UBC Faculty Research and Publications

Trends in extra-corporeal membrane oxygenation for the treatment of acute respiratory distress syndrome… Rush, Barret; Wiskar, Katie; Berger, Landon; Griesdale, Donald 2016

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Trends in extra-corporeal membrane oxygenation for the treatment of acute respiratory distress syndrome in the United States  Barret RUSH, bar890@mail.harvard.edu1,2 Katie WISKAR, katiewiskar@gmail.com1  Landon BERGER, bergerlandon@gmail.com1,3 Donald GRIESDALE, donald.griesdale@vch.ca1,3,4  1. Division of Critical Care Medicine, Department of Medicine, Vancouver General Hospital, University of British Columbia, Room 2438, Jim Pattison Pavilion, 2nd Floor, 855 West 12th Avenue, Vancouver, BC, V5Z 1M9, Canada 2. Harvard T.H. Chan School of Public Health, Harvard University, 677 Huntington Ave, Boston, MA 02115 3. Department of Anesthesia, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada 4. Centre for Clinical Epidemiology and Evaluation, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada   Send Correspondence to:   Dr. Barret Rush MD Division of Critical Care Medicine,  Department of Medicine,  Vancouver General Hospital,  University of British Columbia,  Room 2438, Jim Pattison Pavilion, 2nd Floor, 855 West 12th Avenue, Vancouver, BC,  V5Z 1M9, CANADA      Email: bar890@mail.harvard.edu    Word Count:   Figure Count:   Conflict of Interest: No authors disclose any conflicts of interest  Funding:  Dr. Griesdale is funded by the VGH & UBC Hospital Foundation Best of Health Fund.   Introduction  The acute respiratory distress syndrome (ARDS) is a state of diffuse inflammatory lung injury characterized by acute-onset, non-cardiogenic pulmonary edema with varying degrees of hypoxemia. Despite significant advances in intensive care, mortality from ARDS remains high.1–5  To date, the only interventions that have been shown to improve survival in ARDS are low tidal volume ventilation and prone positionin.6,7 The use of extra-corporeal membrane oxygenation (ECMO) for the treatment of ARDS has received significant attention in the past decade.  ECMO allows for extra-pulmonary gas exchange and very low tidal volume ventilation, “resting” the heart and lungs and buying time for treatment and recovery in cardiorespiratory failure. The 2014 Extra-corporeal Life Support Organization (ELSO) guidelines suggest that ECMO be considered in patients with high-risk hypoxic or hypercarbic respiratory failure despite optimal conventional ventilation.8  However, the role of ECMO in ARDS remains undefined. The 2012 ELSO registry report indicates increased use of ECMO for all-cause respiratory failure in the wake of the 2009 H1N1 influenza pandemic, but does not provide information about patient characteristics associated with ECMO use; nor does it focus on ARDS specifically.9  The goal of our study was to examine patterns of ECMO use for the treatment of ARDS in the United States between 2006 and 2011.      Materials and Methods We report our study in according to the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement.10  A waiver of consent was obtained from the University of British Columbia Institutional Review Board.  Study Population  For this retrospective cohort study, data from the Nationwide Inpatient Sample was examined for the years 2006-2011.  This nationally representative dataset captures approximately 20% of all United States hospital discharges.  It is a complex survey designed to produce national projections released by the Agency for Healthcare Research and Quality (AHRQ).    The cohort was obtained by isolating all patients greater than 18 years of age who had a discharge diagnosis of ARDS.  ICD9 codes for acute respiratory failure following trauma and surgery (518.51), other pulmonary insufficiency, not elsewhere classified, following trauma and surgery (518.52), acute and chronic respiratory failure following trauma and surgery (518.53), acute respiratory failure (518.81) and other pulmonary insufficiency, not elsewhere classified (518.82) were used to define ARDS, consistent with definitions of previous authors.11  Patients who had ICD9 procedure codes for ECMO (39.65 and 37.62) were then segregated from the overall ARDS group.  A flow diagram of patient selection is displayed in Figure 1.  We also queried for the use of inhaled nitric oxide (00.12).  Patient level factors gathered included age, gender, race (White, Black, Hispanic, other or missing), length of stay, hospital mortality, insurance status (coverage vs no coverage), and patient zip code income quartile.  Hospital characteristics obtained included teaching status (teaching vs non-teaching), size (as defined by the AHRQ), and region of the country (Northeast, Midwest, South, West).  Statistical Analysis Data were analyzed using complex survey procedures in SAS version 9.4 (SAS Institute, Cary, NC); national estimates were obtained with appropriate national weights.  Chi-squared tests were used for nominal or ordinal outcomes; independent t tests were used for continuous data.  Trend analysis was performed using linear regression.  All tests were performed at an alpha level of 0.05.  Results  A total of 47,911,414 hospital discharges were examined, representing 235,911,271 hospitalizations using national weights.  There were 1,479,022 discharges that met the definition of ARDS, representing 7,281,206 discharges.  There were 775 patients with a diagnosis of ARDS who underwent ECMO during the study period (Table 1).  Overall in-hospital mortality for the ECMO group was 58.6% versus 25.1% in the non ECMO cohort (p= <0.0001).  Length of stay was longer for patients who underwent ECMO, 15.8 (IQR 28.5) days vs 6.9 (IQR 10.3) days (p=<0.0001).  Patients treated with ECMO were younger, at 47.9 (SD 16.8) years vs 66.4 (SD 16.9) years (p=<0.0001), as well as less likely to be female, 37.7% vs 50.4% (p=<0.0001).  There was no difference in the use of ECMO by zip code income quartile.  Hospital characteristics associated with the use of ECMO included teaching status (92.0% vs 45.6% p=<0.0001) and large hospital size (86.7% vs 64.9% p=<0.0001).  The region of the country where care was delivered was not significant (p=0.11).  The trend in the use of ECMO for ARDS is displayed in Figure 2.  There was a 409% relative increase in the use of ECMO for ARDS in the United States between 2006 and 2011, from 0.0177% to 0.0901% (p=0.0041).  Discussion  There has been a dramatic increase in ECMO use for the treatment of ARDS in the United States.  Patients who receive ECMO are young males who have higher in-hospital mortality and are more likely to be treated in large teaching hospitals compared to those that do not receive ECMO. The increase in ECMO use seen in our study is consistent with ELSO registry data.9  There are several possible reasons for the dramatic uptake in use.  Most significantly, the successful use of ECMO in severe cases of ARDS during the H1N1 influenza epidemic, and the ensuing attention in the literature, led to renewed interest in the therapy.12–17  Furthermore, significant refinements in ECMO technology since its inception allow for easier, safer, and more widespread use.18  Our finding that young males are more likely to receive ECMO is consistent with scoring models proposed to estimate survival probability in ECMO patients, which show that both younger age and male gender are associated with improved survival.19,20  Patients who receive ECMO are more likely to be treated in large, tertiary academic hospitals is unsurprising given the resource-intensive, highly-specialized nature of the therapy.   The 59% percent mortality rate in ECMO patients in our study is concurrent with the latest ELSO registry paper, which showed a 51% mortality rate in adult patients undergoing VV-ECMO for ARDS.9  Other publications of heterogeneous study populations have reported a very wide range of mortality in ECMO-treated ARDS patients, ranging from 16% to 64%.17  The finding that ECMO patients have a higher mortality rate than the control group in our study is highly susceptible to selection bias, as it is usually the sickest patients who receive ECMO as a rescue measure.    The role of ECMO for ARDS remains hotly debated.21,22  Several recent meta-analyses cite insufficient high-quality evidence, as there is a paucity of well-designed randomized control trials, particularly in the current era of lung-protective ventilation.17,23  The CESAR trial seemed to support transfer to an ECMO-capable center for patients with severe ARDS, but results should be interpreted with caution given the lack of standardized therapy in the control group and differences in rates of lung-protective ventilation.24  Studies are underway that will hopefully provide more definitive answers about the role of ECMO and extra-corporeal CO2 removal in treating ARDS.14,25   The strength of our study lies in the use of a large, nation-wide dataset capturing 20 percent of all hospital admissions. This allows for excellent generalizability and accurate representation of the use of ECMO for ARDS in the United States.  The results of our study need to be interpreted in the context of the study design.  Retrospective observational studies based on discharge data are inherently susceptible to patient selection bias, as well as the possibility of coding errors.  Furthermore, we were unable to collect data on patient-level variables including etiology of ARDS, which may influence outcomes. Further high-quality trials are needed to clarify the role of ECMO in ARDS.   Conclusions  The use of ECMO for the treatment of ARDS in the United States increased by over 400% between 2006 and 2012.  Patients who receive ECMO are more likely to be younger males, and to be treated in large tertiary care hospitals. Mortality for the ECMO-treated group was 59%.  Further research is needed to clarify the role of ECMO in treating ARDS.   References 1.  Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med 2005;353(16):1685–93.  2.  Rubenfeld GD, Herridge MS. Epidemiology and outcomes of acute lung injury. Chest 2007;131(2):554–62.  3.  Zambon M, Vincent J-L. Mortality rates for patients with acute lung injury/ARDS have decreased over time. Chest 2008;133(5):1120–7.  4.  Phua J, Badia JR, Adhikari NKJ, et al. Has mortality from acute respiratory distress syndrome decreased over time?: A systematic review. Am J Respir Crit Care Med 2009;179(3):220–7.  5.  Villar J, Blanco J, Añón JM, et al. The ALIEN study: incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation. Intensive Care Med 2011;37(12):1932–41.  6.  Guérin C, Reignier J, Richard J-C, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013;368(23):2159–68.  7.  Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342(18):1301–8.  8.  Extracorporeal Life Support Organization. Guidelines for Adult Respiratory Failure [Internet]. 2013 [cited 2015 Aug 31];Available from: https://www.elso.org/Portals/0/IGD/Archive/FileManager/989d4d4d14cusersshyerdocumentselsoguidelinesforadultrespiratoryfailure1.3.pdf 9.  Paden ML, Conrad SA, Rycus PT, Thiagarajan RR, ELSO Registry. Extracorporeal Life Support Organization Registry Report 2012. ASAIO J Am Soc Artif Intern Organs 1992 2013;59(3):202–10.  10.  Vandenbroucke JP, von Elm E, Altman DG, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. Epidemiol Camb Mass 2007;18(6):805–35.  11.  Reynolds H, McCunn M, Borg U, Habashi N, Cottingham C, Bar-Lavi Y. Acute respiratory distress syndrome: estimated incidence and mortality rate in a 5 million-person population base. Crit Care 1998;2(1):29–34.  12.  Australia and New Zealand Extracorporeal Membrane Oxygenation (ANZ ECMO) Influenza Investigators, Davies A, Jones D, et al. Extracorporeal Membrane Oxygenation for 2009 Influenza A(H1N1) Acute Respiratory Distress Syndrome. JAMA 2009;302(17):1888–95.  13.  Zangrillo A, Biondi-Zoccai G, Landoni G, et al. Extracorporeal membrane oxygenation (ECMO) in patients with H1N1 influenza infection: a systematic review and meta-analysis including 8 studies and 266 patients receiving ECMO. Crit Care Lond Engl 2013;17(1):R30.  14.  Combes A. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome (EOLIA TRIAL) Clinical Trials Number NCT01470703 [Internet]. 2015;Available from: https://clinicaltrials.gov/show/NCT01470703 15.  Mitchell MD, Mikkelsen ME, Umscheid CA, Lee I, Fuchs BD, Halpern SD. A systematic review to inform institutional decisions about the use of extracorporeal membrane oxygenation during the H1N1 influenza pandemic. Crit Care Med 2010;38(6):1398–404.  16.  Munshi L, Telesnicki T, Walkey A, Fan E. Extracorporeal life support for acute respiratory failure. A systematic review and metaanalysis. Ann Am Thorac Soc 2014;11(5):802–10.  17.  Schmidt M, Hodgson C, Combes A. Extracorporeal gas exchange for acute respiratory failure in adult patients: a systematic review. Crit Care Lond Engl 2015;19:99.  18.  Del Sorbo L, Cypel M, Fan E. Extracorporeal life support for adults with severe acute respiratory failure. Lancet Respir Med 2014;2(2):154–64.  19.  Roch A, Hraiech S, Masson E, et al. Outcome of acute respiratory distress syndrome patients treated with extracorporeal membrane oxygenation and brought to a referral center. Intensive Care Med 2014;40(1):74–83.  20.  Schmidt M, Bailey M, Sheldrake J, et al. Predicting survival after extracorporeal membrane oxygenation for severe acute respiratory failure. The Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score. Am J Respir Crit Care Med 2014;189(11):1374–82.  21.  Park PK, Dalton HJ, Bartlett RH. Point: Efficacy of extracorporeal membrane oxygenation in 2009 influenza A(H1N1): sufficient evidence? Chest 2010;138(4):776–8.  22.  Morris AH, Hirshberg E, Miller RR, Statler KD, Hite RD. Counterpoint: Efficacy of extracorporeal membrane oxygenation in 2009 influenza A(H1N1): sufficient evidence? Chest 2010;138(4):778–81; discussion 782–4.  23.  Tramm R, Ilic D, Davies AR, Pellegrino VA, Romero L, Hodgson C. Extracorporeal membrane oxygenation for critically ill adults. Cochrane Database Syst Rev 2015;1:CD010381.  24.  Peek GJ, 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 Lond Engl 2009;374(9698):1351–63.  25.  Francois G. Strategy of UltraProtective Lung Ventilation With Extracorporeal CO2 Removal for New-Onset Moderate to seVere ARDS (SUPERNOVA) [Internet]. 2015 [cited 2015 Aug 31];Available from: https://clinicaltrials.gov/ct2/show/NCT02282657     


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