Introduction
Extracorporeal membrane oxygenation (ECMO) has been in use as rescue therapy for acute respiratory failure for more than half a century. In 1972, Hill et al. reported their experience with ECMO use in a 24 year old man who sustained transection of the thoracic aorta and multiple orthopedic injuries following a motor vehicle accident (1). He developed severe acute respiratory distress syndrome, popularly known as “shock lung” in those days, that remained refractory to conventional therapies. Veno-arterial bypass was established, resulting in a dramatic improvement in oxygenation. Following 3 days of bypass, the patient could be weaned off, leading to a complete recovery.
The first neonatal ECMO survivor was a baby girl, born to a Mexican migrant, who presented to the University of California Hospital, Irvine, in 1975. Despite maximal ventilatory support, she remained severely hypoxic and hypercarbic. Her PaO2 was a rock bottom 17 mm Hg on an FiO2 of 1.0, and she was on the verge of cardiac arrest following recurrent episodes of hypotension and bradycardia. Robert Bartlett, a cardiothoracic surgeon, put her on cardiopulmonary bypass in a last ditch effort to save her life. On angiography, the baby had a large patent ductus arteriosus with a total right-to-left shunt. The ductus was ligated while on continued ECMO support. After several days of cardiopulmonary bypass, the baby was weaned off. She made a slow, steady recovery and had a normal growth curve by 12 months of age. The nurses who took care of her named her Esperanza, meaning hope. Bartlett and colleagues thought this case would be a milestone in the history of neonatal cardiopulmonary bypass; however, in his own words, “Journal editors disagreed, and the report was never published… (2)” (Fig 1)
Figure 1. The first use of neonatal ECMO
Early studies
Following the initial experience, by 1974, ECMO had been carried out in nearly150 patients with acute respiratory failure, with a survival rate of 10-15% (3). Against this background, Zapol et al. conducted the first-ever randomized controlled trial on ECMO in patients with acute respiratory failure. They included patients between 12–65 years of age (3). Patients who remained with a PaO2 of <50 mm Hg on an FiO2 of 1.0 and PEEP of 5 cm H2O for more than two hours were allotted to the “fast” entry protocol; patients who had received optimal medical therapy for 48 hours but had a PaO2 level of <50 mm Hg with an FiO2 of 0.6 and PEEP of 5 cm H2O underwent a “slow” entry into the trial. Pneumonia was the cause of acute respiratory failure in the majority of patients (66%). Veno-arterial ECMO was carried out using roller pumps and anticoagulation, with heparin. Both groups received mechanical ventilation with PEEP, sedation, muscle relaxants, and antibiotics, as appropriate. No standard ventilation protocol was followed. When the PaO2 was consistently >70 mm Hg on an FiO2 <0.6, ECMO could be terminated based on clinician judgment. ECMO was discontinued at the discretion of the physician if there was lack of improvement after 5 days of commencement of ECMO.
The results of ECMO therapy were hugely disappointing in this early trial; 38 of 42 (90.5%) patients in the ECMO arm and 44 of 48 (91.7%) patients in the control arm died at the end of the trial period. The authors observed that survival was more likely in patients who had received a shorter duration of ventilation before ECMO therapy. Interest in ECMO waned for the next several years following the disheartening results of this trial.
In another report published 15 years later, inverse ratio ventilation was compared with low-flow veno-venous ECMO aimed primarily at carbon dioxide removal (4). Although not statistically significant, mortality was higher in the ECMO compared to the control group (44% vs. 33%). The investigators in this trial had limited expertise with ECMO, probably contributing to the poor outcomes observed with ECMO.
Both these randomized controlled trials were carried out before the efficacy of of lung-protective ventilation strategies using low tidal volumes and limitation of plateau pressures was established with the ARDSNet trial of 2000 (5). Besides, extracorporeal design and the overall management of critically ill patients had undergone major refinements by the turn of the century.
The 2009 H1N1 pandemic and the resurgence of ECMO
The 2009 H1N1 pandemic offered an opportunity to test out the efficacy of ECMO among patients with ARDS and severe hypoxia, with reports from many centers across the world. The Australia and New Zealand Extracorporeal Membrane Oxygenation group reported an observational study of 68 patients who underwent ECMO during the H1N1 pandemic. These patients had severe ARDS and were on optimal mechanical ventilatory support. The median PaO2/FiO2 ratio was 56 mm Hg while on a median PEEP level of 18 cm H2O. In this cohort 68 patients, 48 (71%) had survived to ICU discharge; 32 were discharged home while 16 remained in the hospital. This observational study suggested that ECMO could improve survival in patients with viral pneumonia who remained severely hypoxic after the optimization of ventilation strategies (6).
The first randomized controlled trial of modern ECMO: The CESAR trial
The CESAR multicenter, randomized controlled trial was conducted in the UK against this background. The study included patients 18–65 years old with severe acute respiratory failure, defined as a Murray score of >3.0 or a pH of <7.2. A total of 180 patients were randomized; 90 each were allocated to the ECMO and control arms. In the control arm, patients were treated at tertiary referral centers; although there was no specific protocol, a tidal volume of 4–8 ml/kg with the limitation of plateau pressure to <30 cm H2O was generally followed. Patients allocated to receive ECMO were transferred to a single ECMO referral center, at the Glenfield Hospital, Leicester. At the ECMO center, a standardized treatment protocol was initially followed, including lung-protective ventilation combined with diuretic therapy and prone positioning as appropriate. ECMO therapy was commenced if there was no response to the protocolized approach within 12 hours. Veno-venous cannulation was carried out through the percutaneous route. Roller pumps and poly-methyl pentene oxygenators were used in the ECMO circuit.
Among the 90 patients randomized to receive ECMO, 17 were continued on conventional treatment with a protocolized lung-protective ventilation strategy; 14 of them survived. Sixty-eight patients (75%) underwent ECMO. Survival without disability at 6 months, the primary outcome, was significantly higher in patients randomized to the ECMO compared with the control group (63% vs. 47%, p = 0.03). There were more survivors at 6 months in the ECMO compared to the control group. Patients randomized to the ECMO arm experienced longer ICU and hospital stay compared to the control group.
The CESAR trial established the efficacy of ECMO in patients with severe acute respiratory failure compared with a conventional lung-protective ventilation strategy. However, there were a few moot points. First, the improved survival without disability was solely related to referral to a single specialized ECMO center, compared with non-protocolized, conventional management at multiple centers. Second, three patients withdrew from the control arm, and no information was available regarding their status at 6 months. If they had all survived without severe disability, the primary outcome would no longer be statistically significant in favor of ECMO.
The technology and conduct of ECMO have undergone considerable refinement over the past decade. The older polypropylene membranes lead to leakage of plasma into the gas compartment that impairs membrane performance. The currently used poly-methyl pentene hollow fiber membranes (Quadrox, Medos) are vastly superior to the silicone rubber or polypropylene membranes that were used previously (Fig 2). The CESAR trial had used roller pumps. The non-occlusive centrifugal pumps used in current ECMO systems are less prone to hemolysis, although they require larger priming volumes.
Figure 2. A hollow-fibre, poly-methyl pentene oxygenator (Quadrox)
The EOLIA trial
In the EOLIA trial, patients with a PaO2/FiO2 ratio of <50 mm Hg for >3 hours, or <80 mm Hg for >6 hours, or an arterial pH of <7.25 with PCO2 >60 mm Hg for >6 hours were randomized to receive ECMO or continued conventional ventilation (7). Patients in the conventional arm could be crossed over to receive ECMO if they had refractory hypoxemia with oxygen saturation <80% for >6 hours at the clinician discretion. The study was terminated for futility after enrollment of 249 (ECMO: 124, control: 125) patients out of the planned sample size of 331 patients. The 60-day mortality, the primary endpoint, was not significantly different between the ECMO and control groups (35% vs. 46%, p = 0.09). The key secondary endpoint was treatment failure, defined as death or crossover to ECMO in the control group and death in the ECMO group. Treatment failure was significantly higher in the control compared to the ECMO group (58% vs. 35%, p <0.001).
The results of this study need to be interpreted taking into consideration 35 patients (28%) who crossed over from the control to the ECMO arm. It is likely that these patients had a poor chance of survival without ECMO; however, there were 15 (43%) survivors among the patients who crossed over. On intention to treat analysis, these patients, who would have likely died without ECMO, were included in the control group, thus diminishing the impact of ECMO. Even if one third these patients had survived with conventional treatment alone, the primary outcome would still have been in favor of ECMO (8). The other limitation of this study was a power calculation based on 60% mortality in the control group, in contrast to the actual mortality of 46%. A lower mortality of 20% (from 60–40%) was assumed with ECMO compared to the control group in the sample size calculation, which may have been unrealistic. The CESAR trial had revealed a mortality reduction of 16% with ECMO. Early cessation of the trial may also have resulted in an underpowered study.
ECMO in Covid 19
Early reports of the use of ECMO in Covid-19 pneumonia were disappointing, with mortality rates of >80% (9). However, later reports reveal improved survival comparable with acute respiratory failure due to other causes (10). Bertini et al. performed a systematic review with meta-analysis to evaluate the impact of ECMO in Covid-19. The overall in-hospital mortality was 39% among 4044 Covid-19 patients who underwent ECMO (11). The authors compared mortality in Covid-19 patients compared with influenza patients who underwent ECMO. Covid-19 patients who underwent ECMO had higher mortality compared with influenza patients who underwent ECMO (44% vs. 38%, p = 0.03). The available data suggests an increased mortality rate of Covid-19 patients who underwent ECMO during the second compared to the first wave (12,13). The difference in survival may be attributable to changes in the standard of care, patient selection, limitation of resources, and likely impact of variants of the virus. Even after weaning from ECMO, most Covid-19 patients continue to require long-term mechanical ventilation. An important factor may be severe neuromuscular weakness due to prolonged use of sedatives and neuromuscular blockade.
What does the future hold?
Do we require another randomized controlled trial to establish the usefulness of ECMO in acute respiratory failure? It is by no means an easy task to carry out such a trial. The CESAR trial took 5 years for completion. The EOLIA trial took 6 years before being ceased for futility. It may take a much longer period to reach any robust, statistically meaningful conclusions in any future trial, considering the low recruitment rates in these trials. The question of withholding a potentially life-saving modality of treatment as a rescue intervention could also raise an ethical dilemma.
Key points
- ECMO has been in clinical use for nearly 50 years. Early clinical trials with ECMO had revealed no additional benefit compared to conventional mechanical ventilation alone
- ECMO technology has evolved over the years with the use of poly-methyl pentene membranes and centrifugal pumps in preference to roller pumps. Mechanical ventilation has also undergone considerable refinement with a focus on lung-protective ventilation strategies
- Two randomized controlled trials (CESAR and EOLIA) have been carried out in the modern ECMO era. The CESAR trial revealed improved survival without disability at 6 months with ECMO. In the EOLIA trial, the 60-day mortality was lower with ECMO, although the difference did not reach statistical significance. Treatment failure occurred less often with ECMO compared to conventional mechanical ventilation
- The two contemporaneous RCTs do suggest that in severe ARDS, clinicians should focus on evidence-based management, including lung-protective ventilation, sedation, neuromuscular blockade, and prone positioning as the initial line of care
- If life-threatening hypoxemia persists despite conventional measures, ECMO therapy may be a viable rescue intervention. It seems highly probable that the use of ECMO in selected patients with severe acute respiratory failure using an integrated, protocolized approach would lead to improved clinical outcomes
References
1. Hill JD, O’Brien TG, Murray JJ, Dontigny L, Bramson ML, Osborn JJ, et al. Prolonged extracorporeal oxygenation for acute post-traumatic respiratory failure (shock-lung syndrome). Use of the Bramson membrane lung. N Engl J Med. 1972 Mar 23;286(12):629–34.
2. Bartlett RH. Esperanza: The First Neonatal ECMO Patient. ASAIO J. 2017 Nov;63(6):832–43.
3. Zapol WM. Extracorporeal Membrane Oxygenation in Severe Acute Respiratory Failure: A Randomized Prospective Study. JAMA. 1979 Nov 16;242(20):2193.
4. Morris AH, Wallace CJ, Menlove RL, Clemmer TP, Orme JF, Weaver LK, 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 Feb;149(2 Pt 1):295–305.
5. Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome. N Engl J Med. 2000 May 4;342(18):1301–8.
6. ANZIC Influenza Investigators, Webb SAR, Pettilä V, Seppelt I, Bellomo R, Bailey M, et al. Critical care services and 2009 H1N1 influenza in Australia and New Zealand. N Engl J Med. 2009 Nov 12;361(20):1925–34.
7. Combes A, Hajage D, Capellier G, Demoule A, Lavoué S, Guervilly C, et al. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome. N Engl J Med. 2018 May 24;378(21):1965–75.
8. Gattinoni L, Vasques F, Quintel M. Use of ECMO in ARDS: does the EOLIA trial really help? Crit Care. 2018 Jul 5;22(1):171.
9. Ñamendys-Silva SA. ECMO for ARDS due to COVID-19. Heart Lung J Crit Care. 2020 Aug;49(4):348–9.
10. Schmidt M, Hajage D, Lebreton G, Monsel A, Voiriot G, Levy D, et al. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: a retrospective cohort study. Lancet Respir Med. 2020 Nov;8(11):1121–31.
11. Bertini P, Guarracino F, Falcone M, Nardelli P, Landoni G, Nocci M, et al. ECMO in COVID-19 Patients: A Systematic Review and Meta-analysis. J Cardiothorac Vasc Anesth. 2022 Aug;36(8 Pt A):2700–6.
12. Riera J, Roncon-Albuquerque R, Fuset MP, Alcántara S, Blanco-Schweizer P, ECMOVIBER Study Group. Increased mortality in patients with COVID-19 receiving extracorporeal respiratory support during the second wave of the pandemic. Intensive Care Med. 2021 Dec;47(12):1490–3.
13. Barbaro RP, MacLaren G, Boonstra PS, Combes A, Agerstrand C, Annich G, et al. Extracorporeal membrane oxygenation for COVID-19: evolving outcomes from the international Extracorporeal Life Support Organization Registry. Lancet Lond Engl. 2021 Oct 2;398(10307):1230–8.
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