Success With VV ECMO for Respiratory Failure: Is it the Device, the Center, or Both?

In the current issue of the Journal of Cardiothoracic and Vascular Anesthesia, Buchner et al present the results of their single-center retrospective cohort study of patients with influenza associated acute respiratory distress syndrome (ARDS) treated with extracorporeal membrane oxygenation (ECMO) or conventional ventilator therapy at a single center during the 2015 to 2016 influenza season.1Buchner J. Mazzeffi M. Kon Z. et al.Single center experience with veno-venous ECMO for influenza related ARDS.J Cardiothorac Vasc Anesth. 2017Google Scholar This trial is interesting because despite the lack of strong clinical trial evidence demonstrating improvements in either short or long-term mortality, the use of venovenous extracorporeal membrane oxygenation (VV ECMO) for severe ARDS has increased substantially over the past decade.2Schmidt M. Outcomes and complications of adult respiratory ECLS.in: Brogan T.V. Extracorporeal Life Support: The ELSO Red Book. Extracorporeal Life Support Organization, Ann Arbor, MI2017Google Scholar, 3Zapol W.M. Snider M.T. Hill J.D. et al.Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study.JAMA. 1979; 242: 2193-2196Crossref PubMed Scopus (1183) Google Scholar, 4Morris A.H. Wallace C.J. Menlove R.L. 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: 295-305Crossref PubMed Scopus (754) Google Scholar Furthermore, because of this lack of evidence, critical care physicians often reserve ECMO therapy for patients who are imminently dying, and sometimes do, prior to being placed on ECMO. This is largely the result of 2 factors. The first was the publication of the conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR) trial in 2009. CESAR was a large randomized trial that evaluated referral for treatment in an ECMO center versus continued conventional treatment at the referring hospital in adults with severe ARDS, and demonstrated improvements in short and long-term mortality for patients referred to the ECMO center.5Peek G.J. Mugford M. Tiruvoipati R. 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. 2009; 374: 1351-1363Abstract Full Text Full Text PDF PubMed Scopus (2365) Google Scholar The second was the relatively low observed mortality in the published experience of centers using ECMO to treat severe ARDS due to pandemic H1N1 influenza in 2009 given the severity of illness among these patients compared with the much higher mortality rate from published registry data at the time.6Davies A. Jones D. et al.Australia and New Zealand Extracorporeal Membrane Oxygenation (ANZ ECMO) Influenza InvestigatorsExtracorporeal membrane oxygenation for 2009 influenza A(H1N1) acute respiratory distress syndrome.JAMA. 2009; 302: 1888-1895Crossref PubMed Scopus (1293) Google Scholar, 7Brogan T.V. Thiagarajan R.R. Rycus P.T. et al.Extracorporeal membrane oxygenation in adults with severe respiratory failure: A multi-center database.Intensive Care Med. 2009; 35: 2105-2114Crossref PubMed Scopus (343) Google Scholar The CESAR trial evaluated referral to an ECMO center (rather than initiation of ECMO therapy or even intention to treat with ECMO) versus conventional therapy (provided in a hospital other than the study center) as an intervention. This is an important distinction, as only 75% of patients referred to an ECMO center in the study actually received ECMO with the other 25% receiving medical therapy at the ECMO center. Another significant criticism of this study was the lack of a protocol for treatment of controls, which were managed at the referring hospital. Given the potential for significant differences in the management of severe ARDS at a specialized ECMO referral center and the referring hospital, the study could not differentiate the benefit of ECMO per se from that of strict adherence to lung protective ventilation strategies, and appropriate use best practices for ARDS other than ECMO in the experimental group. This is particularly important as the authors noted significant differences in adherence to lung protective ventilation between the 2 groups.5Peek G.J. Mugford M. Tiruvoipati R. 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. 2009; 374: 1351-1363Abstract Full Text Full Text PDF PubMed Scopus (2365) Google Scholar, 8Wallace D.J. Milbrandt E.B. Boujoukos A. Ave, CESAR, morituri te salutant! (Hail, CESAR, those who are about to die salute you!).Crit Care. 2010; 14: 308Crossref PubMed Google Scholar Although Buchner et al was a retrospective analysis conducted on a small cohort, it has several advantages over previous publications. Patient selection was limited to individuals with PCR proven influenza, age under 70, and mechanical ventilation of less than 10 days prior to ECMO initiation, thus removing some of the heterogeneity of the etiology of the acute lung injury present in similar studies. All patients were cared for in the same medical center, albeit in different ICUs, using lung protective ventilation strategies. While some differences did exist between the 2 groups, with respect to tidal volumes, prone positioning, and the use of pulmonary vasodilators, their care was more similar than in the CESAR trial, allowing a more direct comparison between the 2 groups with respect to ECMO initiation.5Peek G.J. Mugford M. Tiruvoipati R. 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. 2009; 374: 1351-1363Abstract Full Text Full Text PDF PubMed Scopus (2365) Google Scholar Despite the lack of high quality evidence due to the lack of prospective clinical trials, there is abundance of physiologic rationale for using ECMO in patients with severe ARDS. Our current understanding of appropriate ventilator management of ARDS favors lung protective ventilation—limiting barotrauma, volutrauma, atelectotrauma, and oxygen toxicity by maintaining low tidal volumes, peak airway pressures, and a lower FIO2 while titrating positive end-expiratory pressure to keep alveoli open and limit cyclical injury from collapse and overdistension. While lung protective ventilation strategies are rational and well supported in the literature, patients with the most severe forms of lung injury, (arguably the ones most susceptible to ventilator induced lung injury) may be difficult to oxygenate and ventilate using a lung protective strategy. Additionally, these sick patients may have smaller volumes of remaining aerated lung that are susceptible to ventilator induced lung injury despite using lung protective strategies with low tidal volumes.9.Schmidt M. Pellegrino V. Combes A. et al.Mechanical ventilation during extracorporeal membrane oxygenation.Crit Care. 2014; 18: 203Crossref PubMed Scopus (120) Google ScholarSchmidt 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: 1704-1713Crossref PubMed Scopus (382) Google Scholar ECMO, by supporting gas exchange independent of positive pressure ventilation, allows stricter adherence to lung protective ventilator strategies, with some investigators proposing “ultra-protective mechanical ventilation” with tidal volumes as low as 1.9 mL/Kg, or even apneic ventilation in these patients.9.Schmidt M. Pellegrino V. Combes A. et al.Mechanical ventilation during extracorporeal membrane oxygenation.Crit Care. 2014; 18: 203Crossref PubMed Scopus (120) Google ScholarSchmidt 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: 1704-1713Crossref PubMed Scopus (382) Google Scholar Despite this knowledge, there still remains a paucity of high quality clinical evidence to demonstrate efficacy and safety, limiting our ability to define ECMO as the standard of care for severe ARDS due to any cause. Although the negative results of early studies are easy to dismiss today given significant refinements in the equipment, a better understanding of mechanical ventilation management, and protocols used to provide ECMO that have improved efficiency of oxygenation and carbon dioxide elimination while reducing the initially reported high rates of device complications and bleeding, more recent randomized controlled trials and observational studies have still failed to demonstrate adequately that ECMO itself provides more benefit than risk in severe ARDS.3Zapol W.M. Snider M.T. Hill J.D. et al.Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study.JAMA. 1979; 242: 2193-2196Crossref PubMed Scopus (1183) Google Scholar, 4Morris A.H. Wallace C.J. Menlove R.L. 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: 295-305Crossref PubMed Scopus (754) Google Scholar, 5Peek G.J. Mugford M. Tiruvoipati R. 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. 2009; 374: 1351-1363Abstract Full Text Full Text PDF PubMed Scopus (2365) Google Scholar, 6Davies A. Jones D. et al.Australia and New Zealand Extracorporeal Membrane Oxygenation (ANZ ECMO) Influenza InvestigatorsExtracorporeal membrane oxygenation for 2009 influenza A(H1N1) acute respiratory distress syndrome.JAMA. 2009; 302: 1888-1895Crossref PubMed Scopus (1293) Google Scholar In 2014, a large meta-analysis of randomized controlled trials and cohort studies comparing ECMO with mechanical ventilation, which included 1,248 patients, was unable to demonstrate a difference in in-hospital mortality between the 2 groups.10Munshi L. Telesnicki T. Walkey A. et al.Extracorporeal life support for acute respiratory failure. A systematic review and metaanalysis.Ann Am Thorac Soc. 2014; 11: 802-810Crossref PubMed Scopus (45) Google Scholar Although they did find a significant mortality benefit when they restricted their analysis to higher quality trials, they admitted that the results of this subgroup analysis were influenced heavily by the CESAR trial with its attendant limitations.10Munshi L. Telesnicki T. Walkey A. et al.Extracorporeal life support for acute respiratory failure. A systematic review and metaanalysis.Ann Am Thorac Soc. 2014; 11: 802-810Crossref PubMed Scopus (45) Google Scholar Negative or equivocal results such as these could be the result of heterogeneity of inclusion and exclusion factors, as well as the timing of initiation of ECMO and lack of standardization of care among controls in observational studies. They also highlight the difficulty of conducting high-quality clinical research among such critically ill patients. However, the lack of demonstrated efficacy for ECMO is striking, given the significant vascular, hemorrhagic, embolic, infectious, and circuit-related complications that still exist for this form of therapy, as well as the resource and economic burden of initiating ECMO. In the CESAR trial, investigators found that the use of ECMO on average doubled the cost of care to an individual patient in the UK national health system.5Peek G.J. Mugford M. Tiruvoipati R. 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. 2009; 374: 1351-1363Abstract Full Text Full Text PDF PubMed Scopus (2365) Google Scholar While the authors cautioned against directly applying their cost analysis to different healthcare delivery systems it is clear that the costs, risks, and care burdens for ECMO are high, and in the absence of high-quality clinical evidence to support its use it will continue to be provided sporadically on a case-by-case basis. Hopefully, the ongoing multicenter, randomized, controlled trial Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome (EOLIA) (ClinicalTrials.gov NCT01470703) will address several of these methodological issues and provide clearer guidance as to the timing and indications for initiating ECMO therapy as well as a better understanding of the complications; but it is clear that more clinical research is necessary. The current study is a notable addition to the VV ECMO literature for its standardization of indications and controls and offers valuable evidence of the efficacy in this patient population. The study again emphasizes the role of treating these patients in a dedicated lung rescue unit by a multidisciplinary team of experts who rapidly can identify and treat these critically ill patients. Patients in the ECMO group had lower in hospital mortality and a five-fold improvement in survival. However, its small size and narrow focus on influenza patients limits our ability to draw additional conclusions or generalize their findings.