Peek GJ, Mugford M, Tiruvoipati R, Wilson A, Allen E, Thalanany MM, 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 Oct 17;374(9698):1351–63.
By the turn of the millennium, refinements in ventilation strategies, including the use of low tidal volumes and optimal application of positive end-expiratory pressure (PEEP), led to improved outcomes in patients with acute respiratory distress syndrome (ARDS). However, the mortality in severe ARDS remained between 34–58% (1,2).
Ventilator-induced lung injury (VILI) may lead to worsening of lung damage in ARDS (3). Volutrauma occurs due to injury related to alveolar overdistension, while the use of high ventilation pressures leads to dissection of air along the facial planes and accumulation in the pleural space. Repeated opening and closing of unstable lung units during each respiratory cycle leads to atelectrauma, characterized by increased stress at the junction between open and closed alveoli. Injurious ventilation patterns provoke biotrauma – a massive surge of inflammatory mediators, including cytokines and chemokines, that trigger lung edema, migration of neutrophils, and capillary vasodilatation. Besides, pulmonary toxicity related to high FiO2 levels may add insult to injury in the severely damaged lung (4).
Considering the inevitable worsening of lung injury induced by suboptimal ventilation strategies, extracorporeal gas exchange was regarded as a viable option for several decades. The concept of venovenous extracorporeal membrane oxygen (VV-ECMO) arose from the basic design of cardiopulmonary bypass, that had been long established for open heart surgery. VV-ECMO involves the drainage of venous blood through a pump into an oxygenator where gas exchange occurs. The oxygenated blood is returned into the venous system. Extracorporeal gas exchange enables using less injurious ventilation techniques while “resting” the lung and allowing it time to heal.
The first-ever randomized controlled trial (RCT) on ECMO for acute respiratory failure by Zapol et al. was published in the Journal of American Medical Association in November 1979 (5). They included patients between 12–65 years of age. The study followed two different protocols – a “fast” and a “slow” entry. Patients with a PO2 below 50 mm Hg while on an FiO2 of 1.0 and PEEP of 5 cm H2O for more than 2 hours were assigned to the fast protocol. Patients who underwent optimal medical therapy for 48 hours, with a PaO2 of less than 50 mm Hg while on FiO2 0.6 and a PEEP of 5 cm H2O, were assigned to the “slow” entry protocol. Pneumonia was the most common cause of acute respiratory failure (66%). Venoarterial bypass was carried out based on contemporary practice, using roller pumps in vogue during the study period. Four types of membrane oxygenators were employed, with intravenous heparin for anticoagulation. If stability was attained, the bypass flow was weaned at 0.5 l every 12 hours. Both groups of patients received mechanical ventilation and adjustment of PEEP based on clinician judgment; no standard protocol was followed. Sedatives, muscle relaxants, and antibiotics were administered as appropriate. ECMO could be weaned off based on the discretion of the clinician if the PaO2 remained consistently >70 mm Hg on an FiO2 <0.6. The clinician, in their best judgment, could also terminate ECMO support if no improvement was observed after 5 days of therapy.
The results of this early RCT were disheartening. Overall, there were just eight survivors, four in each group, with no discernible benefit from ECMO. The authors hypothesized that a shorter duration of mechanical ventilation before initiation of ECMO may improve survival – seven of the eight survivors had been on ventilation for less than a week before the commencement of ECMO.
Several years later, Morris et al. evaluated the impact of extracorporeal CO2 removal combined with low-frequency positive pressure ventilation in another RCT. The results of this study were equally disappointing, with no apparent beneficial effect of extracorporeal CO2 removal on the 30-day survival. The design and devices employed in these early studies were modifications of the heart-lung machine, primarily used during open heart surgery. Considering the major advancements in mechanical ventilation and ECMO technology since these early studies, the CESAR trial investigators aimed to evaluate the safety, efficacy, and cost-effectiveness of ECMO compared with conventional mechanical ventilation in a rigorous RCT.
Population, setting, and design
The CESAR trial was conducted between July 2001 and August 2006 across multiple centers in the UK (6). The study population included patients aged 18–65 years with potentially reversible acute respiratory failure. Patients with a Murray Score ≥3, or uncompensated hypercapnia with a pH <7.2 were eligible. Patients who were being ventilated with a peak inspiratory pressure of >30 cm H2O, or on an FiO2 >0.8 for 7 days, those who had intracranial hemorrhage, contraindication to anticoagulation with heparin, and those in whom limitation of care was planned were excluded. A total of 180 patients were randomized – 90 each to the ECMO and conventional ventilation arms.
Conventional mechanical ventilation was carried out in 92 tertiary centers. Patients from 11 other hospitals were transferred to either the ECMO center or tertiary center depending on the assigned modality of care – ECMO or conventional mechanical ventilation. Eligible patients were randomized in a 1:1 ratio. In the intervention group, patients were transferred to the specialist center for consideration of ECMO therapy. In the control group, conventional mechanical ventilation or high-frequency oscillation ventilation was carried out as appropriate.
The ECMO group
Patients randomized to the ECMO group were transferred to the specialist center at Glenfield Hospital, Leicester. A standardized ventilation protocol was commenced if they were hemodynamically stable. This included restriction of ventilation pressure to 30 cm H2O, and PEEP titrated to oxygen saturation. The FiO2 was adjusted to maintain oxygen saturation >90%. Other modalities of care included the use of prone ventilation, diuretics, and a target packed cell volume of 40%. ECMO was carried out if there was no satisfactory response within 12 hours of protocolized care, with an FiO2requirement of >0.9 or acidosis with pH >7.2, or if hemodynamic instability occurred.
ECMO was carried out in the venovenous mode, following percutaneous cannulation. Ventilation during ECMO was performed in the pressure-controlled mode, at peak pressures of 20–25 cm H2O, PEEP of 10–15 cm H2O, respiratory rate of 10/minute, and FiO2 of 0.3. ECMO was continued until clinical improvement or if irreversible multiorgan failure was deemed to have occurred.
The control group
Patients randomized to the control group were offered the best available care at the tertiary center. A tidal volume of 4–8 ml/kg and plateau pressure <30 cm H2O was recommended; however, considering the pragmatic nature of the trial, a strict protocol was not mandated. Crossover to ECMO was not allowed.
The primary outcome was death or severe disability at 6 months. Severe disability represented confinement to bed and inability to wash or dress independently. The initial sample size of 120 patients per group was based on a reduction in the primary outcome from 73% to 55% with ECMO. The sample size was reduced to 90 patients per group after review by the data monitoring committee during the course of the study.
During the study period, 766 patients were screened for eligibility, of whom 180 were randomized – for consideration for ECMO or conventional management. One hundred and three patients were excluded because ECMO beds were unavailable. Among the 90 patients allocated to the ECMO group, five died before they reached the ECMO center. From among the remaining 85 patients, 68 underwent ECMO, while 17 received the standardized ventilation protocol at the ECMO center.
Primary composite outcome: alive and disability-free at 6 months
Overall, 57/90 patients (63%) allocated to the ECMO arm were alive and free of severe disability at 6 months – among these were 43/68 who actually received ECMO and 14/17 patients who received protocolized ventilation strategy at the ECMO center. In the conventional ventilation arm, 41 of 87 (47%) patients on whom full information was available were alive and free of severe disability at 6 months. Thus, patients allocated for the consideration of ECMO at the specialized center had a significantly reduced risk of death or severe disability at 6 months (relative risk: 0·69; 95% CI: 0·05–0·97, p = 0·03).
Mortality at 6 months
Thirty-three patients (37%) had died before discharge or at 6 months in the ECMO group compared with 45 (45%) in the control group; the difference was not statistically significant (p = 0.07).
Severe disability at 6 months
None of the survivors in the ECMO group experienced severe disability at 6 months, compared to one with severe disability in the conventional group.
Respiratory failure was the cause of death in more patients in the control compared to the ECMO group (60% vs. 24%). Multiorgan failure leading to death was more common in the ECMO group compared to the control group (42% vs. 33%). The ICU and hospital length of stay were longer among patients assigned to the ECMO arm compared to the control group.
Treatment with ECMO came at a price – mean healthcare costs were more than twice as high compared with the control group. All patients underwent initiation of ECMO at the specialist center. The authors hypothesized that if ECMO could be initiated at the referring hospital prior to transfer, it might further improve outcomes.
The two RCTs that preceded the CESAR trial were conducted using outdated technology during an era when the lung protective ventilation strategy had not been established. The CESAR trial was a pragmatic RCT that compared conventional ventilation with transfer to a specialist center for consideration of ECMO. At the specialist center, ECMO was initiated if there was no improvement within a 12-hour period. This strategy is in tune with real-world practice. Patients were randomized at an early stage of illness; transfer to the assigned center was carried out by an expert team, with due consideration of the associated risks. The 6-month follow-up, as part of the primary outcome, was conducted by trained members of the research team, who were blinded to the assigned treatment.
Twenty-two of 90 patients assigned to the ECMO arm did not receive ECMO. This included five patients who died before ECMO could be considered. The specialist center where patients were transferred for consideration of ECMO employed a protocolized ventilation strategy; however, no strict ventilation protocol was followed among patients in the control group who were treated at the 92 tertiary centers. Hence, it could be argued that the improved outcomes may have been at least partly due to a standardized ventilation strategy and perhaps better overall care at the ECMO center. The high survival rate (14/17) of patients who were assigned to ECMO, but managed with conventional ventilation at the specialist center may also point towards such an effect.
The primary outcome was a composite of death and severe disability at 6 months. Composite outcomes may be less preferred; the 6-month mortality, although lower in the ECMO arm, was not significantly different compared to the control group. On analysis based on the assigned treatment (in contrast to intention-to-treat), the mortality difference between groups was still less.
Recruitment was slow and took nearly twice as long as originally planned. The study ultimately took 5 years – a fairly long duration, over which outcomes may have generally improved.
The H1N1 pandemic swept through Australia and New Zealand in the winter of 2009. Among 722 patients who were infected and admitted to ICUs, 68 patients underwent ECMO. These patients had a median PaO2/FiO2 ratio of 56 mm Hg and a median PEEP level of 18 cm H2O. They were more severely ill than those in the CESAR trial based on the median acute lung injury score. The hospital survival of 75% in this observational study further bolstered the evidence to support the use of ECMO among the most severely hypoxic patients (7).
The EOLIA RCT compared ECMO with conventional ventilation in 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 (8). Patients in the conventional ventilation arm were allowed to cross over to receive ECMO if they had refractory hypoxemia with oxygen saturation <80% for >6 hours. The 60-day mortality, the primary endpoint, was not significantly different between the ECMO and control groups (35% vs. 46%, p = 0.09). However, 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 group compared to the ECMO group (58% vs. 35%, p <0.001).
When Covid-19 pneumonia spread across the globe in the recent past, leaving in its trail wave after wave of severely hypoxemic patients, ECMO was widely used by many healthcare systems. In a meta-analysis of 58,472 patients, 4,044 patients underwent ECMO therapy. The mortality was higher with Covid-19 compared to patients with influenza pneumonia who were treated with ECMO (44% vs. 38%) (9). However, ECMO therapy probably saved many lives among patients with severe Covid-19 pneumonia who did not respond to conventional therapies.
The cumulative evidence overwhelmingly supports the use of ECMO in patients with refractory hypoxia, when conventional ventilation strategies fail. However, conducting yet another RCT to cement the evidence in favor of ECMO may remain an elusive goal considering its ubiquitous use in specialized centers across the world.
After long years of disappointing results, the CESAR trial represented the first RCT that evaluated the use of a technologically advanced ECMO design. Although there were shortcomings, it was a pragmatic trial that reflected real-world practice. Patients in the ECMO arm had significantly higher disability-free survival at 6 months compared to a conventional ventilation strategy. The observational trials during the H1N1 pandemic and the subsequent EOLIA trial support the use of ECMO in patients with refractory hypoxia.
Available at: https://link.springer.com/book/10.1007/978-981-19-9940-6
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2. Bersten AD, Edibam C, Hunt T, Moran J, Australian and New Zealand Intensive Care Society Clinical Trials Group. Incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three Australian States. Am J Respir Crit Care Med. 2002 Feb 15;165(4):443–8.
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4. Hochberg CH, Semler MW, Brower RG. Oxygen Toxicity in Critically Ill Adults. Am J Respir Crit Care Med. 2021 Sep 15;204(6):632–41.
5. Zapol WM. Extracorporeal Membrane Oxygenation in Severe Acute Respiratory Failure: A Randomized Prospective Study. JAMA. 1979 Nov 16;242(20):2193.
6. Peek GJ, Mugford M, Tiruvoipati R, Wilson A, Allen E, Thalanany MM, 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 Oct 17;374(9698):1351–63.
7. Critical Care Services and 2009 H1N1 Influenza in Australia and New Zealand. N Engl J Med. 2009 Nov 12;361(20):1925–34.
8. 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.
9. 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):2700–6.
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