A middle aged man with acute pancreatitis developed multiorgan failure and was admitted to the ICU and required ventilation and noradrenaline. He became progressively more hypoxic despite lung protective ventilation, paralysis, inverse ratios and a restrictive fluid regime. He developed bilateral pneumothoraces requiring chest drains. He was retrieved to the nearest refractory hypoxia centre and established on VV ECMO. On the third day of ECMO therapy he developed lateralising signs and was found to have had a large intracranial haemorrhage. Treatment was subsequently withdrawn.
Do patients with ARDS benefit from ECMO?
The first membrane bypass oxygenator was developed in 1956 but it wasn’t until 1972 that ECMO was first used successfully in an adult patient with ARDS. The first randomised controlled trial (RCT) comparing ECMO with mechanical ventilation (mechanical ventilation with positive end expiratory pressure (PEEP) vs venoarterial ECMO and mechanical ventilation with PEEP) was published in 1979 (1), showing a very low survival rate of 9% in both groups. A second RCT was published in 1994, comparing mechanical ventilation vs low frequency mechanical ventilation (with oxygenation primarily achieved with an intratracheal catheter) and extra-corporeal CO2 removal (2), but again showed no significant difference in survival (33% vs 42% in the control group).
Both of these trials recruited small patient numbers, and ECMO has evolved considerably since they were conducted, such as the introduction of venovenous circuits. Conventional management of ARDS has also evolved over the last 44 years, such as lung protective ventilation strategies and the introduction of care bundles resulting in a fall in mortality to 27% for mild ARDS to 45% for severe ARDS (3). It is therefore difficult to interpret this data in the context of current practice.
The first RCT to show a benefit for ECMO was the CESAR trial published in 2009 (4). It is the largest prospective adult ECMO trial conducted to date, enrolling 180 adult patients from 103 referring hospitals to a single ECMO centre. Patients with acute severe respiratory failure were randomised to referral to the ECMO centre, or to continued management at their base hospital. Patients in the control arm were managed according to local practice, although participating hospitals were advised to use a low volume/low pressure strategy. Ninety patients in the trial were randomised to referral to the ECMO centre leaving 90 in the control arm. Of the 90 patients referred, 68 (75%) received ECMO, 17 had conventional treatment, 3 died before transport and 2 died in transit. Patients randomised to ECMO who did not receive it or died were included in the final analysis (intention-to-treat analysis). The 2 groups were of similar age, primary diagnosis, number of organs failed, duration of intermittent positive pressure ventilation (IPPV) on entry, duration of high pressure ventilation and high FiO2 or both, disorder leading to study entry (hypoxia assessed by Murray Score and hypercapnoea) and APACHE II score. There was a significant difference in the primary outcome (death or severe disability at 6 months) between the 2 groups of 37% in the ECMO group vs 53% in the conventional group (relative risk reduction of 31%, CI 3% to 95%, p=0.03). Other outcomes measured including death before 6 months or prior to discharge, severe disability or cause of death showed no significant difference between the 2 groups.
While significant, the results should be interpreted with caution. The use of a composite primary endpoint (death or disability) had a significant effect on the primary outcome (the relative risk for the single endpoint of 6-month mortality was not significant). Additionally, the reason for the observed benefit in the group referred for ECMO is unclear. There were possible differences in mechanical ventilation between study groups (there was no protocol for management of the control group), and only 75% of the patients in the treatment arm actually received ECMO. The results could be interpreted as showing benefit from referral to an ECMO centre, regardless of whether or not the patient is ultimately treated with ECMO.
The results of the CESAR trial are supported by recent observational data from the use of ECMO in Australia and New Zealand during the recent H1N1 pandemic (5,6). ECMO was associated with a hospital survival rate of 75%, which is lower than the predicted mortality based on illness severity.
Mortality from ARDS has fallen dramatically over the last few decades as a result of advances in conventional management (such a lung protective ventilation) that should be standard of care for all patients with ARDS. The CESAR trial showed that transfer of the sickest patients to a tertiary referral centre for consideration of ECMO was associated with improved outcomes, but it is unclear if this benefit resulted from ECMO or from better management using conventional methods. ECMO currently remains a rescue therapy for patients with hypoxaemic respiratory failure.
1. Zapol WM, Snider MT, Hill JD, et al. Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study. JAMA 1979; 242: 2193-6
2. Morris AH, Wallace CJ, Menlove RL, 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: 295-305
3. The ARDS Definition Task Force. Acute Respiratory Distress Syndrome, The Berlin Definition. JAMA, June 20, 2012—Vol 307, No. 23
4. 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 2009; 374: 1351-1363
5. ANZ ECMO Influenza Investigators. Extracorporeal membrane oxy- genation for 2009 influenza A(H1N1) acute respiratory distress syndrome. JAMA 2009; 302: 1888-95
6. Davies A, Jones D, Gattas D. Extracorporeal membrane oxygenation for ARDS due to 2009 influenza A(H1N1) [letter in reply]. JAMA 2010; 303: 942