blood transfusionsthat can cause sensitization to human leukocyte an-tigen, systemic or pulmonary thromboembolism,bleeding, infection, stroke, and limb ischemia(12,18,26). VA ECMO with subclavian or axillary arterycannulation increases the risk of hyperperfusing theupper limbs, resulting in compartment syndrome andsensorimotor neuropathies (18).

Another concern is increased left ventricularafterload when VA ECMO is installed with femoralarterial perfusion, particularly in patients with pul-monary hypertension or decreased heart function.Retrograde blood flow from femoral artery causesincreased left ventricular afterload, leading to sys-tolic dysfunction and difficulty weaning the patientoff VA ECMO (27–30). Increased left ventricularafterload may lead to pulmonary edema and right-sided heart dysfunction especially in patients withaortic or mitral regurgitation. Left ventricular venttube placement or early conversion to central can-nulation should be considered to resolve the issue.

Although the coatings of ALs (Table 2) havedecreased the thrombogenicity of the devices, thedesign of many ALs is primarily square, which causesstagnation and clot formation in the corners. The clot

formation then causes increased resistance in theoxygenator and decreased capacity for gas exchange.Moreover, the blood clots can develop emboli. Asingle device can be used for no longer than 3 to4 weeks because of clot formation, increased resis-tance, and decreased gas exchange function. Accel-erated coagulation also leads to escalated need forsystemic anticoagulation and subsequent bleedingrisk (31,32).

Shear stress in a circuit causes blood damageincluding hemolysis and von Willebrand factor mul-timer degradation (acquired von Willebrand disease).The larger and the longer the shear stress is applied,the more blood damage occurs. Device design, highdevice resistance due to densely packed fibers, andtransoxygenator pressure drop are thought to berelated with shear stress (33–35). Acquired von Wil-lebrand disease is a major complication associated

TABLE 2 Characteristics of Commercially Available Artificial Lungs

Device (Ref. #) Manufacturer UsagePump inSystem

PrimingVolume (ml)

SurfaceArea (m2)

PressureDrop Coating

QUADROX-i Maquet, Rastatt, Germany ECMO No 215 1.8 50 mm Hgat 5.0 l/min

BIOLINE coating (heparin)SOFTLINE coating

(nonheparin)

Affinity NT Medtronic, EdenPraire, Minnesota

ECMO No 270 2.5 50 mm Hgat 5.0 l/min

Cortiva BioActiveSurface (heparin)

Trillium Biosurface(heparin)

Novalung (21) Xenios AG,Heilbronn, Germany

ExtracorporealCO2 removal

Paracorporeal

No 175 1.3 11 mm Hgat 2.5 l/min

Novalung coating(heparin)

Hemolung (22,53,54) ALung Technologies,Pittsburgh, Pennsylvania

ExtracorporealCO2 removal

Paracorporeal

Yes 260 0.59 10 mm Hgat 2.0 l/min

Siloxane/heparincoating

ECMO ¼ extracorporeal membrane oxygenation.

FIGURE 2 Types o

Extr

There are 3 types of A

the patient’s body. A

Naito et al. J A C C V O L . 7 2 , N O . 1 4 , 2 0 1 8

Artificial Lungs for Lung Failure O C T O B E R 2 , 2 0 1 8 : 1 6 4 0 – 5 2

1646

with implantable VADs that provide high shear stress(36). The condition leads to bleeding tendencies,frequent transfusions, or device explant (37,38).Because the resistance of the circuit increases whenan oxygenator is added, the rotational speed of thecentrifugal pump must increase, resulting in a higherpossibility of blood damage with ECMO support (39).

COMPARING ALS AND VADS AS A BTT

The positive impact of VAD support on patientsrequiring a heart transplant has been evident formany years (40). In particular, continuous-flow left

f ALs

ExtracorporealECMO

acorporeal CO2 removal

ParacorporealiLA

Evolving AL (under resea

Ls. An extracorporeal AL is placed outside of the patient’s body. A paracorpor

o ¼ aorta; iLA ¼ interventional lung assist device; LA ¼ left atrium; PA ¼ p

ventricular assist devices have improved survival inpatients with advanced heart failure on the waitinglist for a heart transplant (41,42). Similarly, manylarge series of studies support the efficacy and safetyof ECMO as a BTT in the field of lung failure, andsome report improved survival (7–12). There are noprospective randomized studies that have investi-gated the potential survival benefits of ECMO as BTT.The use of MV or MV and ECMO as BTT is oftenassociated with more complicated operative proced-ures during lung transplant and more post-operativecomplications (7,12). However, in a recent study, weshowed that the use of MV with ECMO as BTT

rch)

ImplantableIntravascular AL (under research)Intrathoracic AL (under research)

eal AL is placed on the patient’s body. An implantable AL is placed in

ulmonary artery; other abbreviations as in Figure 1.

FIGURE 3 Treatment Options for Acute or Acute-on-Chronic Advanced Lung Failure

Acute or acute-on-chronic advanced lung failure

Hypercapnic failure Hypoxic failure

HemodynamicallyStable

Hemodynamicallystable

Hemodynamicallyunstable

Hemodynamicallyunstable

Conventional therapyVV-ECMO (Extracorporeal)

Evolving therapyiLA (Extracorporeal) Arterio-venous Veno-venous with pump

Conventional therapyPeripheral VA-ECMO (Extracorporeal)Central VA-ECMO (Extracorporeal)- Reduces the risks of central hypoxia and increased LV afterload

Evolving therapyRA-PA VV-ECMO using DLC (Extracorporeal)- for patients with RV failure or PHPA-LA with pump (Paracorporeal)- for patients with RV failure or PHPA-LA without pump (Paracorporeal)

VV-ECMO (Extracorporeal)

In conventional strategies, hemodynamically stable patients are supported by venovenous (VV) extracorporeal membrane oxygenation

(ECMO), whereas hemodynamically unstable patients are supported by venoarterial (VA) ECMO. Evolving therapies enable other treatment

options. DLC ¼ double lumen cannula; iLA ¼ interventional lung assist device; LA ¼ left atrial; LV ¼ left ventricular; PA ¼ pulmonary artery;

PH ¼ pulmonary hypertension; RA ¼ right atrium; RV ¼ right ventricular.

J A C C V O L . 7 2 , N O . 1 4 , 2 0 1 8 Naito et al.O C T O B E R 2 , 2 0 1 8 : 1 6 4 0 – 5 2 Artificial Lungs for Lung Failure

1647

significantly increased 1-year post-transplantationsurvival as compared with MV alone (43).

Both VAD therapy and ECMO drastically increasemedical costs. There has been some controversyabout the cost effectiveness of BTT using a VAD;however, a recent study showed that implantableVAD therapy as BTT is cost effective in patients with amedium-to-high risk of death while waiting for atransplant (44). Advances in surgical technique, pa-tient management, and devices may increase the costeffectiveness of VAD support by reducing the dura-tion of hospital and ICU stays, rate of complications,and device cost. ECMO use increases medical costsbecause surgical care of cannulation sites, ICU stay,rehabilitation, and ECMO specialists (nurses andperfusionists) are required (45). Further developmentof ECMO technologies may change the managementof AL support, such that daily care by specialists is notneeded, and improve the cost effectiveness of ALsupport as a BTT.

The INTERMACS (Interagency Registry for Me-chanically Circulatory Support) registry is used togather data from patients receiving mechanicalcirculatory support. INTERMACS profiles stratify

patients with severe heart failure and allow carefulstudy of which patients benefit from VAD therapy. Asimilar registry will be required in the field of lungfailure if ALs are going to be used long term. The in-dications for BTT and DT in patients with lung failurecan then gradually evolve as data are collected.

DT FOR END-STAGE LUNG FAILURE

Patients suffering from end-stage heart failure whoare not indicated for heart transplantation because ofage, malignancy, or systemic disease require DT (46).DT using an implantable, continuous-flow left ven-tricular assist device improves not only survival, butalso QOL (47–50). More than 7,000 people havereceived VAD support as DT with 1- and 3-yearsurvival rates of 75% to 80% and 60% to 62%,respectively (47,51). In contrast to the remarkableprogress with DT for heart failure, there are currentlyno devices that can be used as DT for patients withend-stage lung failure. There are many importantdevice properties that must be improved before long-term AL use is possible including durability, antith-rombogenicity, resistance, and portability.

TABLE 3 Summary of Preclinical Animal Studies of Evolving Artificial Lungs

First Author (Ref. #) Year Animal Number of Animals Device Surface Area (m2) Resistance Blood Flow Through Devices Coating Anticoagulation

Sato et al. (56) 2007 Sheep 8 MC3 1.7 1.8 mm Hg/(l/min) 2.0 l/min No Heparin

Wu et al. (71) 2012 Sheep 9 APL 0.8 m2 Not described 3.5 l/min No Heparin

Skoog et al. (57) 2017 Sheep 5 cTAL 2.4 m2 0.5 mm Hg/(l/min) 3.5 l/min No Heparin

APL ¼ artificial pump-lung; IV ¼ intravenous; LA ¼ left atrium; PA ¼ pulmonary artery; RA ¼ right atrium.

Continued on the next page

Naito et al. J A C C V O L . 7 2 , N O . 1 4 , 2 0 1 8

Artificial Lungs for Lung Failure O C T O B E R 2 , 2 0 1 8 : 1 6 4 0 – 5 2

1648

INDICATIONS

Patients with end-stage lung failure are a heteroge-neous population with many different etiologiesunderlying their need for a transplant, and differentsurvival rates both on the transplant waiting list andafter lung transplant. One of the criteria to be arecipient of a lung transplant is a high risk of death(>50%) from lung disease within 2 years without alung transplant (52). The primary goal of DT for pa-tients with lung failure should be median survival>3 years. Functional improvements that lead toimproved health-related QOL are also very importanttargets. Indications for DT in patients with end-stagelung failure should be determined with careful clin-ical trials yielding definitive results, similar to trialsthat have been conducted on VADs for DT. The ALdevices used for DT should be paracorporeal orimplantable, and the characteristics of the device orcircuit must be determined by the indication for DT.

DEVICE RESISTANCE

There is a great need for a low-resistance AL devicethat can adequately oxygenate and remove carbondioxide at low flow rates. The commercially availableAL with the lowest resistance is the Novalung, aparacorporeal iLA with a heparin-coated oxygenatorthat has been used for prolonged support (53,54).Camboni et al. (53) reported 62 days of Novalungsupport in a pumpless pulmonary artery-left atrialconfiguration with 4 oxygenator exchanges. The gastransfer capacity of the Novalung is limited becausethe device was designed primarily for CO2 removalwith the relatively small surface of 1.3 m2 (55). Theresistance of the Novalung is w5 mm Hg/(l/min) at ablood flow of 2 l/min, whereas resistance of a nativehealthy lung is w1 mm Hg/(l/min). Because of therelatively low oxygenation and higher resistance thanthat of the native healthy lung, the use of iLAs,

including the Novalung, can result in insufficientoxygenation and insufficient unloading of the rightside of the heart, and some patients may need MVsupport even with the AL.

The animal studies using pumpless low-resistanceALs placed in parallel showed little to no blooddamage (Table 3). The MC3 Biolung (MC3 Inc., AnnArbor, Michigan) has a low resistance of 1.8 mm Hg(l/min) (56). Sato et al. (56) conducted a 30-day studyof the MC3 Biolung in sheep and observed stablehemodynamics, blood gases, and organ function.However, device exchanges were required every9.5 days because of increased resistance caused byclot formation. A compliant thoracic AL (cTAL) ach-ieved a resistance lower than that of native healthylungs, 0.5 mm Hg/(l/min). A cTAL without anticoag-ulant coating showed minimal clot formation in a14-day test in sheep and warrants further study (57).

HEMOCOMPATIBILITY

Compared with VADs, ALs have larger contact sur-faces and longer contact time with the blood. AL clotformation is rapid in comparison and must be greatlyreduced before ALs can be used for months or years.Clot formation can be reduced by changes to devicedesigns and coatings and the development of newanticoagulation therapies. For better antithromboge-nicity, improved devices should eliminate recircula-tion and stagnation to avoid focused buildup ofprocoagulant molecules, reduce shear stresses toavoid platelet activation, and reduce the overall sur-face area.

Many circulatory assist devices and ALs containcoatings to decrease their thromobogenicity andreduce the doses of anticoagulation drugs requiredduring support. Among those coatings, heparin coat-ings are widely used. However, heparin coatings arenot perfect for long-term AL, and other coatingmethods may be required. Although the covalent

TABLE 3 Continued

Attachment Length of Support (days) Device Exchange Outcome Cause of Early Termination

Pumpless PA-LA 30 Every 9.5 � 2.1 days onaverage

Elective termination (n ¼ 5)No signs of hemolysis, organ infarction,

or end-organ dysfunction

Device failure (n ¼ 1, day 10)Bleeding due to low platelet (n ¼ 1, day 4)Diffuse gastric mucosal lesion (n ¼1, day 6)

Pump integrated RA-LA 30 No exchange Elective termination (n ¼ 5)No signs of hemolysis, organ infarction,

or end-organ dysfunction

Device failure (n ¼ 1, day 2)Device-related bleeding (n ¼ 1, day 4)Broken IV line (n ¼ 2, day 2 and 12)

Pumpless PA-LA 14 No exchange Elective termination (n ¼ 3)No signs of hemolysis, organ infarction,

or end-organ dysfunction

Bradycardia (n ¼ 1, day 6)Conduit connection fracture (n ¼ 1, day 11)

J A C C V O L . 7 2 , N O . 1 4 , 2 0 1 8 Naito et al.O C T O B E R 2 , 2 0 1 8 : 1 6 4 0 – 5 2 Artificial Lungs for Lung Failure

1649

immobilization of heparin lasts for months to years,the heparin does not retain its anticoagulant activityindefinitely. Chemical modification or degradation ofimmobilized heparin reduces its activity (58). Someresearchers are working on nonfouling coatings thatprevent nonspecific protein adsorption (59). Thesecoatings create a hydration layer on the artificialsurface, making an environment more like the phys-iological environment of healthy endothelial surface.The hydration layer prevents adsorption on thehydrophobic artificial surface and subsequentconformational change and activation of proteins,which should lead to reduced activation of plateletand coagulation factors. Nitric oxide–generatingfibers or use of nitric oxide in the sweep gas hasalso been examined and may reduce platelet activa-tion and adhesion to the artificial surface (60,61).Nitric oxide is a very short-acting substance with ahalf-life of 0.05 to 1.80 ms in the blood that can thusreduce thrombosis at the fiber surface but allows fornormal platelet function when the blood returns tothe patient (60).

Additionally, new drugs that prevent thrombosisbut do not increase bleeding complications arestrongly needed. Patients supported by ECMOtypically require anticoagulation with heparin.Nonetheless, even when maintaining partial throm-boplastin times in an appropriate range, thrombo-embolic events or hemorrhagic events can occur.Bleeding from cannulation sites and surgical sitesmay be critical, and sometimes requires reoperationto control bleeding. Those complications affect sur-vival, the need for blood transfusion, and the dura-tion of ICU stay. Factor XII is attracting attention asan appealing target for new anticoagulation drugs(62,63). Factor XII deficiency is a rare disease (64),and patients with factor XII deficiency are asymp-tomatic. They have a longer partial thromboplastintime than do patients without factor XII deficiencybut no hemorrhagic symptoms, unlike patients withfactor VIII or factor IX deficiency. The exact

mechanisms underlying factor XII’s roles in vivo arestill debated. Nonetheless, blocking factor XII activ-ity may decreased sustained clot formation withoutincreasing bleeding risks.

By combining new technologies and novel drugs,clot formation might be prevented for a longer timethan with the current AL devices, which would be abig step forward in the clinical application of long-term AL used as DT.

DURABILITY AND PORTABILITY

For portability, implantable ALs will have advantagesover paracorporeal ALs. These are obvious from themanagement of heart failure with implantable versusparacorporeal devices. Implantable VADs haveallowed patients with heart failure to go back to theirhomes and perform daily activities with good QOL.Although implantability is necessary for better QOL, along-term paracorporeal AL will likely become avail-able first. Paracorporeal placement allows for easierdetection of clots, device repair, and deviceexchange. Paracorporeal ALs also have fewerrestrictions on their size and the design, as comparedwith implantable ALs. The concept of an implantableALs is not new. Shah-Mirany et al. (65) reported an8-day animal study using an implantable AL in 1972.They argued that the obstacles for implantabilitywere the limited size of the body cavity, thromobo-genicity, and biocompatibility. Even after more than4 decades, these issues have not been addressedcompletely. An implantable AL, historically called theintravascular oxygenator, was developed in the 1980sthrough the 1990s. The hollow fibers of the devicewere designed to be implanted in the inferior venacava through the femoral or internal jugular vein andinlet and outlet conduits exited through a small skinincision. The device did not require extracorporealcirculation, resulting in less blood damage andinflammation responses. However, whereas in vitroand in vivo studies showed good oxygenation and

Naito et al. J A C C V O L . 7 2 , N O . 1 4 , 2 0 1 8

Artificial Lungs for Lung Failure O C T O B E R 2 , 2 0 1 8 : 1 6 4 0 – 5 2

1650

CO2 transfer (66), a clinical trial of the intravascularoxygenator failed to exhibit adequate gas exchangefor use as BTT or DT. Moreover, only 25% of 160 pa-tients survived to discharge from hospital (67). Themain challenge in designing these devices is thelimited space of the vena cava. Too many gas ex-change fibers occlude the vena cava and decreasevenous return, whereas too few fibers lead to poor gasexchange. Despite significant design work fromseveral groups (68,69), no design was found thatprovided sufficient gas exchange to significantly alterclinical outcomes.

Evolving AL technologies include the para-corporeal MC3 Biolung, cTAL, and artificial pump-lung (APL). The MC3 Biolung has a polymethylpentene fiber bundle for gas exchange with surfacearea of 1.7 m2. Blood flows radially through the fiberbundle (70). The cTAL uses flexible polyurethanehousing with a polypropylene fiber bundle withsurface area of 2.4 m2 (57). The design providesmaximized spatial and temporal blood flow unifor-mity, which contributes to improved gas exchangeefficiency and decreased blood damage. The APL isdesigned as a wearable pump-integrated AL andcontains a hollow-fiber membrane bundle (surfacearea 0.8 m2) integrated with a magnetically levitatedcentrifugal pump (71). The overall size of the APL iscomparable to a 12-ounce soda can, which mayprovide better portability than currently availabledevices. Although there are no clinical trials of thesedevices, all these devices exhibited sufficient gasexchange for full respiratory support in preclinicalsheep studies (Table 3) (56,57,71).

IDEAL ALS

In the future, long-term ALs might become an alter-native to lung transplantation, replacing the need fordonor lungs with a fully functional, man-made deviceincorporated into the respiratory and circulatorysystems. Tissue-engineered artificial organs usingautologous cells are also being investigated (72,73).Learning from the experiences and achievements indevices that treat heart failure, it seems appropriateto set a goal of device longevity of at least severalmonths for paracorporeal devices and 2 to 3 years forimplantable devices.

Although paracorporeal devices that can be usedfor months without exchange should becomecommercially available sooner, a primary goal overthe next decade is to establish an implantable AL withlow resistance, high durability, and low levels ofthromobogenicity that will improve survival and QOLof patients with advanced lung failure and couldreplace the need for a lung transplant. Cardiac andthoracic surgeons should lend their unique expertiseto promoting the development and use of next-generation AL devices.

ADDRESS FOR CORRESPONDENCE: Dr. NorihisaShigemura, Division of Cardiovascular Surgery,Temple University Health System and Lewis KatzSchool of Medicine, 3401 North Broad Street, Suite301, Zone C, 3rd Floor, Philadelphia, Pennsylva-nia 19140. E-mail: Norihisa.Shigemura@tuhs.temple.edu.Twitter: @TempleHealthMed.

RE F E RENCE S

1. National Heart, Lung, and Blood Institute.Morbidity and Mortality: 2012 Chart Book onCardiovascular, Lung, and Blood Diseases.Bethesda, MD: National Institutes of Health, 2012.

2. Acute Respiratory Distress Syndrome Network,Brower RG, Matthay MA, et al. Ventilation with lowertidal volumes as compared with traditional tidal vol-umes for acute lung injury and the acute respiratorydistress syndrome. N Engl J Med 2000;342:1301–8.

3. Brodie D, Bacchetta M. Extracorporeal mem-brane oxygenation for ARDS in adults. N Engl JMed 2011;365:1905–14.

4. Peek GJ, Mugford M, Tiruvoipati R, et al.Efficacy and economic assessment of conven-tional ventilatory support versus extracorporealmembrane oxygenation for severe adult respi-ratory failure (CESAR): a multicentre rando-mised controlled trial. Lancet 2009;374:1351–63.

5. Yusen RD, Edwards LB, Dipchand AI, et al. TheRegistry of the International Society for Heart

and Lung Transplantation: Thirty-third AdultLung and Heart-Lung Transplant Report-2016;focus theme: primary diagnostic indications fortransplant. J Heart Lung Transplant 2016;35:1170–84.

6. Tane S, Noda K, Shigemura N. Ex vivo lungperfusion: a key tool for translational science inthe lungs. Chest 2017;151:1220–8.

7. Bermudez CA, Rocha RV, Zaldonis D, et al.Extracorporeal membrane oxygenation as abridge to lung transplant: midterm outcomes.Ann Thorac Surg 2011;92:1226–31; discussion1231–2.

8. Biscotti M, Gannon WD, Agerstrand C, et al.Awake extracorporeal membrane oxygenation asbridge to lung transplantation: a 9-year experi-ence. Ann Thorac Surg 2017;104:412–9.

9. Fuehner T, Kuehn C, Hadem J, et al. Extracor-poreal membrane oxygenation in awake patientsas bridge to lung transplantation. Am J Respir CritCare Med 2012;185:763–8.

10. Hayanga AJ, Aboagye J, Esper S, et al. Extra-corporeal membrane oxygenation as a bridge tolung transplantation in the United States: anevolving strategy in the management of rapidlyadvancing pulmonary disease. J Thorac CardiovascSurg 2015;149:291–6.

11. Hoopes CW, Kukreja J, Golden J, Davenport DL,Diaz-Guzman E, Zwischenberger JB. Extracorpo-real membrane oxygenation as a bridge to pul-monary transplantation. J Thorac Cardiovasc Surg2013;145:862–7; discussion 867–8.

12. Toyoda Y, Bhama JK, Shigemura N, et al.Efficacy of extracorporeal membrane oxygena-tion as a bridge to lung transplantation. J ThoracCardiovasc Surg 2013;145:1065–70; discussion1070–1.

13. Tirado-Conde G, Ortega Antelo M, Naranjo JM,Esquinas AM. Implications of non-invasive me-chanical ventilation in lung transplantation. Oldand new frontiers? Int J Pul Respir Sci 2017;1:555555.

J A C C V O L . 7 2 , N O . 1 4 , 2 0 1 8 Naito et al.O C T O B E R 2 , 2 0 1 8 : 1 6 4 0 – 5 2 Artificial Lungs for Lung Failure

1651

14. Biscotti M, Bacchetta M. The “sport model”:extracorporeal membrane oxygenation using thesubclavian artery. Ann Thorac Surg 2014;98:1487–9.

15. Biscotti M, Vail E, Cook KE, Kachulis B,Rosenzweig EB, Bacchetta M. Extracorporealmembrane oxygenation with subclavian arterycannulation in awake patients with pulmonaryhypertension. ASAIO J 2014;60:748–50.

16. Jacob S, MacHannaford JC, Chamogeorgakis T,et al. Ambulatory extracorporeal membraneoxygenation with subclavian venoarterial cannu-lation to increase mobility and recovery in a pa-tient awaiting cardiac transplantation. Proc (BaylUniv Med Cent) 2017;30:224–5.

17. Javidfar J, Brodie D, Costa J, et al. Subclavianartery cannulation for venoarterial extracorporealmembrane oxygenation. ASAIO J 2012;58:494–8.

18. Wong JK, Melvin AL, Joshi DJ, et al. Cannula-tion-related complications on veno-arterial extra-corporeal membrane oxygenation: prevalence andeffect on mortality. Artif Organs 2017;41:827–34.

19. Aggarwal V, Einhorn BN, Cohen HA. Currentstatus of percutaneous right ventricular assistdevices: First-in-man use of a novel dual lumencannula. Catheter Cardiovasc Interv 2016;88:390–6.

20. Ravichandran AK, Baran DA, Stelling K,Cowger JA, Salerno CT. Outcomes with the Tan-dem Protek Duo dual-lumen percutaneous rightventricular assist device. ASAIO J 2018;64:570–2.

21. Zwishcenberger JB, Conrad SA, Alpard SK,Grier LR, Bidani A. Percutaneous extracorporealarteriovenous CO2 removal for severe respiratoryfailure. Ann Thorac Surg 1999;68:181–7.

22. Moss CE, Galtrey EJ, Camporota L, et al.Retrospective observational case series of low-flow venovenous extracorporeal carbon dioxideremoval use in patients with respiratory failure.ASAIO J 2016;62:458–62.

23. Lick SD, Zwischenberger JB, Alpard SK,Witt SA, Deyo DM, Merz SI. Development of anambulatory artificial lung in an ovine survivalmodel. ASAIO J 2001;47:486–91.

24. Schmid C, Philipp A, Hilker M, et al. Bridge tolung transplantation through a pulmonary arteryto left atrial oxygenator circuit. Ann Thorac Surg2008;85:1202–5.

25. Takewa Y, Tatsumi E, Taenaka Y, et al. He-modynamic and humoral conditions in stepwisereduction of pulmonary blood flow duringvenoarterial bypass in awake goats. ASAIO J 1997;43:M495–9.

26. Fischer S, Simon AR, Welte T, et al. Bridge tolung transplantation with the novel pumplessinterventional lung assist device NovaLung.J Thorac Cardiovasc Surg 2006;131:719–23.

27. Lazzeri C, Bernardo P, Sori A, et al. Venous-arterial extracorporeal membrane oxygenation forrefractory cardiac arrest: a clinical challenge. EurHeart J Acute Cardiovasc Care 2013;2:118–26.

28. Ma P, Zhang Z, Song T, et al. Combining ECMOwith IABP for the treatment of critically Ill adultheart failure patients. Heart Lung Circ 2014;23:363–8.

29. Naito N, Nishimura T, Iizuka K, et al. Novelrotational speed modulation system used withvenoarterial extracorporeal membrane oxygena-tion. Ann Thorac Surg 2017;104:1488–95.

30. Rihal CS, Naidu SS, Givertz MM, et al. 2015SCAI/ACC/HFSA/STS Clinical Expert ConsensusStatement on the Use of Percutaneous MechanicalCirculatory Support Devices in Cardiovascular Care(Endorsed by the American Heart Association, theCardiological Society of India, and Sociedad LatinoAmericana de Cardiologia Intervencion; Affirma-tion of Value by the Canadian Association ofInterventional Cardiology-Association Canadiennede Cardiologie d’intervention). J Card Fail 2015;21:499–518.

31. Mazzeffi M, Greenwood J, Tanaka K, et al.Bleeding, transfusion, and mortality on extracor-poreal life support: ECLS Working Group onThrombosis and Hemostasis. Ann Thorac Surg2016;101:682–9.

32. Dalton HJ, Garcia-Filion P, Holubkov R, et al.Association of bleeding and thrombosis withoutcome in extracorporeal life support. PediatrCrit Care Med 2015;16:167–74.

33. Lawahito S, Maeda T, Yoshikawa M, et al.Blood trauma induced by clinically accepted oxy-genators. ASAIO J 2001;47:492–5.

34. Venema LH, Sharma AS, Simons AP, Bekers O,Weerwind PW. Contemporary oxygenator designrelative to hemolysis. J Extra Corpor Technol2014;46:212–6.

35. Hendrix RHJ, Ganushchak YM, Weerwind PW.Contemporary oxygenator design: shear stress-related oxygen and carbon dioxide transfer. ArtifOrgans 2018;42:611–9.

36. Crow S, Chen D, Milano C, et al. Acquired vonWillebrand syndrome in continuous-flow ventric-ular assist device recipients. Ann Thorac Surg2010;90:1263–9; discussion 1269.

37. Goda M, Jacobs S, Rega F, et al. Time course ofacquired von Willebrand disease associated withtwo types of continuous-flow left ventricularassist devices: HeartMate II and CircuLite SynergyPocket Micro-pump. J Heart Lung Transplant2013;32:539–45.

38. Suarez J, Patel CB, Felker GM, Becker R,Hernandez AF, Rogers JG. Mechanisms of bleedingand approach to patients with axial-flow leftventricular assist devices. Circ Heart Fail 2011;4:779–84.

39. Heilmann C, Geisen U, Beyersdorf F, et al.Acquired von Willebrand syndrome in patientswith extracorporeal life support (ECLS). IntensiveCare Med 2012;38:62–8.

40. Frazier OH, Rose EA, McCarthy P, et al.Improved mortality and rehabilitation of trans-plant candidates treated with a long-termimplantable left ventricular assist system. AnnSurg 1995;222:327–36; discussion 336–8.

41. Miller LW, Pagani FD, Russell SD, et al. Use ofa continuous-flow device in patients awaitingheart transplantation. N Engl J Med 2007;357:885–96.

42. Pagani FD, Miller LW, Russell SD, et al.Extended mechanical circulatory support with a

continuous-flow rotary left ventricular assist de-vice. J Am Coll Cardiol 2009;54:312–21.

43. Hayanga AJ, Du AL, Joubert K, et al. Me-chanical ventilation and extracorporeal membraneoxygenation as a bridging strategy to lung trans-plantation: significant gains in survival. Am JTransplant 2018;18:125–35.

44. Alba AC, Alba LF, Delgado DH, Rao V, Ross HJ,Goeree R. Cost-effectiveness of ventricular assistdevice therapy as a bridge to transplantationcompared with nonbridged cardiac recipients.Circulation 2013;127:2424–35.

45. Hayanga JWA, Shigemura N, Aboagye JK,et al. ECMO support in lung transplantation: acontemporary analysis of hospital charges in theUnited States. Ann Thorac Surg 2017;104:1033–9.

46. Hunt SA, Abraham WT, Chin MH, et al. 2009focused update incorporated into the ACC/AHA2005 Guidelines for the Diagnosis and Manage-ment of Heart Failure in Adults: a report of theAmerican College of Cardiology Foundation/American Heart Association Task Force on PracticeGuidelines: developed in collaboration with theInternational Society for Heart and Lung Trans-plantation. Circulation 2009;119:e391–479.

47. INTERMACS (Interagency Registry for Me-chanically Assisted Circulatory Support) QuarterlyStatistical Report 2017 Q1. . Available at: http://www.uab.edu/medicine/intermacs/images/Federal_Quarterly_Report/Statistical_Summaries/Federal_Partners_Report_2017_Q1.pdf. Accessed April 1,2018.

48. Park SJ, Milano CA, Tatooles AJ, et al. Out-comes in advanced heart failure patients with leftventricular assist devices for destination therapy.Circ Heart Fail 2012;5:241–8.

49. Rogers JG, Aaronson KD, Boyle AJ, et al.Continuous flow left ventricular assist device im-proves functional capacity and quality of life ofadvanced heart failure patients. J Am Coll Cardiol2010;55:1826–34.

50. Slaughter MS, Rogers JG, Milano CA, et al.Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med2009;361:2241–51.

51. Jorde UP, Kushwaha SS, Tatooles AJ, et al.Results of the destination therapy post-food anddrug administration approval study with acontinuous flow left ventricular assist device: aprospective study using the INTERMACS registry(Interagency Registry for Mechanically AssistedCirculatory Support). J Am Coll Cardiol 2014;63:1751–7.

52. Weill D, Benden C, Corris PA, et al.A consensus document for the selection of lungtransplant candidates: 2014–an update from thePulmonary Transplantation Council of the Inter-national Society for Heart and Lung Trans-plantation. J Heart Lung Transplant 2015;34:1–15.

53. CamboniD,PhilippA,ArltM,PfeifferM,HilkerM,Schmid C. First experience with a paracorporealartificial lung in humans. ASAIO J 2009;55:304–6.

54. Strueber M, Hoeper MM, Fischer S, et al.Bridge to thoracic organ transplantation in pa-tients with pulmonary arterial hypertension usinga pumpless lung assist device. Am J Transplant2009;9:853–7.

Naito et al. J A C C V O L . 7 2 , N O . 1 4 , 2 0 1 8

Artificial Lungs for Lung Failure O C T O B E R 2 , 2 0 1 8 : 1 6 4 0 – 5 2

1652

55. Muller T, Lubnow M, Philipp A, et al. Extra-corporeal pumpless interventional lung assist inclinical practice: determinants of efficacy. EurRespir J 2009;33:551–8.

56. Sato H, Hall CM, Lafayette NG, et al. Thirty-day in-parallel artificial lung testing in sheep. AnnThorac Surg 2007;84:1136–43; discussion 1143.

57. Skoog DJ, Pohlmann JR, Demos DS, et al.Fourteen day in vivo testing of a compliantthoracic artificial lung. ASAIO J 2017;63:644–9.

58. Biran R, Pond D. Heparin coatings forimproving blood compatibility of medical devices.Adv Drug Deliv Rev 2017;112:12–23.

59. Amoako KA, Sundaram HS, Suhaib A, Jiang S,Cook KE. Multimodal, biomaterial-focused anti-coagulation via superlow fouling zwitterionicfunctional groups coupled with anti-platelet nitricoxide release. Adv Mater Interfaces 2016;3:1500646.

60. Amoako KA, Montoya PJ, Major TC, et al.Fabrication and in vivo thrombogenicity testing ofnitric oxide generating artificial lungs. J BiomedMater Res A 2013;101:3511–9.

61. Tevaearai HT, Mueller XM, Tepic S, et al. Nitricoxide added to the sweep gas infusion reduceslocal clotting formation in adult blood oxygena-tors. ASAIO J 2000;46:719–22.

62. Kenne E, Nickel KF, Long AT, et al. Factor XII: anovel target for safe prevention of thrombosis andinflammation. J Intern Med 2015;278:571–85.

63. Weitz JI. Factor XI and factor XII as targets fornew anticoagulants. Thromb Res 2016;141 Suppl2:S40–5.

64. Factor XII deficiency. National Organization forRareDisorders. .Available at:https://rarediseases.org/rare-diseases/factor-xii-deficiency/. Accessed April 1,2018.

65. Shah-Mirany J, Head LR, Ghetzler R,Formolo AJ, Palmer AS, Bodell BR. An implantableartificial lung. Ann Thorac Surg 1972;13:381–7.

66. Conrad SA, Zwischenberger JB,Eggerstedt JM, Bidani A. In vivo gas transfer per-formance of the intravascular oxygenator in acuterespiratory failure. Artif Organs 1994;18:840–5.

67. Conrad SA, Bagley A, Bagley B, Schaap RN.Major findings from the clinical trials of theintravascular oxygenator. Artif Organs 1994;18:846–63.

68. Hattler BG, Lund LW, Golob J, et al.A respiratory gas exchange catheter: in vitro andin vivo tests in large animals. J Thorac CardiovascSurg 2002;124:520–30.

69. Gattaneo GF, Reul H, Schmitz-Rode T,Steinseifer U. Intravascular blood oxygenationusing hollow fibers in a disk-shaped configuration:experimental evaluation of the relationship be-tween porosity and performance. ASAIO J 2006;52:180–5.

70. Akay B, Reoma JL, Camboni D, et al. In-par-allel artificial lung attachment at high flows in

normal and pulmonary hypertension models. AnnThorac Surg 2010;90:259–65.

71. Wu ZJ, Zhang T, Bianchi G, et al. Thirty-day in-vivo performance of a wearable artificial pump-lung for ambulatory respiratory support. AnnThorac Surg 2012;93:274–81.

72. Pflaum M, Kuhn-Kauffeldt M,Schmeckebier S, et al. Endothelialization andcharacterization of titanium dioxide-coated gas-exchange membranes for application in thebioartificial lung. Acta Biomater 2017;50:510–21.

73. Wiegmann B, Seggern H, Hoffler K, et al.Developing a biohybrid lung – sufficient endothe-lialization of poly-4-methyl-1-pentene gas ex-change hollow-fiber membranes. J Mech BehavBiomed Mater 2016;60:301–11.

KEY WORDS artificial lung, destinationtherapy, extracorporeal membraneoxygenation, heart failure, lung failure,transplantation, ventricular assist device

Go to http://www.acc.org/jacc-journals-cme to takethe CME/MOC/ECME quizfor this article.