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International Heart and Vascular Disease Journal Volume 4, Number 10, June 2016
Journal of the Cardioprogress Foundation
REVIEW ARTICLE
Extracorporeal Membrane Oxygenation
in Respiratory Diseases in Adults
Rajapriya Manickam, Ravi Manglani, Lisa Paul, Wilbert S. Aronow, MD*
Lincoln Medical Center, New York Medical College/Westchester Medical Center, NY, USA
Authors:
Rajapriya Manickam, MD, Division of Pulmonary, and Critical Care Medicine, Lincoln Medical Center, NY, USA;
Ravi Manglani, MD, Division of Pulmonary, and Critical Care Medicine, Lincoln Medical Center, NY, USA; Lisa Paul, MD, Division of Pulmonary, Critical Care, and Sleep Medicine, New York Medical College/ Westchester Medical Center, Valhalla, NY, USA;
Wilbert S. Aronow, MD, FCCP, FACC, FAHA, Division of Cardiology, New York Medical College/ Westchester Medical Center, Valhalla, NY, USA.
Extracorporeal membrane oxygenation (ECMO) was first used in adults in 1972 in a young patient with posttraumatic acute respiratory distress syndrome (ARDS). The technology is derived from the cardiopulmonary bypass machine used for cardiac surgery, modified for a longer-term support of respiratory and/or cardiac function. There are two major types of support that may be provided with ECMO, veno-venous ECMO (VV-ECMO) and veno-arterial ECMO (VA-ECMO). The former is used in patients with good cardiac function, in an effort to support lung function, while the latter is used in patients with poor cardiac function, in an effort to support the failing heart. Significant advances continue to be made in the field of extracorporeal life support (ECLS) and the modality promises to supplement the management options available for the niche role in management of patients with severe cardiac and respiratory disease. In this review, we discuss the latest developments and usage of ECMO in respiratory diseases in adults.
Key words
Extracorporeal membrane oxygenation, respiratory diseases, adults
Abstract
Corresponding author. Tel. 914-493-5311. E-mail: wsaronow@aol.com
Introduction
Extracorporeal membrane oxygenation was first used in adults in 1972 in a young patient with posttraumatic acute respiratory disease syndrome (ARDS) [1]. The technology arose from cardiopulmonary bypass machine used for cardiac surgery but modified for longer-term support of respiratory and/or cardiac function. Its initial progress was plagued by various complications that ranged from finding the compatible pump mechanisms, to hemolysis, to blood clotting within the tubing, to finding a suitable method of oxygenation of the extracted blood.
Most of the complications were related to the oxygenators. Initially used oxygenators were the simple, less expensive bubble oxygenators where blood is exposed directly to gas. The direct blood-gas interface caused blood trauma and protein degradation, leading to hemolysis, platelet destruction, and microem-boli [2, 3]. These systems were eventually replaced with membrane oxygenators, where the blood is separated from gas by a semi-permeable membrane, mimicking human lung and fewer complications [4, 5, 6]. This was a major step in advancement of the technology and with the subsequent improvement in membrane material facilitated safer extracorporeal oxygenation for prolonged period of time
A large randomized controlled trial [7] conducted in 1974 did not show significant difference in mortality between ECMO versus conventionally treated adult ARDS patients and dampened the initial enthusiasm about ECMO. Technology advances and the 2009 H1N1 influenza pandemic spurred the interest on ECMO as a rescue therapy, especially for young patients with ARDS who were failing conventional therapy [8]. This review article is aimed to familiarize readers about ECMO, its indications, its utility, possible complications, and gives a glimpse of possible future directions of care especially in pulmonary disease.
Overview
ECMO refers to the process of long-term extracorporeal support for oxygenation while the failing heart
or lung rejuvenates. This is achieved by draining de-oxygenated blood via a cannula to an external circuit of primed tubing to a membrane oxygenator which oxygenates the blood and a centrifugal pump which returns the oxygenated blood back into the circulation. Although there are various other components in the circuit, the main ones are the oxygenator and the pump. Typically, the blood flow through the circuit is at the rate of 100ml/kg/minute and requires placement of large bore cannulas, usually 21-24 French for adults. Another significant fact is that CO2 removal is more efficient than oxygenation because of the solubility and diffusion properties of CO2 relative to O2
There are two major types of support that may be provided with ECMO (Table 1), Veno-venous ECMO (VV-ECMO) and veno- arterial ECMO (VA-ECMO).
VV-ECMO
In VV- ECMO, blood is extracted from a large vein into the ECMO circuit where gas exchange takes place. The oxygenated blood is then pumped back into the venous system, which then passes through the right atrium, and the patient's heart pumps the oxygenated blood through the pulmonary and then to the systemic circulation. As it requires the patient's native heart to pump the blood through the circuit, VV-ECMO can be used only in patients with good cardiac function to support the lungs. It does not provide support to maintain cardiac output.
Vessel cannulation may be done in several ways, ranging from a femoral-jugular approach, to a bi-femoral setting, or to a single bicaval double lumen cannula. The oxygenated blood from ECMO mixes with the deoxygenated blood in the right atrium. The systemic oxygen tension will be low and will depend on the cardiac output and the hemoglobin concentration of the patient. One of the major technical problems in VV-ECMO is recirculation. As the oxygenated blood from the circuit is sent back to a vein, some of the oxygenated blood can directly go back to the draining cannula without going to the systemic circulation. A 30% recirculation is generally considered
Table 1. Types of ECMO
VV- ECMO VA-ECMO
Cannulation type — Blood drained from vein and returned to vein Vein: jugular-femoral, right atrium -femoral, femoral-femoral, saphenous-saphenous — Blood drained from vein and returned to artery. Vein: internal jugular, femoral artery: femoral, axillary, subclavian, aorta
Circuit Connected in series with heart and lung Connected in parallel to heart and lung
Cardiac Support yes No
Cardiac effects Preload: decreased. Afterload: increased May reduce right ventricular afterload. No other hemodynamic effects
Arterial PaO2 60-150 mmHg 45-80 mmHg
Indications Cardiogenic shock Respiratory failure with preserved cardiac function
acceptable and more commonly seen with single site double lumen cannula where the entry and exit point are close to each other. Factors that can increase the recirculation percentage are position of the cannula (distal to the right atrium), higher pump flow, and low cardiac output.
VA-ECMO
In VA- ECMO, deoxygenated blood is drained into the circuit for oxygenation and ventilation,and returns into the systemic circulation on the arterial side. Thus, VA- ECMO bypasses the heart as well as the lungs, providing both hemodynamic and respiratory support while allowing the native lung and heart to rest and heal. The VA- ECMO mode is similar to the conventional cardiopulmonary bypass used for cardiac surgeries but adopted for a longer period of support. Cannulation can be central or peripheral. In peripheral cannulation, blood is drained from the proximal femoral or jugular vein and returned via the carotid or femoral or axillary artery. The cannulas used are smaller than the central cannulation and can be done emergently at bedside. Central cannulation usually requires sternotomy or thoracotomy and blood is drained from near the right atrium and returned to the proximal ascending aorta. It is a preferred option when used immediately after cardiopulmonary bypass as the same cannulas can be connected to the VA-ECMO circuit.
The cannula position, diameter and length, along with the patient's venous filling, vascular resistance, and pump speed play an important role in the overall blood flow and the hemodynamics. A proportion of the blood flow (~15-20%) can continue to go through the lungs during a VA-ECMO. Therefore, in a patient with poor lung function, the proportion of blood going through the lungs, which are not adequately oxygenated, mix with well-oxygenated blood provided by the ECMO circuit in the aorta. Hence, in the case of peripheral VA ECMO, the coronary arteries, cerebral blood vessels, and proximal branches of the aorta may receive blood with lower oxygen content. Thus, the decision on the location of the cannulas assumes an important role in VA-ECMO [9] in patients with poor lung function.
Indications in Respiratory Diseases ARDS
Extracorporeal life support (ECLS), particularly VV-ECMO, has been used as a rescue therapy in patients with severe ARDS. Though some studies have shown improvement in mortality among ARDS patients
over the years, it is still unacceptably high in severe ARDS at 40-52% [10,11]. ECMO started to gain popularity as a rescue therapy in this population since the 2009 H1Ni influenza pandemic. The exact indications for ECMO have varied across institutions. Broadly, it is indicated for refractory hypoxemia on conventional ventilation therapy, severe acidosis, and hypercapnia. The Murray score is a scoring system that includes the chest roentgenogram , PaO2/FiO2 ratio, positive end-expiratory pressure (PEEP), and compliance to stratify these patients [12]. According to ELSO (extracorporeal life support organization) guidelines for adult with ARDS [13], ECMO is indicated when despite the optimal care for 6 hours or more, the predicted mortality risk is >80% which is associated with a PaO2/FiO2 <150 on FiO2>90% and/ or a Murray score of 3-4. ECMO should be considered when the mortality risk is >50% which is associated with a PaO2/FiO2 <150 on Fio2>90% and/or a Murray score of 2-3. As of July 2012 [14], the overall survival in adult patients on ECMO for respiratory failure in the past five years ranged from 53% to 61% which is similar to other recent studies [15].
While considering ECMO in patients, one of the most important considerations is the reversibility of the pulmonary disease. Other pre-ECMO characteristics of the patients like advanced age, high ICU severity score, multiorgan dysfunction, immunocom-promised status, and poor neurological status negatively impact ECMO outcome [15,16]. Various studies have shown that the earlier the patient placed on ECMO, the better the outcome [17, 18, 19, 20, 21]. Ventilator associated lung injury (VILI) is a significant cause of morbidity and mortality in ventilated patient [22, 23], and reduction in the duration of mechanical ventilation prior to ECMO minimize ventilator associated lung injury and that possibly explains the survival benefit. The ventilator setting while the patient is on ECMO (Table 2) is minimal and lung protective, helps the lung to rest, and reduces VILI.
Table 2. Ventilator settings while on ECMO
Peak inspiratory pressure 20-25 cm H2O
Positive end-expiratory pressure 10-15 cm H2O
FIO2 <0.5
Respiratory rate 8-10 breaths/min
Tidal volume 3-4ml/kg
Low volume ventilation prevents VILI in ventilated patients. The problem while on low volume ventilation will be the raising of PCO2 and acidosis. With the help of extracorporeal CO2 removal (ECCO2R) technique,
this problem can be overcome. Combining ECCO2 R with low tidal volume ventilation could prove to be the best strategy for management of severe ARDS patients.
Current Evidence
The results of the smaller studies and the first US ECMO multicenter randomized controlled trial conducted by the National Heart and Lung institute in 1974 were discouraging and did not show measurable mortality benefit [24, 25]. In this study, the survival in both conventional and ECMO groups was very poor, only around 10%. These studies were conducted when ECMO technology was primitive. We did not have much understanding in the management of ARDS and was receiving high tidal volume ventilation. However subsequent studies in neonates and children showed a mortality benefit, and it was widely accepted and used in a pediatric population[26, 27].
Some centers continued to work on ECMO in adult populations, and over a period of time, various observational studies demonstrated safe and successful application of ECMO in critically ill adults [28, 29]. The survival rate recorded in the ELSO registery [30] was 41% in 1995, and overall 197 patients had received ECMO for ARDS at that time. This was comparable to European studies published in that time period [31] where around 850 patients received ECMO between 1992-1999. The better outcome with recent studies is attributed to the advanced technology in ECMO as well as the use of low tidal volume lung protective strategies. Morris et al [32] conducted a randomized clinical trial in 1994, which also did not show a mortality benefit as compared with standard therapy. In spite of all the controversies, ECMO gained popularity as a rescue therapy for severe ARDS adult patients during the 2009 H1N1 influenza pandemic [33, 34, 35].
The landmark trial was the CESAR trial [Conventional ventilator support vs Extracorporeal membrane oxygenation for Severe Adult Respiratory failure] [36] concluded in 2006 and published in 2009. It is the major randomized control trial and the first in the literature to show a mortality benefit in patients who were transferred to an ECMO. A total of 180 patients were randomized 1:1 to two groups. A control group continued to receive the conventional ventilation therapy at tertiary care centers, while the intervention group was referred to an ECMO center for consideration of ECMO. Among the 90 patients that were transferred to a center with ECMO capabilities, only 68(75%) patients received ECMO and of which,
63% (57/90) patients survived to six months without disability, compared to 47% (41/87) of those that received conventional therapy (RR 0.69%, 95%CI 0.50.97, p=0.03).
There are two major criticisms to the above study. The intervention in the CESAR trial was. referral to a center with ECMO capabilities rather than treatment with ECMO, and actually 25% of the intervention group did not actually receive ECMO. The other major criticism is that the study did not dwell on the management of the patients in the conventional ventilation arm, and it is unclear as to how many patients received low tidal volume lung protective ventilation.
The Australia and New Zealand ECMO Influenza Investigators [33] reported their experience in treating the 2009 outbreak of H1N1 Influenza infection that led to a number of young otherwise healthy patients developing severe ARDS. Among 201 intensive care unit patients in the study, 68 (30%) received ECMO. The mortality in this group was 21% (14 patients), compared with 9% on the non-ECMO group. This accompanies other papers that failed to show a mortality benefit [36, 37]. Meanwhile, other studies showed a mortality benefit [39, 40]. This conflicting evidence necessitated a large multicenter randomized controlled trial that can prove or disprove the benefit of ECMO.
The French group REVA (Research Network on Respiratory Failure and Artificial Ventilation) is conducting the EOLIA study (ECMO to rescue Lung Injury in ARDS), an international multicenter randomized controlled trial in patients with severe ARDS, which is an attempt to provide better evidence. Patients are promptly randomized into ECMO and conventional therapy groups in which the limitations of the CESAR trial are addressed. The results of this study are eagerly awaited.
Chronic Obstructive Pulmonary Disease
In chronic obstructive pulmonary disease (COPD), invasive mechanical ventilation is associated with many complications including ventilator associated pneumonia, dynamic hyperinflation of lungs, ventilator dependence, and impaired delivery of aerosolized medi-cations[41, 42]. A modality of ECLS includes extracorporeal carbon- dioxide removal (ECCO2 R) that helps remove carbon dioxide (CO2) from the circulation. ECCO2R is an intermediate level of ECLS with little technical difference than the complete ECLS provided by ECMO. The blood flow is lower (0.3-0.5litres/min) and able to remove ~25% of CO2. It has been shown
to reduce the need of invasive mechanical ventilation (IMV) and has also been used to assist removal of CO2 in patients already on mechanical ventilation, in an effort to reducethe number of days on the ventilator and intensive care unit stay.
A pump-less ECCO2 R A-V circuit has been used to prevent mechanical ventilation in patients in severe exacerbations of COPD [43, 44]. This modality has also been used as a supportive therapy for patients who are already on mechanical ventilation to facilitate early extubation, early mobilization and physiotherapy, even while on ECCO2 R [45, 46, 47]. A feasibility pilot study was done to assess the possibility of early extubation and early ambulation in patients receiving mechanical ventilation using single site ECCO2R, with excellent results. Further studies are required to define the criteria and the patient population that would most benefit from this modality.
ECMO as a Bridge to Lung Transplant
Lung transplant waiting lists are increasing, and there is severe paucity of suitable organ donors. Patients with end- stage lung disease awaiting transplant who are failing medical management need a bridge until a donor becomes available. ECMO helps transitioning of care before, during and after the transplant procedure. The initial concept of bridging originated with left ventricular assist devices (LVADs) for cardiac transplant [48, 49]. Initial studies of patients on ECMO had poor perioperative outcomes [50]. Recently, ECMO has been used safely in patients during transplant and aid their recovery [51-52]. ECMO and ECCO2 R modalities have been used to reduce the need for mechanical ventilation and help participate in rehabilitation and physiotherapy, which has further improved outcomes. It also helped to avoid ventilator-associated complications [53].
Experiences from large academic centers and from international centers have come in throughout the last decade, with many showing improved survival and favorable outcomes. The university of Kentucky and the university of California successfully bridged 31 patients as of 2013 and achieved a 80% 3-year survival [54]. The university of Pittsburgh has used ECMO as a bridge for 31 patients with 25 surviving to transplant. This group demonstrated a 74% survival in the ECMO group [55]. A French group reported their experience with lung transplant with ECMO in 36 patients with 30 making it to transplant. The 2-year survival was reported as 60.5% but outcomes in patients with cystic fibrosis was significantly better than
in those with idiopathic pulmonary fibrosis (IPF). This observation suggests that ECMO outcomes may vary depending on the underlying etiology of the lung disease [56].
Extracorporeal Cardiopulmonary Resuscitation
Extracorporeal cardiopulmonary resuscitation (E-CPR) is the term used for institution of ECLS during cardiopulmonary resuscitation to help return of spontaneous circulation (ROSC). A growing body of evidence suggests the utility of ECLS in cardiopulmonary resuscitation in improving outcomes and survival in patients with intra-hospital cardiac arrests (IHCA) and out of hospital cardiac arrests (OHCA)[57, 58, 59, 60]. In prospective observational trials of IHCAs, survival to discharge varied from 20% to 32%, with p values of <0.0001 and 0.002 respectively [57, 58] with a good neurological outcome. Similarly, out of hospital arrests also showed comparable outcomes, with survival of 29.2% at 3 months and a p value of 0.018 [57]. The recently published prospective pilot study, The CHEER trial [61] was carried out for refractory IHCA and OHCA in Australia. These patients had a ROSC of >30 minutes with an initial rhythm of ventricular fibrillation. The reported survival rates were 54% with 13 out of 24 patients surviving to hospital discharge. Further studies are ongoing, so that we can further delineate the patient populations with the most expected survival benefit.
Pulmonary Hypertension and Pulmonary Embolism
ECLS has been used as an emerging therapy in patients with severely decompensated right ventricular (RV) failure and pulmonary hypertension of various etiology. ECMO may be implemented briefly to support the patient while medical management is being optimized during a crisis or as a bridge for lung transplant [62]. Commonly, VA- ECMO is applied, which will decompress the right ventricle, leading to reduction in right ventricular pressures and also preferentially shunts the blood into the ECMO circuit leading to better oxygenation and ventilation [63]. It can provide a bridge to successful lung transplantation in World Health Organization group I pulmonary artery hypertension patients with end-stage cardiopulmonary failure. A retrospective review of use of ECMO for massive pulmonary embolisms in 21 patients demonstrated improvement in survival to 62% when used along with conventional medical management [64].
This improved survival has been supported by other published cases [65].
Future Directions
The most important implication of ECLS is early mobilization, early rehabilitation and early physiotherapy, which has time and again showed to positively impact clinical outcomes [66, 67]. This, along with reduced ventilator requirements and hence less associated complications like VILI will prove to be more beneficial to select groups of patients [68, 69]. As of now, ECLS is being used only in select centers as a rescue therapy for refractory respiratory failure, cardiogenic shock and as a bridge to lung and heart transplant. Advancements in technology in manufacturing of circuitry will lead to compact consoles and ambulatory ECMO machines as a destination therapy for end stage lung disease. The expanding utility of ECLS is rapidly encompassing all forms of respiratory failure from various causes and severe right ventricular failure.
Weaning of ECMO
Weaning from ECMO is a crucial step, and there are no standard protocols as of yet. It is basically provider dependent and usually based on some rough guidelines from scientific societies. Weaning from VA ECMO and VV ECMO are different. However the most basic requisite before weaning is the recovery of the lung and or cardiac function significantly so that the lung and or cardiac rest is no longer needed.
In VV ECMO, weaning is a process where contribution of ECMO to gas exchange (oxygenation and CO2 removal) is progressively decreased while the native lung takes over its function. The actual circuit blood flow need not be altered to assess the pulmonary function. The clinical parameters that can indicate recovery of pulmonary function [9] are (a) progressive increase in SaO2 above SvO2, (b) improvement in SaO2 for a given circuit gas flow or a reduced gas flow, (c) improvement in respiratory mechanics - lung compliance, airway resistance, (d) radiological improvement. ELSO guidelines indicates that when the native lung can support 50-80% total gas exchange at a moderate ventilator setting (FiO2 <0.6-0.5, low PEEP) ECMO discontinuation can be considered. Weaning from VV ECMO (Table 3) is performed by progressively decreasing the gas flow to the oxygenator. At zero flow, if the patient able to maintain stable hemodynamic and ventilator parameters for 4-24hours (varies from center to center) then the patient can be
Table 3. Weaning VV-ECMO in respiratory failure
■ Sweep gas flow set at 0 L/min
' FiO2 set at 0.21 on the membrane
Pump flow not modified
The device may be withdrawn if
— PaO2 >60 mmHg, SaO2 >90 %
— FiO2 on the ventilator <60 %
— Inspiratory plateau pressure <30 cm H2O
For at least 1-2 hours and up to 12 hours
effectively off of ECMO. Extracorporeal support can be then discontinued and decannulated. The goal is to resume mechanical ventilation with ventilator settings that are less injurious and can maintain good oxygenation and ventilation, which would have been impossible prior to initiation of ECMO. Weaning is generally possible in ARDS after 7-10 days on ECMO.
If the patient is on VA-ECMO and the indication of ECMO is for cardiac causes, the myocardial recovery is required before weaning can be initiated. The parameters need to be monitored in these patients are (a) return of pulsatile arterial pressure waveform for 24hrs, hemodynamic stability with baseline mean arterial pressure greater than 60 mmHg in the absence or with low doses of catecholamine (b) decreasing central venous and/or pulmonary pressures (c) improvement of pulmonary function, PaO2/FiO2 <100mmHg. Weaning in VA ECMO is carried out by reducing blood flow through the circuit hourly. Once the blood flow is as low as 1-2 liters/minute and the patient has been hemodynamically stable for few hours, surgical decannulation may be carried out. Doppler echocardiography parameters help in assessing cardiac function while weaning.
Successful weaning from ECMO depends on the underlying cause, it's reversibility, associated comorbidities, and severity of organ dysfunction at the time of ECMO initiation.
Complications on ECMO
Application of ECMO is associated with number of complications. A specialized center with extensively trained personnel and well-experienced staff is required to implement it safely to demonstrate the survival benefit. Improvement in technology and the circuit has decreased complications rate over the past decade. The Extracorporeal Life Support Organization (ELSO) database14 gives us the rates of complications of patients on ECMO and guidelines to follow for their management. Complications can be broadly classified as physiological and mechanical (Table 4).
The most common complications among them are clot formation and bleeding. As blood passes through
Table 4. Complications of ECMO
Physiological complications Mechanical, related to circuit
Bleeding — cannula site — Intracranial, GI, Pulmonary Thromboembolic Hemolysis Neurologic — seizures, stroke, encephalopathy Failure of oxygenator Pump failure Cannula problems
the circuit, activation of clotting factors and emboli is a major concern. Anticoagulation is usually done by heparin drip, maintaining activated thromboplastin time of 1.5 times normal values. The reported incidence is 12-17%. Localized bleeding from the cannula insertion site (16%) or from the surgical site (17%) is common and can be managed with simple compression. Major bleedings like intracranial bleeding is reported in 3.9%, pulmonary and gastrointestinal bleeding reported in 8% and 5%, respectively. The hematologic consequences of an ECMO circuit include hemolysis, acquired von Willebrand factor deficiency, and thrombocytopenia contributes to the bleeding and thrombotic risks. After hematological adverse effects, infection remains the significant problem with a reported rate is 21.3%. The other potential complications are encephalopathy, renal dysfunction, and liver injury.
The complications of VA-ECMO are similar to VV-ECMO, with added possible complications (a) pulmonary hemorrhage (b) cardiac thrombosis and (c) limb ischemia from peripheral arterial cannulation. When the left ventricular contractility is poor, the left ventricle continues to dilate from persistent preload and the left ventricular end-diastolic pressure increases. This in turn increases the pulmonary pressure causing pulmonary hemorrhage. With VA- ECMO the pulsatility of the blood flow is lost, and blood stagnates in the aortic root ,increasing the risk of cardiac thrombosis and systemic emboli.
Ethical Considerations
The patients' families must be extensively educated about the process of ECMO and counseled about the possibility of unfavorable outcomes, in spite of the extraordinary measures being taken to maintain life Even after a successful recovery from ECMO, the neurological outcome may still be poor. End of life discussions must be held, either with the patient, or with health care surrogates. The goal of care should be well established as families may wish to continue therapy even if the treating team feels that the patient's condition has progressed to an irreversible state. Daily updates and clear discussion about the prognosis with patients and their families help in avoiding such situations.
Conclusions
Every day, significant advances continue to be made in the field of ECLS. The modality promises to supplement the management options available for severe cardiac and respiratory disease. More widespread data from multiple centers are needed to add to current knowledge and help us understand its role in management of different patient populations and its potential indications.
Conflict of interest: None declared.
References
1. Hill JD, O'Brien TG, Murray JJ, Dontigny L, et al. Prolonged extracorporeal oxygenation for ARDS post-traumatic respiratory failure (shock-lung syndrome). Use of the Bramson membrane lung. N Engl J Med. 1972; 286:629-34
2. Andersen, M.N. and Duchiba: Blood Trauma Produced by Pump Oxygenators. J. Thorac. Cardiovasc. Surg., 57:238, 1969.
3. Lee, W.H., Jr. and Hairston, P.: Structural Effects on Blood Proteins at the Gas-Blood Interface. Fed. Proc., 30:1615, 1971.
4. Kayser, K.L.: Blood-gas Interface Oxygenators Versus Membrane Oxygenators. Ann. Thorac. Surg., 17:459, 1974.
5. Vervloet, A.F., Edwards, M.J., and Edwards, M.L.: Minimal Apparent Blood Damage in Lande-Edwards Membrane Oxygenator at Physiologic Gas Tensions. J. Thorac. Cardiovasc. Surg., 60:774, 1970.
6. Clark, R. E., et al. "Comparison of bubble and membrane oxygenators in short and long perfusions." The Journal of thoracic and cardiovascular surgery 78.5 (1979): 655-666.
7. Zapol WM, Snider MT, Hill JD, et al.Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study.JAMA 1979, 242:2193-2196.
8. Peek, Giles J., et al. "Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial."Lancet (London, England) 374.9698 (2009): 1351-1363.
9. Lafçi, Gokhan, et al. "Use of extracorporeal membrane oxygenation in adults." Heart, Lung and Circulation 23.1 (2014): 10-23.
10. Pierrakos C, Vincent JL. The changing pattern of acute respiratory distress syndrome over time: a comparison of two periods. Eur Respir J 2012; 40: 589-595.
11. Ranieri VM, Rubenfeld GD, Thompson BT, et al: Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012; 307: pp. 2526-2533
12. Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 1988;138(3):720-723.
13. Extracorporeal life support organization guidelines. ELSO Guidelines for Adult Respiratory Failure v1.3. http://www.elso. org/resources/Guidelines.aspx
14. Extracorporeal Life Support Organization. Registry report: international summary. Ann Arbor: ELSO; July 2012.
15. LC Chiu, FC Tsai, HC Hu,et al. "Survival predictors in acute respiratory distress syndrome with extracorporeal membrane oxygenation." The Annals of thoracic surgery 99.1 (2015): 243-250.
16. Schmid C, Philipp A, Hilker M, Rupprecht L, Arlt M, Keyser A, et al. Venovenous extracorporeal membrane oxygenation for acute lung failure in adults. J Heart Lung Transplant 2012;31:9-15.
17. Brogan TV, Thiagarajan RR, Rycus PT, et al. Extracorporeal membrane oxygenation in adults with severe respiratory failure: a multi-center database. Intensive Care Med 2009;35:2105-2114.
18. Pranikoff T, Hirschl RB, Steimle CN, et al. Mortality is directly related to the duration of mechanical ventilation before the initiation of extracorporeal life support for severe respiratory failure. Crit Care Med 1997;25:28-32.
19. Schmidt M, Zogheib E, Rozé H, et al. The PRESERVE mortality risk score and analysis of long-term outcomes after extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. Intensive Care Med 2013;39:1704-1713.
20. Hemmila MR, Rowe SA, Boules TN, Miskulin J, McGillicuddy JW, Schuerer DJ, et al. Extracorporeal life support for severe acute respiratory distress syndrome in adults. Ann Surg 2004;240:595-605.
21. JJ Lee, SM Hwang, JH Ko,et al. "Efficacy of veno-venous extracorporeal membrane oxygenation in severe acute respiratory failure." Yonsei medical journal 56.1 (2015): 212-219.
22. Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes foracute lung injury and the acute respiratory distress syndrome. N EnglJ Med 2000;342(18):1301-1308.
23. Serpa Neto A, Cardoso SO, Manetta JA, et al.: Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. JAMA 2012; 308: 1651-1659.
24. Zapol WM, Snider MT, Hill JD, et al. Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study. JAMA 1979;242:2193-6.
25. Morris AH, Wallace CJ, Menlove RL, et al. Randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome. Am J Respir Crit Care Med 1994;149:295-305.
26. Bartlett RH, Roloff DW, Cornell RG, Andrews AF, Dillon PW,Zwischenberger JB. Extracorporeal circulation in neonatal respiratoryfailure: a prospective randomized study. Pediatrics 1985;76(4):479-487.
27. UK Collaborative ECMO Trail Group. UK collaborative ran-domisedtrial of neonatal extracorporeal membrane oxygenation. Lancet 1996; 348(9020):75-82.
28. Kolobow T, Gattinoni L, Tomlinson T, Pierce JE: Control of artificial breathing using an extracorporeal membrane lung. Anesthesiology 1977, 46:138-141.
29. Gattinoni L, Pesenti A, Mascheroni D, et al.: Low-frequency positive pressure ventilation with extracorporeal CO2-removal in severe acute respiratory failure. JAMA 1986, 256:881-886.
30. Extracorporeal Life Support Organization: Extracorporeal Life Support Registry. Ann Arbor, Michigan: Extracorporeal Life Support Organization, 1995.
31. Lewandowski K. Extracorporeal membrane oxygenation for sever acute respiratory failure. Crit Care 2000;4:156-168 doi:10.1186/ cc689.
32. Morris AH, Wallace CJ, Menlove RL, et al: Randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome. Am J Respir Crit Care Med 1994,149:295-305
33. Davies A, Jones D, Bailey M, Beca J, Bellomo R, Blackwell N, etal. Extracorporeal membrane oxygenation for 2009 influenzaA(H1N1l acute respiratory distress syndrome. JAMA 2009;302(17):1888-1895.
34. Freed DH, Henzler D, White CW, Fowler R, Zarychanski R, HutchisonJ, et al. Extracorporeal lung support for patients who had severe respiratory failure secondary to influenza A (H1N1) 2009 infectionin Canada. Can J Anaesth 2010;57(3):240-247.
35. Nair P, Davies AR, Beca J, Bellomo R, Ellwood D, Forrest P, et al.Extracorporeal membrane oxygenation for severe ARDS in pregnant and postpartum women during the 2009 H1N1 pandemic. Intensive Care Med 2011;37(4):648-654.
36. Peek GJ, Mugford M, Tiruvoipati R, etal. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet 2009;374:1351-63.
37. Combes A, Pellegrino V. Extracorporeal membrane oxygenation for 2009 influenza A H1N1-associated acute respiratory distress syndrome. Semin Respir Crit Care Med 2011; 32:18894.
38. Pham T, Combes A, Roze H, et al. Extracorporeal membrane oxygenation for pandemic influenza AH1 N1-induced acute respiratory distress syndrome: a cohort study and propensity-matched analysis.
39. Am J Respir Crit Care Med 2013;187:276-85.
40. Noah MA, Peek GJ, Finney SJ, et al. Referral to an extracorporeal membrane oxygenation center and mortality among patients with severe 2009 influenza AH1N1. JAMA 2011; 306:1659-68.
41. Miller RR III, Markewitz BA, Rolfs RT, et al. Clinical findings and demographic factors associated with ICU admission in Utah due to novel 2009 influenza AH1N1 infection. Chest 2010;137:752-8.
42. Ai-Ping C, Lee KH, Lim TK. In-hospital and 5-year mortality ofpatients treated in the ICU for acute exacerbation of COPD: aretrospective study. Chest 2005;128:518-24.
43. Bekaert M, Timsit JF, Vansteelandt S, et al. Attributable mortality of ventilator-associated pneumonia: a reappraisal using causal analysis.Am J Respir Crit Care Med 2011;184:1133-9.
44. Brederlau J, Wurmb T, Wilczek S, et al. Extracorporeal lung assist might avoid invasive ventilation in exacerbation of COPD. Eur Respir J 2012;40:783-785.
45. Kluge S, Braune SA, Engel M, et al . Avoiding invasive mechanical ventilation by extracorporeal carbon dioxide removal in patients failing noninvasive ventilation. Intensive Care Med 2012;38:1632-1639.
46. Cardenas VJ Jr, Lynch JE, Ates R, Miller L, Zwischenberger JB. Venovenous carbon dioxide removal in chronic obstructive pulmonary disease: experience in one patient. ASAIO J 2009;55:420-422.
47. Wang D, Zhou X, Liu X, Sidor B, Lynch J, Zwischenberger JB. Wang-Zwische double lumen cannula-toward a percutaneous and ambulatory paracorporeal artificial lung. ASAIO J 2008;54:606-61 1.
48. Javidfar J, Brodie D, Wang D, Ibrahimiye AN, Yang J, Zwischenberger JB, Sonett J, Bacchetta M. Use of bicaval dual-lumen catheter for adult venovenous extracorporeal membrane oxygenation. Ann Thorac Surg 2011;91:1763-1768
49. Arabia FA, Smith RG, Rose DS, et al. Success rates of long-term circulatory assist devices used currently for bridge to heart transplantation. ASAIO J 1996;42:M542-6
50. Birks EJ, Yacoub MH, Banner NR, et al. The role of bridge to transplantation: should LVAD patients be transplanted? Curr Opin Cardiol 2004;19:148-53.
51. Maurer JR, Frost AE, Estenne M, Higenbottam T, Glanville AR, for The International Society for Heart and Lung Transplantation, the American Thoracic Society, the American Society of Transplant Physicians, the European Respiratory Society. International guidelines for the selection of lung transplant candidates. Transplantation 1998;66:951-6.
52. George TJ, Beaty CA, Kilic A, Shah PD, Merlo CA, Shah AS.Outcomes and temporal trends among high-risk patients after lung transplantation in the United States. J Heart Lung Transplant 2012; 31:1182-91.
53. Javidfar J, Brodie D, Iribarne A, et al. Extracorporeal membrane oxygenation as a bridge to lung transplantation and recovery. J Thorac Cardiovasc Surg 2012;144:716-21.
54. Mason DP, Thuita L, Nowicki ER, Murthy SC, Pettersson GB,Blackstone EH. Should lung transplantation be performed for patients on mechanical respiratory support? The US experience. J Thorac Cardiovasc Surg 2010;139:765-73.
55. Hoopes CW, Kukreja J, Golden J, et al. Extracorporeal membrane oxygenation as a bridge to pulmonary transplantation. J Thorac Cardiovasc Surg 2013; 145:862-7
56. Toyoda Y, Bhama JK, Shigemura N, et al. Efficacy of extracorporeal membrane oxygenation as a bridge to lung transplantation. J Thorac Cardiovasc Surg 2013; 145:1065-70
57. Lafarge M, Mordant P, Thabut G, et al. Experience of extracorporeal membrane oxygenation as a bridge to lung transplantation in France. J Heart Lung Transplant 2013; 32:905-13.
58. Chen YS, Lin JW, Yu HY, et al. Cardiopulmonary resuscitation with assisted extracorporeal life-support versus conventional cardiopulmonary resuscitation in adults with in-hospital cardiac arrest: an observational study and propensity analysis. Lancet 2008; 372:554-61.
59. Shin TG, Choi JH, Jo IJ, et al. Extracorporeal cardiopulmonary resuscitation in patients with inhospital cardiac arrest: a comparison with conventional cardiopulmonary resuscitation. Crit CareMed 2011;39:1-7.
60. Shin TG, Jo IJ, Sim MS, et al. Two-year survival and neurological outcome of in-hospital cardiac arrest patients rescued by extracorporeal cardiopulmonary resuscitation. Int J Cardiol 2013; 168:3424-30
61. Maekawa K, Tanno K, Hase M, Mori K, Asai Y. Extracorporeal cardiopulmonary resuscitation for patients with out-of-hospi-tal cardiac arrest of cardiac origin: a propensity-matched study and predictoranalysis. Crit Care Med 2013;41:1186-96.
62. Stub D, Bernard S, Pellegrino V, et al. Refractory cardiac arrest treated with mechanical CPR, hypothermia, ECMO and early reperfusion (the CHEER trial). Resuscitation, 86, 88-94.
63. Abrams DC, Brodie D, Rosenzweig EB, Burkart KM, Agerstrand CL, Bacchetta MD. Upper-body extracorporeal membrane oxygenation as a strategy in decompensated pulmonary arterial hypertension. Pulm Circ 2013;3:432-5.
64. Rosenzweig E, Brodie D, Abrams D, Agerstrand C, Bacchetta M.Extracorporeal membrane oxygenation as a novel bridging strategy for acute right heart failure in group 1 PAH. ASAIO J 2014;60:129-33.
65. Maggio P, Hemmila M, Haft J, Bartlett R. Extracorporeal life support for massive pulmonary embolism. J Trauma 2007; 62:570-6.
66. Hashiba K, Okuda J, Maejima N, Iwahashi N, et al. Percutaneous cardiopulmonary support in pulmonary embolism with cardiac arrest. Resuscitation, 83(2), 183-187.
67. Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational therapy in mechanically ventilated,critically ill patients: a randomised controlled trial. Lancet 2009; 373:1874-82.
68. Needham DM, Korupolu R, Zanni JM, et al. Early physical medicine and rehabilitation for patients with acute respiratory failure: a quality improvement project. Arch Phys Med Rehabil 2010; 91:536-42.
