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Respiratory failure in adults represents the final common pathway for a wide range of dis-eases and is associated with substantial mor-bidity and mortality [13]. Early reports in the 1970s revealed mortality for adults with severe acute hypoxemic respiratory failure to be 8590% [46]. Despite years of focused research and advancements in therapies, mortality in these patients has improved but remains high, at approximately 2040% [1,2]. In this article, we will review the development of extracorpo-real life support and the evidence supporting its use in the setting of severe acute respiratory failure in adults.

HistoryOne of the guiding principles that has led to improved survival in patients with severe acute respiratory failure has been the use of lung-pro-tective ventilatory strategies. It has been dem-onstrated in both laboratory and clinical studies that even brief periods of mechanical ventila-tion lead to interstitial lung damage secondary to ventilator-induced lung injury (VILI) [3,710]. VILI is further worsened in patients requir-ing increased levels of ventilator support, even in patients without prior evidence of lung dis-ease [11,12]. Increased ventilatory requirements

not only lead to worsening lung injury but have also been linked to increased mortality. A study published by the Acute Respiratory Distress Syndrome (ARDS) Network investigators in 2000 demonstrated that, in adult patients with ARDS, mortality was significantly reduced sec-ondary to a reduction in tidal volume from 12 to 6 ml/kg along with a limitation of plateau pressure below 30 cm H

2O [11].

If lung protection is a gateway to improved outcomes in patients with ARDS, then one may speculate that extracorporeal life support, pro-vided in the form of extracorporeal membrane oxygenation (ECMO), could lead to dramatic improvements in overall mortality in patients with severe acute respiratory failure. ECMO provides either cardiac and/or pulmonary sup-port as an alternate means of gas exchange to immediately improve oxygenation and ventila-tion. ECMO also allows providers to decrease ventilatory support below toxic settings to rest the lungs while the patient recovers from the underlying insult.

Extracorporeal membrane oxygenation was first developed and implemented in 1971 in an adult trauma patient. The first successful use of ECMO in a neonate occurred in 1974 [13,14], and since the 1980s, its use in the setting of

Kyle J Rehder1, David A Turner1 and Ira M Cheifetz11Duke University Medical Center, Division of Pediatric Critical Care Medicine, Durham, NC, USA Author for correspondence:Tel.: +1 919 681 3550 Fax: +1 919 681 8357 [email protected]

Extracorporeal membrane oxygenation (ECMO) is a recognized and accepted therapeutic option in the treatment of neonatal and pediatric respiratory failure. However, early studies in adults did not demonstrate a survival benefit associated with the utilization of ECMO for severe acute respiratory failure. Despite this historical lack of benefit, use of ECMO in adult patients has seen a recent resurgence. Local successes and a recently published randomized trial have both demonstrated promising results in an adult population with high baseline mortality and limited therapeutic options. This article will review the history of ECMO use for respiratory failure; investigate the driving forces behind the latest surge in interest in ECMO for adults with refractory severe acute respiratory failure; and describe potential applications of ECMO that will likely increase in the near future.

Keywords: acute lung injury adult etiology extracorporeal membrane oxygenation H1N1 subtype influenza A virus mechanical ventilation mortality respiratory distress syndrome respiratory insufficiency therapy

Use of extracorporeal life support in adults with severe acute respiratory failureExpert Rev. Respir. Med. 5(5), 627633 (2011)

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cardiorespiratory failure has increased dramatically [15]. Outcomes in neonates have been extremely positive, with multiple trials demonstrating a survival benefit with ECMO as compared with standard therapies [1618]. In neonates, it is clear that the lung rest provided by ECMO can be successful in a variety of respira-tory diseases, including respiratory distress syndrome, meconium aspiration syndrome, persistent pulmonary hypertension of the newborn, congenital diaphragmatic hernia and sepsis.

Similarly, ECMO is commonly used for pediatric respiratory failure, despite the lack of randomized controlled trials to sup-port this practice. Overall ECMO survival in pediatric respira-tory failure is approximately 55% in a cohort of patients with an extremely high mortality without ECMO [15,1921].

By contrast, the initial clinical trial of ECMO in adults, per-formed by the NIH in the 1970s, demonstrated no benefit in the management of patients with venoarterial ECMO as com-pared with conventional therapy, with mortality rates greater than 90% in both groups [6]. However, in this study, ventilator settings remained largely unchanged in both the ECMO and non-ECMO groups, negating the potential benefit of lung protection or lung rest during ECMO.

Subsequently, Gattinoni et al. used low-flow venovenous (VV) ECMO in a series of 43 adult respiratory failure patients [22]. In this investigation, the focus was on removal of carbon dioxide with the artificial membrane while also decreas-ing ventilator support. The results of this study were more prom-ising, showing 49% survival in patients receiving extracorporeal support, but there was no control group for comparison [22]. An additional randomized control trial of 40 adult ARDS patients compared inverse-ratio ventilation coupled with ECMO to con-ventional mechanical ventilation. Overall survival was 38%, but again, no survival benefit was demonstrated for the ECMO cohort [23].

Given these two randomized controlled trials, demonstrat-ing lack of survival benefit with ECMO in adult patients, the use of this technology in adults has been limited until recently, with adults representing only 7% of respiratory ECMO patients reported to the Extracorporeal Life Support Organization data-base [15]. However, technological advances, continued experience and honing of techniques have increased survival of adults with respiratory failure treated with ECMO to 56% for the years 20062010 [15], with higher rates of survival for viral pneumo-nias [15,24,25]. Despite the lack of earlier studies demonstrating clinical benefit, these local successes, along with the clear benefits of EMCO in neonatal and pediatric patients, have led to grow-ing recent interest in the utilization of ECMO for severe acute respiratory failure in the adult population.

Technological advances and refined techniques have been crucial to improved ECMO successes. New polymethylpentene oxygenators, heparin-coated circuits and centrifugal pumps have significantly extended the life of ECMO circuits, reducing inflammatory response and blood loss with pump changes [26]. Improved anticoagulation practices and percutaneous placed catheters have minimized major bleeding episodes, a major complication in the initial NIH randomized trial [4,6,27,28].

Finally, the selective use of VV ECMO over venoarterial ECMO has also been associated with reduced morbidity and mortality [15,29].

Naturally, as extracorporeal support technology and expe-rience have advanced, mechanical ventilation strategies and technology have also advanced, further obscuring the optimal treatment for severe acute respiratory failure. The use of low tidal volume, open-lung ventilator strategies have coupled with improved medical management with antibiotics, diuretics, glucocorticoids and possibly neuromuscular blocking agents to dramatically improve survival in conventionally managed patients [1,3039].

Even in the setting of improved outcomes with conventional therapies, two recent events have reignited the continued debate about the use of ECMO for severe acute respiratory failure in adults. First, in the spring of 2009, a new influenza strain (H1N1 influenza) led to dramatic increases in hypoxemic respiratory failure in otherwise healthy, young adults, many of which were refractory to conventional therapy. In many of these patients, ECMO was successfully utilized with reported survival rates ranging from 66 to 86% [24,4044]. The second, concurrent event was the publication of a novel randomized control trial demon-strating significant disability-free mortality benefit to ECMO compared with standard management for adult respiratory fail-ure, which is described in more detail later [45]. In both cases, results for patients receiving ECMO were favorable, suggesting that ECMO may be the optimal therapy for adult patients with refractory acute respiratory failure.

ECMO resurgence during the 2009 H1N1 influenza pandemicThe 2009 outbreak of the novel H1N1 influenza virus led to an unexpected increase in the use of ECMO for adult respiratory failure [24,40,4244,46]. In contrast to typical seasonal influenza outbreaks which have the greatest morbidity for the very young and very old, the 2009 H1N1 influenza strain caused signifi-cant morbidity and mortality in young adults [47]. When physi-cians were faced with profound severe acute respiratory failure in these otherwise healthy adults, they turned to ECMO as means of supporting their patients through what was felt to be a time-limited, reversible disease. ECMO was utilized in these situations despite the lack of data demonstrating convincing clinical benefit.

The first published ECMO experience for H1N1-associated ARDS came out of Australia and New Zealand in late 2009 [24]. This retrospective, observational study of 15 intensive care units (ICUs) compared 68 patients with influenza associated ARDS treated with ECMO to 133 patients who received conventional management. At the time of reporting, 71% of the ECMO patients had survived to ICU discharge, with 21% mortality and 8% remaining in the hospital. By comparison, the non-ECMO cohort had 13% mortality at the time of reporting. Patients who were treated with ECMO had a significantly longer duration of mechanical ventilation, ICU length of stay and hospital length of stay when compared with the non-ECMO group.

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In this series, as ECMO was used as a rescue therapy once conventional therapies failed, it is not surprising that the ECMO cohort had a higher mortality than the non-ECMO cohort. However, the survival of the ECMO cohort was greater than the 55% mortality that would have been expected based on the ELSO database for adult patients with severe acute respiratory failure [15]. It is unclear whether the survival benefit demonstrated in this study was: related to an unknown feature of the novel influenza strain; because the ECMO cohort was a relatively young and previ-ously healthy population prior to their infection (median age: 36 vs 44; p = 0.02 and a lower likelihood of Acute Physiology and Chronic Health Evaluation [APACHE III] comorbidities: 8 vs 23%, p = 0.02); or due improvements in the application of ECMO technology. In addition, data would also suggest that viral pneu-monia responds well to ECMO therapy, with a cumulative survival of 65% [15]. Regardless of the cause, the promising mortality rates reported early in the H1N1 epidemic led to relative increased use of ECMO for H1N1-related severe acute respiratory failure [4244,46].

Worldwide, the 2009 H1N1 epidemic led to a dramatic increase in reported ECMO use for adult respiratory failure, with 420 cases in 2009 compared with 186 in 2008 and 151 in 2007; with a similar increase noted in pediatric patients [15]. Ultimately, between 5 and 30% of critically ill adults (defined as patients admitted to ICUs or mechanically ventilated patients) with 2009 H1N1 influenza were treated with ECMO, with other centers reporting survival rates similar to the Australia and New Zealand cohort [24,40,44,47].

The success of ECMO during the H1N1 pandemic raised many questions regarding resource management during wide-spread pandemics [25,48]. Ethically, providers may not be able to withhold a treatment with clear benefit, yet the resource-intensive nature of ECMO may limit its use for every potential patient during a widespread outbreak. In adults, this dilemma is further complicated by the prior data suggesting a lack of benefit related to the use of ECMO [6,23]. In addition, on an institutional level, the utilization of ECMO in an area with unproven benefit, such as adult ARDS, may also impact the ability of a center to provide ECMO for critically ill infants and children with a much bet-ter established survival benefit. This conflict demonstrates the importance of continued investigation to identify prospective predictors of successful outcomes.

Is ECMO the answer when conventional therapy fails? The CESAR trialDirect comparisons of outcomes for patients receiving conven-tional support versus ECMO are daunting for many reasons. The first of these is that patients are generally only placed on ECMO as a rescue therapy; that is, only those patients who have failed conventional management, and likely have very high baseline mortality, progress to treatment with ECMO. Beyond the dispa-rate baseline mortality risk, questions remain regarding utiliza-tion of resources, ethics of consent and standards of conventional therapy [49,50].

Despite these challenges, Peek et al. in collaboration with the UKs National Health Service, completed an ambitious random-ized control study of ECMO Versus Conventional Management

for Severe Adult Respiratory Failure (CESAR trial) [45]. In con-trast to neonatal and pediatric respiratory failure where ECMO is a widely accepted treatment option, the role of ECMO in adult respiratory failure retained clinical equipoise, given the prior data demonstrating lack of benefit of ECMO for this population.

Publication of the CESAR trial, which was completed imme-diately prior to the H1N1 pandemic, likely contributed to the dramatic upswing in ECMO utilization in late 2009 and early 2010. This randomized control trial identified adults aged 1865 years with severe but potentially reversible respiratory failure. A total of 180 patients were randomized to continue con-ventional therapy at tertiary ICUs or transfer to a single center (Glenfield Hospital, Leicester, UK) for potential use of ECMO for refractory respiratory failure. Patients in this study were treated exclusively with VV ECMO, and almost all had refrac-tory hypoxemic respiratory failure. Disability-free survival at 6 months in the ECMO referral group was 63% compared with 47% in patients treated with conventional therapy (relative risk: 0.69; p = 0.03). 6-month mortality also favored ECMO but did not reach statistical significance (relative risk: 0.73; p = 0.07). Patients referred for ECMO incurred about twice the length of hospital stay and twice the cost of hospitalization compared with the conventional therapy group.

It is important to note that this study provides an important assessment of referral to an ECMO center, rather than the use of ECMO alone. In this manner, the comparison also included the significant risk of transferring and transporting a critically ill patient to an ECMO center, as noted by the five patients ran-domized to the ECMO arm and included in the analysis, but who died prior to arrival at the ECMO center. Despite these deaths, disability-free survival was still significantly improved in the ECMO referral group. However, only 63 of the 85 surviving ECMO referral patients were actually treated with ECMO, which is consistent with this authors experience of patients referred for consideration of ECMO.

A major criticism of the CESAR trial is the lack of a formal-ized ventilator management strategy at the tertiary ICUs for the conventional therapy group in comparison with the likely more standardized approach to ventilator management at the single ECMO referral center [50]. But again, this scenario is commonly encountered in clinical practice and is an important issue involved in the clinical practice of managing this complex population of patients. Generalizability of this study has also been questioned given that it represented a single ECMO referral center [50].

Despite the criticisms, the CESAR trial represents our only direct comparison of conventional management of severe acute respiratory failure with ECMO in the modern era of lung-pro-tective ventilation. The results are promising and support the continued development and use of ECMO for refractory respira-tory failure in adult patients [51]. While further data are needed, these data and recent experience with ECMO contradict the traditional notion that ECMO should be limited to neonates, infants and children, and may represent the beginning of an exciting new era in the management of refractory respiratory failure in adults.

Use of extracorporeal life support in adults with severe acute respiratory failure


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Expert commentaryProviders experienced with ECMO will attest to patients lives that have been saved utilizing this technology. In particular, neonatal and pediatric practitioners have had great successes with ECMO, yet the benefit in adult respiratory failure is still questioned [50,52,53]. The aforementioned recently published adult studies demonstrating that ECMO may also be of substantial benefit in adults with severe acute respiratory failure have re-energized the discussion around the use of ECMO in adults. The potential value of ECMO for adult respiratory failure has yet to be quantified, but excitement surrounds the increasing experience and success with ECMO in adult populations.

This application of ECMO in adult populations represents the unique scenario in which neonatal and pediatric experience and evidence are being applied to adult populations. Most ECMO centers have a well-structured and organized program for both neonatal and pediatric patients, and as interest in ECMO for adult respiratory failure intensifies, it is imperative to highlight the multidisciplinary team required to develop a successful ECMO program. As adult ECMO programs develop, both independently and in conjunction with existing neonatal and pediatric programs, it is essential to recognize the crucial nature of the collaborative effort required of intensivists, surgeons, respiratory therapists, perfusion specialists and nurses to safely and effectively manage patients with this complex technology [54].

Five-year view: future directions & remaining questionsIn the coming years, providers will continue to refine manage-ment strategies for ECMO patients, including the optimal timing of initiating and weaning from ECMO support. It is clear that the strategy of resting the lungs on ECMO can be life saving in the setting of severe acute respiratory failure, but the optimal ventilator strategies on ECMO, including the mode of ventila-tion, requires careful study. In addition, more research is required regarding the application of other adjunctive therapies for adults with severe acute respiratory failure. The use of steroids to pre-vent the fibrotic stage of ARDS likely still applies to patients on ECMO [33]. However, it is unknown if surfactant may be benefi-cial during an ECMO course. Similarly, airway clearance is often

an important aspect of therapy for adults with respiratory failure of multiple etiologies, yet the riskbenefit ratio of aggressive chest physiotherapy and/or bronchoscopy in an anticoagulated ECMO patient also remains unknown.

Other standard management strategies may also be affected by ECMO. One area of growing research is the pharmacodynamics of medicines used for patients on ECMO, most notably antimi-crobials. Adequate treatment for proven or presumed infections in these critically ill patients is essential, and we are still limited in our knowledge of how potential drug interactions with the artificial membrane and tubing associated with ECMO may affect an individual patients volume of distribution and medication dosing [5560].

Another important ongoing consideration is the potential need to transport these critically ill patients. There is substan-tial risk associated with transporting these potential ECMO patients, as evidenced by the five deaths in the CESAR trial prior to arrival at the ECMO referral center. A potential solu-tion is mobile ECMO, where specialists from the tertiary hos-pital initiate ECMO at the referral hospital prior to patient transfer. Several centers have successfully developed mobile ECMO programs of this nature [6164]. It is reasonable to expect more mobile ECMO programs to be developed in the future to aid in the safe transfer of these unstable and critically ill patients, but resource utilization, safety, and regulatory issues are key considerations. To this end, efforts have been made to develop smaller, transportable ECMO circuits [51,65,66]. These simplified circuits may also be used with increased frequency in intensive care units as they may lessen the personnel staffing burden of ECMO, however, patient safety dictates that ECMO providers must strike a balance between lower complexity and appropriate monitoring.

It is still uncertain how far boundaries may be pushed with ECMO to help patients who may have no other chance for sur-vival. Our center, among others, has begun using ambulatory VV ECMO for critically ill adolescents and adults as a bridge to lung transplantation [54,67,68], who otherwise would have been not considered for transplant due to the severity of their illness [69,70]. While data thus far are limited, rapid recovery and shortened ICU stays after lung transplantation have been very promising

Key issues

Extracorporeal membrane oxygenation (ECMO) is a highly resource-intensive therapy and successful implementation requires extensive teamwork form surgeons, intensivists, respiratory therapists, perfusion specialists and nurses.

While ECMO may be associated with significant morbidity, higher cost and longer hospitalizations, it allows physicians to save the lives of some patients who would not survive on conventional therapy alone, and may provide decreased long-term morbidity when compared with conventional therapies.

Direct comparisons between ECMO and conventional therapies remain challenging, largely because ECMO is used as rescue therapy when conventional therapy is unable to meet clinical goals.

The overall survival for adults with severe acute respiratory failure treated with ECMO likely lies between 55 and 65%, with rates for adults with H1N1 influenza potentially being somewhat higher.

Many questions remain about the optimal management strategies for adult patients requiring ECMO for severe acute respiratory failure, including patient selection, the timing of initiation and weaning from ECMO, and adjunct therapies.

Innovative applications of ECMO may allow for expanded use, including the safe interhospital transfer of critically ill patients and the utilization of ECMO for new patient populations.



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in our ambulatory ECMO patients [54]. Similarly, case reports have shown successful use of ECMO in patients despite relative contraindications to ECMO, including recent trauma, multi-organ involvement and immunosuppression [7174,101]. It remains to be seen if any of the lessons learned in these unique patient populations might be applicable to other patients with severe acute respiratory failure treated with ECMO.

These many questions demonstrate the need for continued research into the optimal techniques and management strate-gies for patients requiring ECMO. Whenever possible, different strategies should be tested in a methodologically rigorous fashion. However, owing to the highly complex nature and rapid develop-ment of the technology and the previously mentioned difficulties

involved in direct comparisons of ECMO, it is likely that much of our knowledge will grow through continued center-specific experience and investigation as ECMO utilization increases for adults with severe acute respiratory failure.

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.



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Website

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