An 60 year old woman developed ARDS secondary to pneumococcal meningitis. Despite optimal ventilatory management and restrictive fluid intake her oxygenation remained severely impaired. She was referred to the regional respiratory failure unit who established her on mobile ECMO for retrieval. She remained on ECMO for five days, weaned off the ventilator after three further days and made a full neurological recovery leaving hospital two weeks later.
Is there sufficient evidence to promote the use of Extracorporeal Membrane Oxygenation (ECMO) for the management of severe refractory hypoxia in the United Kingdom?
Sam Clark
Since 2009 and the publication of the CESAR trial (1), there have been significant changes in the management of severe refractory hypoxaemia. In 2010, the Department of Health published The Management of Severe Refractory Hypoxaemia in Critical Care in the UK, best practice guidance (2). This document recommended a tiered system of advanced respiratory care in this country with 5 adult ECMO centres throughout the country designed to offer additional advance respiratory support therapies and early identification of patients, who were the most likely to benefit from ECMO.
The story began in 1885, when von Frey and Gruber first developed a machine to provide oxygenated blood to isolated organs. Gibbon invented the first heart –lung machine in 1937, but this exposed the blood directly to bubble oxygenators and therefore caused significant side effects limiting its to a few hours. Finally, in 1956, Clowes and team designed the first machine that separated the liquid and gas phases improving safety and efficiency. Further developments followed until in 1979, Zapol et al (3) published the first randomized control trial (RCT) examining the effectiveness of ECMO in ARDS. They found that the majority of patients died of progressive reduction of transpulmonary gas exchange and decreased compliance due to diffuse pulmonary inflammation, necrosis, and fibrosis and concluded that ECMO can support respiratory gas exchange but did not increase the probability of long-term survival in patients with severe acute respiratory failure. A further trial by Morris et al (4) in 1994, examining extra corporeal CO2 removal, also found no mortality benefit. However, there have been considerable changes in both technologies, the standard management of severe hypoxia and patient selection since these original studies were published. For example many of the pumps are now continuous flow as opposed to pulsatile. Also, on further examination, in both trial arms of these studies, the patients suffered from considerable daily blood loss with 2.5L and 2.7L respectively secondary to bleeding, mechanical consumption and clotting within the circuits themselves, which suggests one explanation for the lack of improved survival in the control arms. More recent data suggests that this transfusion requirement has dropped considerably even as low as 1 unit packed red cells per day (5).
As mentioned above, the publication of the CESAR trial in 2009 changed people’s perception of ECMO as a viable and cost effective treatment for ARDS in adult patients. It was a randomized controlled trial with multiple centres referring to a single specialist centre for advanced respiratory support including ECMO. The inclusion criteria was adult patients (aged 18-65) with severe but reversible respiratory failure, and a Murray score of 3 or more or uncompensated hypercapnoea with a pH of less than 7.20 despite optimum conventional treatment. Murray scores of 2.5 were considered if the deterioration was rapid. Reversibility was determined by the ECMO consultant on duty at the time of referral. Exclusion criteria were: peak inspiratory pressures greater than thirty or FiO2 >0.8 for more than 7 days; intracranial bleeding; any other contraindication to limited heparinisation; or any other contraindication to further active treatment. CESAR showed a significant improvement in patient overall survival without severe disability at six months compared to those in the conventional arm with a relative risk of 0.69 (CI 0.05-0.97). It is, however, worth noting that the analyses were done on an intention to treat analysis and that only 68 of the 90 patients in the treatment arm received ECMO. There was also a significant difference in the numbers of patients receiving low volume, low pressure ventilation strategies (93 to 70% respectively, p<0.0001). A concurrent financial viability study run within CESAR showed that transfer and treatment at the specialist centre had a mean cost of approximately twice that of conventional treatment but there was an acceptable cost effectiveness of approximately £19,000/QALY.
The other significant event of 2009 centered around concerns about H1N1 influenza virus, the possibility of a pandemic and the burdens placed on critical care around the Western world. Two studies published based on the experiences at that time also demonstrated benefits from placing patients on ECMO as opposed to the sole use of conventional techniques (6,7) First was the ANZ ECMO study published in 2009. It was an observational study based on 15 centres in Australia and New Zealand looking 194 patients with H1N1 influenza A. Of the 68 patients treated with ECMO, 48 had survived to ICU discharge (71%, CI 60-82%) with 6 remaining in ICU (2 of whom were still on ECMO) at time of publication. The second was based on experiences from the UK from one of the four adult ECMO centers. Noah et al compared their ECMO referred patients to patients matched from a concurrent longitudinal cohort study of critically ill patients. They used three methods to match patients: individual, propensity scoring and GenMatch matching. Of the 80 patients referred, 69 received ECMO and 22 died. Hospital mortality compared to controls was approximately 24% versus 46.7-52.5% depending on which of the matching technique was used. Both of these studies suggested that ECMO had distinct survival benefits compared to conventional therapy alone and had results similar to the ELSO published data (8).
Overall, both a substantial body of the current evidence and current thinking in UK practice believes that ECMO is beneficial for the management of severe refractory hypoxia, and this is unlikely to change soon, but there are important studies pending that may alter clinical practice in the future, including the EOLIA trial (ECMO to rescue Lung Injury in severe ARDS – a multicentered international RCT trial similar to the CESAR trial) and SUPERNOVA trial (an ECCO2-R trial).
References:
1) Peek GL, Mugford M, Tiruoipati 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;374:1351-63.
2) Department of Health: The Management of Severe Refractory Hypoxia in Critical Care in the UK . 2010 D16/S(HSS)/a.
3) Zapol WM, Snider MT, Hill JD et al. Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study. JAMA 1979;242:2193-96.
4) Morris AH, Wallace CJ, Menlove RL, et al. Randomised clinical trial of pressure-controlled inverse ratio ventilation and extra corporeal carbon dioxide removal for adult respiratory distress syndrome. AM J Respir Crit Care Med 1994;149:295-305.
5) Buscher. Update on ECMO. http://intensivecarenetwork.com/ecmo-update-2014-buscher/. Unpublished data.
6) 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; 302:1888.
7) Noah MA, Peek GJ, Finney SJ, et al. Referral to an extracorporeal membrane oxygenation center and mortality among patients with severe 2009 influenza A(H1N1). JAMA 2011; 306:1659
8) 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
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