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01.12.2018 | Research | Ausgabe 1/2018 Open Access

Critical Care 1/2018

Feasibility and safety of low-flow extracorporeal CO2 removal managed with a renal replacement platform to enhance lung-protective ventilation of patients with mild-to-moderate ARDS

Zeitschrift:
Critical Care > Ausgabe 1/2018
Autoren:
Matthieu Schmidt, Samir Jaber, Elie Zogheib, Thomas Godet, Gilles Capellier, Alain Combes
Abbreviations
AE
Adverse event
ANOVA
One-way analysis of variance
aPTTr
Activated partial thromboplastin time ratio
ARDS
Acute respiratory distress syndrome
Crs
Respiratory-system compliance
ECCO2R
Extracorporeal carbon-dioxide removal
ECMO
Extracorporeal membrane oxygenation
FiO2
Fraction of inspired oxygen
MV
Mechanical ventilation
PaO2
Partial alveolar oxygen pressure
PBW
Predicted body weight
PEEP
Positive end-expiratory pressure
Pplat
Plateau pressure
RR
Respiratory rate
RRT
Renal replacement therapy
SAE
Severe adverse event
VILI
Ventilator-induced lung injury
VT
Tidal volume

Background

Over the past few decades, highly significant progress has been made in understanding the pathophysiology of the acute respiratory distress syndrome (ARDS). Recognition of ventilation-induced lung injuries (VILIs) has led to radical modifications of the ventilatory management of these patients [ 1, 2]. The landmark trial by the ARDSNet group demonstrated that ventilating ARDS patients with a low tidal volume (VT) of 6 ml/kg (vs 12 ml/kg) significantly decreased mortality [ 3]. However, recent results showed that lung hyperinflation still occurs in approximately 30% of ARDS patients, despite ventilation with the ARDSNet strategy [ 4]. That analysis suggested a beneficial effect of VT reduction, even for patients already with plateau pressure (P plat) < 30 cmH 2O [ 5]. Decreasing VT and P plat will also lower the driving pressure, which was recently identified as a major risk factor for mortality in ARDS patients [ 6].
VT reduction to < 6 ml/kg to achieve very low P plat induces severe hypercapnia, which raises intracranial pressure, causes pulmonary hypertension, decreases myocardial contractility, reduces renal blood flow, and releases endogenous catecholamines [ 7, 8]. This strategy is therefore not possible for most ARDS patients on conventional mechanical ventilation (MV) [ 9]. Extracorporeal carbon-dioxide removal (ECCO 2R) may be used to achieve VT < 6 ml/kg, thereby lowering P plat and driving pressure in this setting [ 1013]. However, the ability to decrease MV intensity with these ECCO 2R devices, especially those based on a renal replacement therapy (RRT) platform, are limited to animal [ 14] or single-center [ 11, 1517] studies.
The aim of this prospective, multicenter study was to evaluate the safety and feasibility of a low-flow ECCO 2R device managed by an RRT platform (PrismaLung®; Gambro-Baxter, Meyzieu, France) to enable very low tidal volume ventilation in patients with mild-to-moderate ARDS.

Methods

Study design and procedure

This pilot study was conducted during a 14-month period (March 2016–June 2017) in five medical and surgical intensive care units (ICUs) experienced in the care of ARDS patients and use of extracorporeal gas-exchange devices. It was approved by appropriate legal and ethics authorities (Comité de Protection des Personnes Ile-de-France 6, Paris, France; no. 15.1026). The clinical trial protocol was registered with www.​clinicaltrials.​gov (ClinicalTrials.gov identifier: NCT02606240).

Patients

As predefined, 20 consecutive patients were included. Inclusion criteria were: mild-to-moderate ARDS according to the Berlin definition [ 18], 100 mmHg < partial alveolar oxygen pressure/fraction of inspired oxygen (PaO 2/FiO 2) < 300 mmHg with positive end-expiratory pressure (PEEP) > 5 cmH 2O on MV expected to last > 24 h; and bilateral opacities on chest imaging. Exclusion criteria were: age < 18 years, pregnancy, patients with decompensated heart failure or acute coronary syndrome, severe chronic-obstructive pulmonary disease, respiratory acidosis with partial pressure of blood carbon dioxide (PCO 2)> 80 mmHg, acute brain injury, severe liver insufficiency (Child–Pugh scores > 7) or fulminant hepatic failure, heparin-induced thrombocytopenia, systemic anticoagulation contraindicated, decision to limit therapeutic interventions, catheter access to femoral vein or jugular vein impossible, pneumothorax, and platelet count < 50 G/L.

ECCO2R system

ECCO 2R was provided by a low-flow, standalone (without concomitant RRT), CO 2-removal device (Prismalung®; Gambro-Baxter) integrated into the Prismaflex® platform (Gambro-Baxter). The polymethylpentene, hollow fiber, gas-exchanger membrane (surface area 0.32 m 2) was connected to the extracorporeal circuit, with standard tubes and a Luer-Lock system. A 13-Fr hemodialysis venous catheter (Gamcath™®; Gambro-Baxter) was aseptically and percutaneously inserted under ultrasonography guidance into the right jugular (15 cm) or the femoral (25 cm) vein after an unfractionated heparin bolus (80 IU/kg). Systemic heparinization was started after catheter insertion aiming for an activated partial thromboplastin time ratio (aPTTr) 1.5–2.0× that of the control. Blood was drawn from the superior vena cava and reinjected into the right atrium through the distal lumen. The Prismaflex® device monitored continuous venous, arterial line, and filter pressures.

Study protocol

Patients were sedated, paralyzed, and ventilated in accordance with the EXPRESS trial protocol [ 19]: VT at 6 ml/kg of predicted body weight (PBW); PEEP set to achieve P plat of 28–30 cmH 2O; and respiratory rate (RR) set at 20–35 breaths/min to maintain approximately the same minute ventilation as before study initiation. After priming, the Prismaflex® device was connected to the patient and extracorporeal blood flow was progressively increased to 400–450 ml/min. Sweep-gas flow through the membrane remained at 0 L/min during this phase such that, initially, no CO 2 was removed.
Following a 2-h run-in time, VT was gradually reduced from 6 to 5, 4.5, and 4 ml/kg PBW every 30 min and PEEP adjusted to reach 23 ≤ P plat ≤ 25 cmH 2O. At each VT level: if arterial PaCO 2 rose by > 20% from the baseline PaCO 2 obtained at 6 ml/kg, the sweep-gas flow through the ECCO 2R device was switched on with 100% oxygen at 10 L/min; if PaCO 2 was maintained within ± 20% of baseline PaCO 2, VT was gradually decreased to a minimum of 4 ml/kg ; and if PaCO 2 remained < 20% at 4 ml/kg PaCO 2 under the aforementioned ECCO 2R settings, the RR could be decreased to 15–18 breaths/min. On the other hand, the RR could also be increased up to 35 breaths/min to maintain PaCO 2 within the targeted range. If undesirable hypercapnia/acidosis persisted (i.e., > 20% 6 ml/kg PaCO 2), VT was reincreased to the previous step level. Refractory hypoxemia and/or hypercapnia could be managed, at the attending physician’s discretion, with nitric oxide, prone positioning, and/or venovenous extracorporeal membrane oxygenation (ECMO).
The ECCO 2R-facilitated very low tidal volume ventilation strategy was continued for at least 24 h. The potential for weaning off very low tidal volume ventilation and ECCO 2R was assessed daily if PaO 2/FiO 2 > 200 by setting MV according to conventional ARDSnet settings (VT = 6 ml/kg, PEEP = 5–10 cmH 2O, RR = 20–30 breaths/min, FiO 2 = 40%) and switching off the sweep-gas flow through the ECCO 2R device. If, under these conditions, the patient remained stable for at least 12 h with P plat < 25 cmH 2O and PaCO 2 < 50 mmHg (allowing for RR up to 30–35 breaths/min), the ECCO 2R device and venous catheter were removed. The manufacturer determined the Prismalung® membrane’s maximum duration to be 72 h.

Data collection

Ventilator settings (VT, PEEP, RR, P plat, minute ventilation, FiO 2), hemodynamic parameters (mean arterial pressure, heart rate, vasopressor dose) and arterial blood-gas values (pH, PaO 2, PaCO 2, HCO 3 , lactate), heparin dose, and aPTTr were collected at baseline, after the run-in-time, 30 min after every VT reduction, and at least twice a day during the subsequent days on ECCO 2R. Blood-chemistry determinations were obtained daily. Respiratory-system compliance and driving pressure were calculated according to the standard formulas [ 6, 20]. CO 2 clearance by ECCO 2R (ml/min) during the first 24 h was calculated as follows [ 17]:
(CtCO 2PRE – CtCO 2POST) × 22.4 × ECCO 2R blood flow / 1000,
where CtCO 2PRE and CtCO 2POST were the pre and post oxygenator blood CO 2 content, and CtCO 2 (mmol/l) = (0.0307 × PCO 2) + HCO 3 actual.
Serious adverse events (SAEs) were prospectively defined as: any event that is fatal or immediately life-threatening, permanently disabling, severely incapacitating, or requires prolonged hospitalization; OR any event that may jeopardize the patient and requires medical or surgical intervention to prevent one of these outcomes; AND any event that the attending physician perceives might be directly related to enrollment in the clinical trial. An AE was defined as: study related when it could be attributed to a study procedure and could readily have been produced by the study procedure; or nonstudy related when it was related primarily to the underlying disease or to ARDS and its sequelae. Other AEs not fulfilling this definition were recorded in the patients’ case-report forms. After ECCO 2R discontinuation, subjects were monitored for AEs until hospital discharge or day 8 post enrollment, whichever occurred first.

Statistical analyses

Statistical analysis was performed by one-way analysis of variance (ANOVA) for repeated measures, followed by a Bonferroni post-hoc test for comparison between different times. Results are expressed as mean ± SD and p < 0.05 defined statistical significance. Analyses were computed with StatView v5.0 (SAS Institute Inc., Cary, NC, USA) and SPSS v22 (SPSS Inc., Chicago, IL, USA) software.

Results

Twenty patients with mild ( n = 8) or moderate ARDS ( n = 12) were included; 18 underwent jugular cannulation. Patients’ baseline characteristics are reported in Table  1. Neuromuscular blockade, nitric oxide, and prone positioning were applied before inclusion to 16, 9, and 8 patients, respectively. Ventilator settings during the VT reduction phase are presented in Table  2 and Fig.  1. At baseline, all patients received protective ventilation with VT set at 6.10 ± 0.30 ml/kg PBW and PEEP at 13.4 ± 3.6 cmH 2O. VT was gradually lowered to 4 ml/kg for all but one patient (who remained at the 4.5 ml/kg step because PaCO 2 increased > 20% from baseline at the 4.5 ml/kg step despite ECCO 2R; see Table  2). While P plat was decreased < 25 cmH 2O with VT reduction to 4 ml/kg, PEEP was significantly increased from 13.4 ± 3.6 cmH 2O at baseline to 15.0 ± 3.4 cmH 2O, according to the very low tidal volume ventilation strategy. As a result, the driving pressure was reduced from 13.0 ± 4.8 to 7.9 ± 3.2 cmH 2O ( p < 0.05). Mean PaCO 2 increased from 43 ± 8 to 53 ± 9 mmHg and mean pH decreased from 7.39 ± 0.1 to 7.32 ± 0.10 from baseline to 4 ml/kg VT, while RR was not modified. The mean CO 2-removal rate was 51 ± 26 ml/min with 421 ± 40 ml/min blood flow and sweep-gas flow set at 10 ± 0.3 L/min. Importantly, VT and driving pressure reductions with ECCO 2R were not accompanied by significant changes of PaO 2/FiO 2, respiratory-system compliance, and hemodynamic status (Table  2). In the 24 h following ECCO 2R initiation, nitric oxide was applied to four patients, of whom two also received prone positioning. No patients required ECMO for worsening hypoxemia while receiving very low tidal volume ventilation.
Table 1
Baseline characteristics of the 20 patients
Characteristic
Value
Sex (male/female)
11/9
Age (years)
60 ± 12
Body mass index (kg/m 2)
30 ± 7
Medical/surgical
14/6
SAPS II
56 ± 21
SOFA score at ECCO 2R insertion
9.3 ± 4.3
Pulmonary ARDS risk factor
 Community-acquired pneumonia
5 (25)
 Nosocomial pneumonia
6 (30)
 Inhalation pneumonia
5 (25)
Nonpulmonary ARDS risk factor
 Pancreatitis
2 (10)
 Other
2 (10)
Pre-ECCO 2R adjuvant therapy
 Neuromuscular blockade
16 (80)
 Prone positioning
8 (40)
 Nitric oxide
9 (45)
 Recruitment maneuvers
0 (0)
 ECMO
0 (0)
Time from intubation to ECCO 2R initiation (days)
4 (2–7)
Outcome
 Mechanical ventilation duration (days)
13 (9–38)
 ICU length of stay (days)
18 (14–41)
 Day-28 mortality
3 (15)
Data presented as n (%), mean ± standard deviation, or median (25–75% interquartile range)
ARDS acute respiratory distress syndrome, ECCO 2 R extracorporeal carbon-dioxide removal, ECMO extracorporeal membrane oxygenation, ICU intensive care unit, SAPS Simplified Acute Physiology Score, SOFA Sequential Organ-Failure Assessment
Table 2
Time course of ventilation parameters during the run-in phase
Parameter
Baseline
( n = 20)
VT 5 ml/kg
( n = 20)
VT 4.5 ml/kg
( n = 20)
VT 4 ml/kg
( n = 19) a
Ventilation variable
 VT (ml/kg PBW) b
6.10 ± 0.30
5.04 ± 0.22 c
4.49 ± 0.12 c
3.98 ± 0.18 c
 RR (breaths/min)
26 ± 4
26 ± 4
26 ± 4
25 ± 6
 PEEP (cmH 2O) b
13.4 ± 3.6
13.4 ± 3.3
14.4 ± 3.3v
15.0 ± 3.4
 P plat (cmH 2O) b
26.3 ± 3.5
24.1 ± 3.0 c
23.3 ± 2.8 c
22.8 ± 2.6 c
 Driving pressure (cmH 2O) b
13.0 ± 4.8
10.7 ± 3.8v
8.9 ± 3.3v
7.9 ± 3.2 c
 Compliance (ml/cmH 2O)
33.8 ± 14.2
33.6 ± 12.7
36.0 ± 13.3
36.9 ± 13.4
 PaO 2/FiO 2
188 ± 75
192 ± 80
191 ± 71
184 ± 67
Blood gases
 pH b
7.39 ± 0.1
7.36 ± 0.10
7.34 ± 0.10 c
7.32 ± 0.10 c
 PaO 2 (mmHg)
96 ± 36
93 ± 30
96 ± 24
89 ± 19
 PaCO 2 (mmHg) b
43 ± 8
46 ± 7
49 ± 9 c
53 ± 9 c
 HCO 3 (mmol/L)
26 ± 4
26 ± 4
27 ± 5
27 ± 4
 Lactate (mmol/L)
1.4 ± 0.6
1.2 ± 0.4
1.2 ± 0.5
1.2 ± 0.4
Patients on ECCO 2R, n d
7
14
19
Patients with PaCO 2 > 50 mmHg
2
9
9
11
ECCO 2R
 Blood flow (ml/min)
424 ± 39
425 ± 38
421 ± 40
 Sweep-gas flow (L/min)
10 ± 0.3
10 ± 0.3
10 ± 0.3
 CO 2 removal (ml/min)
51 ± 26
Hemodynamic
 Mean arterial pressure (mmHg)
76 ± 11
79 ± 20
76 ± 12
77 ± 19
 Heart rate (beats/min)
86 ± 15
85 ± 13
85 ± 14
83 ± 15
 Patients on norepinephrine
9
9
9
10
 Norepinephrine dose (μg/kg/min)
0.61 ± 1.10
0.55 ± 1.00
0.55 ± 0.99
0.50 ± 0.97
Values presented as mean ± standard deviation or n (%)
ECCO 2 R extracorporeal carbon-dioxide removal, FiO 2 fraction of inspired oxygen, HCO 3 bicarbonate, PaCO 2 partial alveolar carbon dioxide pressure, PaO 2 partial alveolar oxygen pressure, PBW predicted body weight, PEEP end-expiratory positive pressure, P plat plateau pressure, RR respiratory rate, VT tidal volume
aOne patient’s PaCO 2 increased > 20% at the VT 4.5 ml/kg step and did not undergo further VT reduction
b p < 0.05, analysis of variance
c p < 0.05 vs baseline
dECCO2R initiated according to the study protocol when patients had a 20% increase in PaCO 2 from baseline following VT decrease
Operational characteristics of the ECCO 2R device recorded in the hour following therapy initiation, including access, return, and filter pressures, are presented in Table  3. Overall mean duration of ECCO 2R was 31 ± 21 h. It was continued up to 41 ± 24 h until weaning because of improved respiratory condition for 10 patients and was stopped early because of ECCO 2R-membrane clotting for 10 patients after 20 ± 10 h. The mean daily heparin dose was 19,900 ± 7710 IU/24 h and the mean aPTTr was 1.8 ± 0.6. No cannulation-related complication occurred. One patient suffered a nonfatal cardiac arrest while on ECCO 2R but this was unrelated to the device. Other AEs included two mild hemoptyses that resolved rapidly without embolization and were not related to heparin overdose. The overall day-28 mortality was 15%.
Table 3
Operational characteristics of extracorporeal carbon-dioxide removal for the 20 patients with acute respiratory distress syndrome
Characteristic
Value
Blood flow (ml/min) a
421 ± 42
Time of utilization (h)
30.6 ± 21.0
Access pressure (mmHg) a
− 145 ± 14
Filter pressure (mmHg) a
301 ± 19
Return pressure (mmHg) a
154 ± 21
Heparin bolus at insertion (IU)
3100 ± 1330
Heparin (IU/kg/24 h)
230 ± 78
Activated partial thromboplastin time ratio
1.8 ± 0.6
Serious adverse event b
 Nonfatal cardiac arrest
1 (5)
Study-related adverse event
 Mild hemoptysis resolved with stopping anticoagulation c
2 (10)
 Membrane clotting
10 (50)
  Time it occurred (h)
20.0 ± 9.7
Values presented as mean ± standard deviation or n (%)
aRecorded in the hour following initiation of extracorporeal carbon-dioxide removal
bNot device related
cResolved without embolization and not related to heparin overdose

Discussion

The results of this multicenter pilot study showed that a low-flow ECCO 2R device managed by the RRT platform easily and safely enabled very low tidal volume ventilation with highly significant decreases of P plat and driving pressure in patients with mild-to-moderate ARDS.
Total energy determinants (i.e., mechanical power) are transmitted to the lung by the ventilator-generated volume, pressure, flow, and RR [ 21]. Decreasing MV intensity and, thereby limiting VILI, requires a diminution of the total mechanical power transferred to the lung [ 21]. More than 15 years ago, it was demonstrated that volume-limited ventilation with 6 ml/kg PBW significantly lowered ARDS-associated mortality [ 3]. However, recent data suggested that some ARDS patients are exposed to hyperinflation and overdistension, despite protective ventilation with 6 ml/kg VT and P plat limited to < 30 cmH 2O. Pertinently, Hager et al. [ 5] demonstrated that lower P plat was associated with less mortality and that no safe low P plat threshold could be identified in patients with acute lung injury/ARDS. Furthermore, based on a prospective series of 485 consecutive patients with acute lung injury on MV, Needham et al. [ 22] showed that, compared with a mean VT < 6.5 ml/kg PBW, the adjusted hazard ratios for 2-year mortality for a mean VT of 6.5–8.5 ml/kg PBW was 1.59 (95% CI 1.19–2.14; p = 0.001). Amato et al. [ 6] recently reported that, in addition to VT, P plat, and PEEP, normalizing VT to respiratory-system compliance (C rs) and using a ratio as an index indicating the “functional” size of the lung might provide a better predictor of ARDS patients’ outcomes than VT alone. That ratio, termed the driving pressure ( ΔP = VT / C rs), can be routinely calculated as the P plat – PEEP for patients who are not making inspiratory efforts. Their analyses indicated that VT reductions or PEEP increases driven by random treatment-group assignment were beneficial only when associated with ΔP decreases and that no other ventilation variable had such a mediating effect on mortality [ 6]. More recently, lower ΔP was also was also associated with lower ARDS-patient mortality in the large LUNG-SAFE cohort [ 23].
Furthermore, reducing VT to 4 ml/kg PBW in patients already receiving protective ventilation was associated with less inflammatory and morphological signs of VILI in ARDS patients [ 11]. This particular study used ECCO 2R to mitigate the respiratory acidosis, and its potent deleterious effects [ 7, 8, 24], which developed in all patients receiving VT < 6 ml/kg IBW [ 10, 11]. Results based on previous case series using various ECCO 2R devices showed the feasibility of this strategy in ARDS patients, although AEs (e.g., cannulation-related accidents, limb ischemia, hemorrhage, hemolysis, infections, pump malfunction, membrane clotting, and catheter displacement) were reported [ 10, 11, 2528].
Our results demonstrated that this strategy might be safely, efficiently, and easily applied to ARDS patients in most ICUs worldwide, because it did not require specific or large venous accesses and the RTT platform we used is widely available with minimal modification of existing devices and a simple software update. ECCO 2R with this RRT platform has indeed obtained promising results in animals [ 14]. By decreasing VT to 4 ml/kg PBW and adjusting PEEP to a lower P plat target of 23–25 cmH 2O, we were able to drastically decrease the driving pressure to < 8 cmH 2O, which might mean less VILI and ultimately fewer deaths [ 6]. Importantly, we did not observe worsening oxygenation that might have indicated lung derecruitment following the mean airway-pressure decrease [ 28, 29], although some patients with the most severe forms of ARDS continued to receive nitric oxide or prone positioning following ECCO2R initiation. The PEEP increase resulting from the ventilator strategy used might have counterbalanced that potential hazard [ 11, 13, 28, 30]. The absence of worsening oxygenation also argues against alveoli nitrogen washout and potential absorption atelectasis, which is less likely to occur in low-flow ECCO2R than during high-flow VV-ECMO.
Several limitations of our work should be addressed. First, because our population was small, this study should only be considered “a proof-of-concept” demonstrating the feasibility and safety of the strategy tested. We cannot rule out that there is still a substantial risk of adverse events that could have been missed in this small study. Second, our population included only patients with mild or moderate ARDS. Because severe ARDS patients might experience greater PaCO 2 increases and more severe hypoxemia after VT reduction, the Prismalung® performance remains unknown in this context. Third, to achieve VT reduction down to 4 ml/kg in a larger population of patients without the risks of inducing major PaCO 2 increases not compensated by the low-flow ECCO 2R device, we also applied the modified EXPRESS strategy to patients with mild ARDS. Because of higher PEEP settings in this population of patients with higher compliance, it should be acknowledged that this approach may induce overdistension despite lowering the driving pressure. In addition, potential benefits of a very low tidal volume ventilation strategy have only been suggested in moderate-to-severe ARDS patients until now [ 10, 11]. Fourth, we did not evaluate lung morphological and inflammatory markers or the long-term clinical efficacy of the device. Fifth, due to its smaller membrane oxygenator surface, the CO 2-removal rate of the Prismalung® was lower than those reported in other studies using similar blood flows [ 17, 28], explaining the gradual increase in PaCO 2 observed during the VT reduction phase. This mild respiratory acidosis might have been corrected by increasing the RR, at the expense of an increase in mechanical power. Indeed, the physicians treating these patients decided to tolerate this mild acidosis, as recent data also suggest an increased RR might be associated with a poorer ARDS prognosis [ 31]. Lastly, despite our heparin-infusion protocol that also included a bolus at catheter insertion, 50% of the treated patients experienced membrane clotting before the end of the experimental protocol, as reported previously for other case series given low-flow ECCO 2R [ 11, 15]. This technical downside deserves further investigations as it could limit the efficacy and impact the cost–benefit ratio of the device. The development of regional circuit anticoagulation strategies, with blood flows up to 500 ml/min, might enhance ECCO 2R membrane duration, as was the case for RRT hemofilters [ 32].

Conclusions

In summary, our pilot study findings demonstrated that a low-flow ECCO 2R device managed by an RRT platform enabled very low tidal volume ventilation with moderate increase in PaCO 2 in patients with mild-to-moderate ARDS. This less-invasive ECCO 2R technique was easily and safely implemented. However, before this technique can be widely disseminated, more data are needed to demonstrate the clinical benefit of VT, P plat, and driving pressure reductions rendered possible by ECCO 2R [ 33]. The ongoing international randomized clinical trials SUPERNOVA (ClinicalTrials.gov identifier: NCT02282657) and REST (Clinical-Trials.gov identifier: NCT02654327) focused on moderate ARDS will help clarify this potential.

Funding

Gambro-Baxter provided devices and CO 2-removal kits, and financial support to conduct this study.

Availability of data and materials

Please contact author for data requests.

Ethics approval and consent to participate

The study was approved by the Comité de Protection des Personnes Ile-de-France 6, Paris, France (no. 15.1026). The clinical trial protocol was registered with www.​clinicaltrials.​gov (ClinicalTrials.gov identifier: NCT02606240, 17 November 2015). Informed consent was obtained from all patients or their surrogates.

Competing interests

MS has received lecture fees from Maquet. SJ has received lecture fees from Drager, Fisher-Paykel, and Xenios. EZ has received consultant fees from Gambro. TG has received lecture fees and travel reimbursements for meetings from Gambro-Baxter and General Electrics. GC has received lecture fees from Alung and Baxter. AC has received lecture fees from Baxter and Maquet. AC is the primary investigator of the EOLIA trial (ClinicalTrials.gov identifier: NCT01470703), partly supported by Maquet.

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