The study was approved by the ethics committee of the Regensburg University Hospital (reference 07/012), and the ethics committees of all involved study centers. Before enrolment, written informed consent was obtained from the legal proxy of each patient. Patients were enrolled from September 2007 through December 2010 at eight intensive care units (ICU) in Germany and two ICU’s in Austria.
Entry criteria were: (1) presence of ARDS according to the American-European Consensus Conference  defined by bilateral infiltrates on chest X-ray, and a PaO2/FIO2 <200 present for at least 2 h. At the time of screening patients could not have any evidence of left ventricular failure; (2) age ≥18 years; (3) history of mechanical ventilation <7 days); (4) plateau pressure >25 cmH2O at defined ventilator settings (PEEP/FIO2-table + V
T = 6 ml/kg); (5) absence of severe hemodynamic instability with high demand for vasopressors (mean arterial pressure ≥70 mmHg with continuous norepinephrine infusion ≤0.4 μg/kg/min). Exclusion criteria were: decompensated heart insufficiency, acute coronary syndrome, severe chronic obstructive pulmonary disease, advanced malignancy with life expectancy <6 months, chronic dialysis treatment, lung transplant patients, proven heparin-induced thrombocytopenia (HIT), morbid obesity (body mass index >40 kg/m2), cirrhosis of the liver Child Class ≥B (Child–Pugh scores ≥7), or acute fulminant hepatic failure, severe peripheral arterial occlusive disease, absence of limb doppler pulse, and acute brain injury (Glasgow Coma Scale ≤9).
To identify patients presenting with established ARDS and to help further rule out patients with acute cardiogenic pulmonary edema, the screening was followed by a stabilization period for 24 h, characterized by lung protective mechanical ventilation with high PEEP (≥12 cmH2O), the use of supportive measures, and hemodynamic evaluation (echocardiography). Patients who had ARDS criteria (PaO2/FIO2 <200) after 24 h despite optimal supportive treatment were identified as those with established ARDS , and were randomized through phone hot line by a random number table generated by the involved statistician with respect to the stratum pulmonary/non-pulmonary ARDS (Fig. 1). The principal investigator (TB) performed visits aimed at information and supervision of the study protocol in the participating centers. An independent Data Safety Monitoring Board monitored the study.
Treatment of the study group
The intensive care management in both groups followed the ‘best clinical evidence’ recommended by the European Society of Intensive Care Medicine . The daily monitoring included the assessment of awakeness/sedation (Richmond Agitation Sedation Scale [RASS]) and the daily evaluation of the Sequential Organ Failure Assessment (SOFA) and the Simplified Acute Physiology Score (SAPS-II).
After randomization to the treatment group, percutaneous cannulation and initiation of pumpless extracorporeal lung assist (iLA AV, Novalung, Heilbronn, Germany) was performed. Unlike “classic” pump-driven extracorporeal carbon dioxide removal, iLA does not require a blood pump, because the extremely low resistance of this circuit allows flows of about 1–2 l/min with normal arterial pressures (for more detailed description: [10, 15]). Evaluation, cannulation and clinical monitoring for avECCO2-R can be found in electronic supplementary material (ESM).
After initiation of avECCO2-R, adaptation of the ventilation strategy according to study protocol was performed as follows: a rapid titration down to V
T 3 ml/kg/PBW, PEEP following ARDSNet “high-PEEP/FIO2” table , respiratory rate 10–25/min with an inspiratory/expiratory ratio of 1:1. Termination of the avECCO2-R therapy and decannulation was performed according to a defined algorithm (see ESM).
Treatment of the control group
The ventilatory management followed the algorithm of the study group except for the use of a V
T = 6 ml/kg/PBW. The target blood gases for both groups were: PaO2 ≥60 mmHg and arterial pH ≥7.2. The use of buffering (tris-(hydroxymethyl) aminomethane [TRIS]) was permitted if the patient had hypercapnia and respiratory acidosis (pH <7.2).
Weaning and extubation procedures
In both groups daily screening was performed as a precondition for carrying out a spontaneous breathing trial (SBT): ability to breathe spontaneously (FIO2 ≤0.4, SaO2 ≥90 %, PEEP ≤8 cmH2O, hemodynamic stability, RASS score ≥−1, body temperature <38.5°).
SBT was carried out over 1 h with augmented spontaneous breathing (ASB) 5 cmH2O with an active humidifier or, 10 cmH2O with HME filter (PEEP ≤8 cmH2O, flow trigger <3 l/min). Patients were extubated when no deterioration was observed over a 1 h period.
At the time of screening (24 h prior to randomization) physiologic data were recorded and relevant laboratory, radiographic and clinical findings were collected. Throughout the complete study period, data on ventilator settings, laboratory, physiologic, radiographic and interventional data were recorded. Relevant data of the ventilation management (V
T, PEEP, P
plat, minute ventilation, proportion of spontaneous ventilation on minute ventilation, arterial oxygen saturation) as well as results of the blood gas analyses (PaO2, PaCO2, pH) were recorded three times daily (8 a.m., 2 p.m., 10 p.m.) and the mean values of repeated measures were used for further analysis. SOFA score, SAPS-II and RASS scores were calculated daily (8 a.m.).
In addition, in a subgroup of study patients of the Regensburg University Hospital, depending on ‘in-the-daytime’-availability of requested lab values, the levels of proinflammatory cytokines (tumour necrosis factor [TNF], interleukin 6 [IL-6] and interleukin 8 [IL-8]) were assessed from serum probes of avECCO2-R-patients (n = 20) and control patients (n = 15) at various time points during the study, since the measurement of these parameters is part of the routine laboratory program in this hospital. Furthermore, in all participating centers the daily cumulative doses of vasopressors (norepinephrine, adrenaline, dobutamine), sedative and analgesic agents (sufentanil, propofol, midazolam) and net fluid balances were calculated in each patient and recorded.
The primary outcome parameter was the proportion of days without assisted ventilation in a 28-day period (“ventilator-free” days within 28 days [28-VFD]) and in a 60 days period (“ventilator-free” days within 60 days [60-VFD]) .
Secondary outcomes were: inspiratory plateau pressure levels (P
plat), the proportion of spontaneous breathing as a percentage of the minute ventilation (automatically calculated by the ventilator’s software), the RASS score, hemodynamic changes, the incidence of complications or adverse reactions, the frequency and duration of other adjunctive therapeutic measures, transfusion requirements [packed red blood cell transfusions (units), fresh frozen plasma units, platelet transfusion], the daily cumulative doses of analgesic and sedative agents, cumulative catecholamine requirements/24 h throughout the study period, frequency and duration of renal replacement therapy, the number of failing organs, the “organ-failure-free days” within 28 days after randomisation, and “in-hospital” mortality.
Assuming an increase in 28-VFD from 6.0 ± 10 (control group) to 11.0 ± 8 (study group ), we estimated that 53 patients would be needed per group for a power of 0.8 and an alpha of 0.05 (calculation by Charitè Centrum für Therapieforschung, Berlin, Germany). We assumed a “drop-out-rate” of 10 % and we calculated that 120 patients would need to be enrolled. However, after an interim analysis with 56 patients by the Data Safety Monitoring Board, it was decided to limit the study period to 3 years, since a statistical significant difference was not expected in a longer study period.
We used a Student’s t-test, the Wilcoxon test, the chi-square test or Fisher’s exact test to assess differences between the groups, as appropriate. A Kaplan–Meier curve was calculated and plotted to assess the days until successful weaning from the ventilator. Furthermore, a nonparametric analysis of longitudinal data in factorial experiments was performed. Changes in interesting clinical outcomes with respect to time were analyzed using multivariate nonparametric analysis of longitudinal data in a two-factorial design (1st [independent] factor: groups, 2nd [dependent] factor: repetitions in time). Therefore, all the time points were simultaneously compared on the corresponding response curves (analysis according to Brunner [Brunner-analysis 18]). Additionally, a post hoc analysis was performed in patients with greater hypoxemia (PaO2/FIO2 ≤150) regarding primary outcome parameters. The reported P values are two-sided and significance was set at P < 0.05.