for the CESAR trial collaboration: Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial

Department of Cardiothoracic Surgery, Glenfield Hospital, Leicester, UK.
The Lancet (Impact Factor: 45.22). 09/2009; 374(9698):1351-63. DOI: 10.1016/S0140-6736(09)61069-2
Source: PubMed


Severe acute respiratory failure in adults causes high mortality despite improvements in ventilation techniques and other treatments (eg, steroids, prone positioning, bronchoscopy, and inhaled nitric oxide). We aimed to delineate the safety, clinical efficacy, and cost-effectiveness of extracorporeal membrane oxygenation (ECMO) compared with conventional ventilation support.
In this UK-based multicentre trial, we used an independent central randomisation service to randomly assign 180 adults in a 1:1 ratio to receive continued conventional management or referral to consideration for treatment by ECMO. Eligible patients were aged 18-65 years and had severe (Murray score >3.0 or pH <7.20) but potentially reversible respiratory failure. Exclusion criteria were: high pressure (>30 cm H(2)O of peak inspiratory pressure) or high FiO(2) (>0.8) ventilation for more than 7 days; intracranial bleeding; any other contraindication to limited heparinisation; or any contraindication to continuation of active treatment. The primary outcome was death or severe disability at 6 months after randomisation or before discharge from hospital. Primary analysis was by intention to treat. Only researchers who did the 6-month follow-up were masked to treatment assignment. Data about resource use and economic outcomes (quality-adjusted life-years) were collected. Studies of the key cost generating events were undertaken, and we did analyses of cost-utility at 6 months after randomisation and modelled lifetime cost-utility. This study is registered, number ISRCTN47279827.
766 patients were screened; 180 were enrolled and randomly allocated to consideration for treatment by ECMO (n=90 patients) or to receive conventional management (n=90). 68 (75%) patients actually received ECMO; 63% (57/90) of patients allocated to consideration for treatment by ECMO survived to 6 months without disability compared with 47% (41/87) of those allocated to conventional management (relative risk 0.69; 95% CI 0.05-0.97, p=0.03). Referral to consideration for treatment by ECMO led to a gain of 0.03 quality-adjusted life-years (QALYs) at 6-month follow-up [corrected]. A lifetime model predicted the cost per QALY of ECMO to be pound19 252 (95% CI 7622-59 200) at a discount rate of 3.5%.
We recommend transferring of adult patients with severe but potentially reversible respiratory failure, whose Murray score exceeds 3.0 or who have a pH of less than 7.20 on optimum conventional management, to a centre with an ECMO-based management protocol to significantly improve survival without severe disability. This strategy is also likely to be cost effective in settings with similar services to those in the UK.
UK NHS Health Technology Assessment, English National Specialist Commissioning Advisory Group, Scottish Department of Health, and Welsh Department of Health.

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    • "Venovenous extracorporeal membrane oxygenation (ECMO), also known as " extracorporeal gas exchange, " is a temporary support of the failing respiratory system [1] [2] that is increasingly used as an adjunct to mechanical ventilation in patients who cannot be safely treated with mechanical ventilation alone [3] [4]. Moreover, ECMO is increasingly used as a first-line treatment, that is, as an alternative to mechanical ventilation in patients bridged to lung transplantation [5], patients with exacerbation of chronic obstructive pulmonary disease (COPD) [6] [7], and patients with acute respiratory distress syndrome (ARDS) [8] [9]. "
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    ABSTRACT: Purpose: Partial pressure of carbon dioxide (PCO2), strong ion difference (SID), and total amount of weak acids independently regulate pH. When blood passes through an extracorporeal membrane lung, PCO2 decreases. Furthermore, changes in electrolytes, potentially affecting SID, were reported. We analyzed these phenomena according to Stewart's approach. Methods: Couples of measurements of blood entering (venous) and leaving (arterial) the extracorporeal membrane lung were analyzed in 20 patients. Changes in SID, PCO2, and pH were computed and pH variations in the absence of measured SID variations calculated. Results: Passing from venous to arterial blood, PCO2 was reduced (46.5 ± 7.7 vs 34.8 ± 7.4 mm Hg, P < .001), and hemoglobin saturation increased (78 ± 8 vs 100% ± 2%, P < .001). Chloride increased, and sodium decreased causing a reduction in SID (38.7 ± 5.0 vs 36.4 ± 5.1 mEq/L, P < .001). Analysis of quartiles of ∆PCO2 revealed progressive increases in chloride (P < .001), reductions in sodium (P < .001), and decreases in SID (P < .001), at constant hemoglobin saturation variation (P = .12). Actual pH variation was lower than pH variations in the absence of measured SID variations (0.09 ± 0.03 vs 0.12 ± 0.04, P < .001). Conclusions: When PCO2 is reduced and oxygen added, several changes in electrolytes occur. These changes cause a PCO2-dependent SID reduction that, by acidifying plasma, limits pH correction caused by carbon dioxide removal. In this particular setting, PCO2 and SID are interdependent.
    Full-text · Article · Sep 2014 · Journal of Critical Care
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    • "The only randomized, prospective study of ECMO together with protective ventilation was done by Peek et al. in 180 patients with severe ARDS (Murray score > 3 or pH < 7.20). It showed a significant reduction in a composite criterion combining mortality and severe handicap at six months (37 versus 53%) in patients on ECMO, compared with conventional ventilatory support [7]. Even if the protocol of this study, which included transfer to a referral center of patients in the ECMO arm and routine use of protective ventilation only in the same arm, does not allow comparison of ECMO with optimized management of ARDS, it highlights the value of resorting to a center skilled in the use not only of ECMO, but also in the treatment of severe ARDS. "
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    ABSTRACT: The influenza H1N1 epidemics in 2009 led a substantial number of people to develop severe acute respiratory distress syndrome and refractory hypoxemia. In these patients, extracorporeal membrane oxygenation was used as rescue oxygenation therapy. Several randomized clinical trials and observational studies suggested that extracorporeal membrane oxygenation associated with protective mechanical ventilation could improve outcome, but its efficacy remains uncertain. Organized by the Société de Réanimation de Langue Française (SRLF) in conjunction with the Société Française d'Anesthésie et de Réanimation (SFAR), the Société de Pneumologie de Langue Française (SPLF), the Groupe Francophone de Réanimation et d'Urgences Pédiatriques (GFRUP), the Société Française de Perfusion (SOFRAPERF), the Société Française de Chirurgie Thoracique et Cardiovasculaire (SFCTV) et the Sociedad Española de Medecina Intensiva Critica y Unidades Coronarias (SEMICYUC), a Consensus Conference was held in December 2013 and a jury of 13 members wrote 65 recommendations to answer the five following questions regarding the place of extracorporeal life support for patients with acute respiratory distress syndrome: 1) What are the available techniques?; 2) Which patients could benefit from extracorporeal life support?; 3) How to perform extracorporeal life support?; 4) How and when to stop extracorporeal life support?; 5) Which organization should be recommended? To write the recommendations, evidence-based medicine (GRADE method), expert panel opinions, and shared decisions taken by all the thirteen members of the jury of the Consensus Conference were taken into account.
    Full-text · Article · May 2014 · Annals of Intensive Care
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    • "With superiority for moribund patients, venovenous extracorporeal membrane oxygenation (VV ECMO) is recommended to support patients with severe but potentially reversible respiratory failure refractory to conventional therapy [3-6]. The encouraging results in the CESAR trial and remarkable effect of ECMO in 2009 H1N1 and 2013 H7N9 pandemichas brought it into the spotlight worldwide [7-10]. However, direct circulation of blood across synthetic surfaces escalates a pro-inflammatory response, further exacerbating a disease process that is already associated with the activation of the inflammatory cascade [11]. "
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    ABSTRACT: Backgrounds: Extracorporeal membrane oxygenation (ECMO) has been recommended for treatment of acute, potentially reversible, life-threatening respiratory failure unresponsive to conventional therapy. Intestinal mucosal barrier dysfunction is one of the most critical pathophysiological disorders during ECMO. This study aimed to determine whether combination with CRRT could alleviate damage of intestinal mucosal barrier function during VV ECMO in a porcine model. Twenty-four piglets were randomly divided into control(C), sham(S), ECMO(E) and ECMO + CRRT(EC) group. The animals were treated with ECMO or ECMO + CRRT for 24 hours. After the experiments, piglets were sacrificed. Jejunum, ileum and colon were harvested for morphologic examination of mucosal injury and ultrastructural distortion. Histological scoring was assessed according to Chiu's scoring standard. Blood samples were taken from the animals at -1, 2, 6, 12 and 24 h during experiment. Blood, liver, spleen, kidney and mesenteric lymphnode were collected for bacterial culture. Serum concentrations of diamine oxidase (DAO) and intestinal fatty acid binding protein (I-FABP) were tested as markers to assess intestinal epithelial function and permeability. DAO levels were determined by spectrophotometry and I-FABP levels by enzyme linked immunosorbent assay. Microscopy findings showed that ECMO-induced intestinal microvillus shedding and edema, morphological distortion of tight junction between intestinal mucous epithelium and loose cell-cell junctions were significantly improved with combination of CRRT. No significance was detected on positive rate of serum bacterial culture. The elevated colonies of bacterial culture in liver and mesenteric lymphnode in E group reduced significantly in EC group (p < 0.05). Compared with E group, EC group showed significantly decreased level of serum DAO and I-FABP (p < 0.05). CRRT can alleviate the intestinal mucosal dysfunction and bacterial translocation during VV ECMO, which may extenuate the ECMO-associated SIRS and raise the clinical effect and safety.
    Full-text · Article · Apr 2014 · Journal of Cardiothoracic Surgery
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