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October - 2019

   

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Extracorporeal Life Support for Adults With Respiratory Failure and Related Indications-A Review

D Brodie, A Slutsky, A Combes JAMA, 2019, 322(6):557-568

Comment

This expert review takes us through the history and current state of evidence and experience for ECMO / extracorporeal life support for adults with acute respiratory failure. It provides;

  • historical context
  • Definition of terms 
  • Basic physiological and anatomical considerations
  • Overview of complications
  • Trial history
    • 1994 (Morris et al) randomized 40 patients with severe ARDS to pressure-controlled inverse ratio ventilation followed by venovenous ECCO2R vs conventional mechanical ventilation. Trial stopped early for futility, with no significant survival difference between groups (42% controls vs 33% intervention arm, P = .8). Increased bleeding in ECCO2R was major issue, with marked differences in blood product use, partly due to aggressive anticoagulation use for intensely thrombogenic circuit surfaces of the time.
    • 2009 an inflection point in the use of ECMO;
      • CESAR pragmatic trial 180 adults with severe ARDS randomized to conventional management at any of 68 UK hospitals vs transfer to single ECMO center, where patients received a management protocol including ECMO, if needed. Only 76% of patients in the ECMO group received ECMO, and control group were not mandated to receive low-volume, low-pressure ventilation (only 70% did at any point during their course). With this in mind the 16% absolute reduction in primary end point of death or severe disability at 6 months (63% vs 47%; relative risk [RR], 0.69 [95% CI, 0.05-0.97]; P = .03) is difficult to interpret. The CESAR trial is important, demonstrating relative safety, if not effectiveness.
      • Influenza A(H1N1)–associated ARDS pandemic: nonrandomized study of ECMO in patients with H1N1-associated ARDS suggested improved outcomes with ECMO. A subsequent series of similar patients, none of whom were treated with ECMO, demonstrated nearly identical outcomes. Further H1N1-associated ARDS ECMO vs matched control studies have been inconsistent.
  • 2018 EOLIA: Multicenter, international RCT of 249 very severe ARDS patients, randomized to standard care (protocolized mechanical ventilation) or ECMO with lower ventilator pressures, volumes, and respiratory rates. Overall 90% of controls and 66% of ECMO patients were probed, and crossover from control to “rescue” ECMO for failure of conventional management was allowed based on strict criteria. The trial was stopped early for futility, with a nonstatistically significant, yet large reduction in mortality with ECMO (35% vs 46%; RR, 0.76 [95% CI, 0.55-1.04]; P = .09). The overall rate of complications in the ECMO group was reassuringly low, with no statistically significant difference between groups in ischemic or hemorrhagic strokes. 
    • With EOLIA negative with a large reduction in mortality, an additional RCT seems unlikely. This is reinforced by the long recruitment (5.5 years), and 28% crossover to ECMO demonstrating lack of equipoise.
    • Goligher et al published a post hoc Bayesian analysis of EOLIA. Overall, the probability of a mortality benefit at 60 days (RR<1) was high, ranging from 88% to 99%. The probability of an absolute risk reduction of 2% or more ranged from 78% to 98%, depending on the chosen priors. This analysis strongly suggests that there is a mortality benefit to ECMO in very severe ARDS. As the editorialists wrote, it is no longer a question of “‘Does ECMO work?’, instead the key question...is ‘By how much does ECMO work, in whom, and at what cost?’”
  • Moderate to severe ARDS:  Does ECMO or ECCOR improve outcome in moderate to severe ARDS? A multicentre RCT using 3 different devices was recently completed, planning underway for a multicenter RCT using a predictive enrichment strategy for choosing the patients most likely to benefit from ECCO2R. An RCT of ECCO2R in patients with acute hypoxemic respiratory failure (PaO2:FIO2 ratio150) with an intended enrollment of more than 1100 patients is ongoing in the United Kingdom. This may result in evidence for ECCOR2R in moderate or even mild ARDS, although this remains speculative at this time.
  • Bridge to transplant: ECMO in conjunction with minimal sedation, liberation from mechanical ventilation, and early mobilization, may assist patients to maintain/improve physical conditioning while waiting for an organ donor.
  • COPD: while it seems plausible that ECCO2R may offer benefit, evidence is required.
  • Right heart failure: there is experience of benefit of VA ECMO in PE, acute pulmonary hypertension.
  • Regionalisation, financial, ethical implications are discussed.

 

There remains a lot to learn, and a lot to study. Overall this modality appears here to stay.

 

Abstract

Importance: The substantial growth over the last decade in the use of extracorporeal life support for adults with acute respiratory failure reveals an enthusiasm for the technology not always consistent with the evidence. However, recent high-quality data, primarily in patients with acute respiratory distress syndrome, have made extracorporeal life support more widely accepted in clinical practice.

Observations: Clinical trials of extracorporeal life support for acute respiratory failure in adults in the 1970s and 1990s failed to demonstrate benefit, reducing use of the intervention for decades and relegating it to a small number of centers. Nonetheless, technological improvements in extracorporeal support made it safer to use. Interest in extracorporeal life support increased with the confluence of 2 events in 2009: (1) the publication of a randomized clinical trial of extracorporeal life support for acute respiratory failure and (2) the use of extracorporeal life support in patients with severe acute respiratory distress syndrome during the influenza A(H1N1) pandemic. In 2018, a randomized clinical trial in patients with very severe acute respiratory distress syndrome demonstrated a seemingly large decrease in mortality from 46% to 35%, but this difference was not statistically significant. However, a Bayesian post hoc analysis of this trial and a subsequent meta-analysis together suggested that extracorporeal life support was beneficial for patients with very severe acute respiratory distress syndrome. As the evidence supporting the use of extracorporeal life support increases, its indications are expanding to being a bridge to lung transplantation and the management of patients with pulmonary vascular disease who have right-sided heart failure. Extracorporeal life support is now an acceptable form of organ support in clinical practice. 

Conclusions and Relevance: The role of extracorporeal life support in the management of adults with acute respiratory failure is being redefined by advances in technology and increasing evidence of its effectiveness. Future developments in the field will result from technological advances, an increased understanding of the physiology and biology of extracorporeal support, and increased knowledge of how it might benefit the treatment of a variety of clinical conditions.

October


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