Raiko Blondonnet

Soluble Receptor for Advanced Glycation End-Products Predicts Impaired Alveolar Fluid Clearance in Acute Respiratory Distress Syndrome

RATIONALE Levels of the soluble form of the receptor for advanced glycation end-products (sRAGE) are elevated during acute respiratory distress syndrome (ARDS) and correlate with severity and prognosis. Alveolar fluid clearance (AFC) is necessary for the resolution of lung edema but is impaired in most patients with ARDS. No reliable marker of this process has been investigated to date. OBJECTIVES To verify whether sRAGE could predict AFC during ARDS. METHODS Anesthetized CD-1 mice underwent orotracheal instillation of hydrochloric acid. At specified time points, lung injury was assessed by analysis of blood gases, alveolar permeability, lung histology, AFC, and plasma/bronchoalveolar fluid measurements of proinflammatory cytokines and sRAGE. Plasma sRAGE and AFC rates were also prospectively assessed in 30 patients with ARDS. MEASUREMENTS AND MAIN RESULTS The rate of AFC was inversely correlated with sRAGE levels in the plasma and the bronchoalveolar fluid of acid-injured mice (Spearmans ρ = -0.73 and -0.69, respectively; P < 10(-3)), and plasma sRAGE correlated with AFC in patients with ARDS (Spearmans ρ = -0.59; P < 10(-3)). Similarly, sRAGE levels were significantly associated with lung injury severity, and decreased over time in mice, whereas AFC was restored and lung injury resolved. CONCLUSIONS Our results indicate that sRAGE levels could be a reliable predictor of impaired AFC during ARDS, and should stimulate further studies on the pathophysiologic implications of RAGE axis in the mechanisms leading to edema resolution. Clinical trial registered with www.clinicaltrials.gov (NCT 00811629).

Soluble Forms and Ligands of the Receptor for Advanced Glycation End-Products in Patients with Acute Respiratory Distress Syndrome: An Observational Prospective Study

Background The main soluble form of the receptor for advanced glycation end-products (sRAGE) is elevated during acute respiratory distress syndrome (ARDS). However other RAGE isoforms and multiple ligands have been poorly reported in the clinical setting, and their respective contribution to RAGE activation during ARDS remains unclear. Our goal was therefore to describe main RAGE isoforms and ligands levels during ARDS. Methods 30 ARDS patients and 30 mechanically ventilated controls were prospectively included in this monocenter observational study. Arterial, superior vena cava and alveolar fluid levels of sRAGE, endogenous-secretory RAGE (esRAGE), high mobility group box-1 protein (HMGB1), S100A12 and advanced glycation end-products (AGEs) were measured in duplicate ELISA on day 0, day 3 and day 6. In patients with ARDS, baseline lung morphology was assessed with computed tomography. Results ARDS patients had higher arterial, central venous and alveolar levels of sRAGE, HMGB1 and S100A12, but lower levels of esRAGE and AGEs, than controls. Baseline arterial sRAGE, HMGB1 and S100A12 were correlated with nonfocal ARDS (AUC 0.79, 0.65 and 0.63, respectively). Baseline arterial sRAGE, esRAGE, S100A12 and AGEs were associated with severity as assessed by PaO2/FiO2. Conclusions This is the first kinetics study of levels of RAGE main isoforms and ligands during ARDS. Elevated sRAGE, HMGB1 and S100A12, with decreased esRAGE and AGEs, were found to distinguish patients with ARDS from those without. Our findings should prompt future studies aimed at elucidating RAGE/HMGB1/S100A12 axis involvement in ARDS. Trial Registration clinicaltrials.gov Identifier: NCT01270295.

A Pathophysiologic Approach to Biomarkers in Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is an acute-onset hypoxic condition with radiographic bilateral lung infiltration. It is characterized by an acute exudative phase combining diffuse alveolar damage and lung edema followed by a later fibroproliferative phase. Despite an improved understanding of ARDS pathobiology, our ability to predict the development of ARDS and risk-stratify patients with the disease remains limited. Biomarkers may help to identify patients at the highest risk of developing ARDS, assess response to therapy, predict outcome, and optimize enrollment in clinical trials. After a short description of ARDS pathobiology, here, we review the scientific evidence that supports the value of various ARDS biomarkers with regard to their major biological roles in ARDS-associated lung injury and/or repair. Ongoing research aims at identifying and characterizing novel biomarkers, in order to highlight relevant mechanistic explorations of lung injury and repair, and to ultimately develop innovative therapeutic approaches for ARDS patients. This review will focus on the pathophysiologic, diagnostic, and therapeutic implications of biomarkers in ARDS and on their utility to ultimately improve patient care.

Sevoflurane for Sedation in Acute Respiratory Distress Syndrome. A Randomized Controlled Pilot Study

Rationale: Sevoflurane improves gas exchange, and reduces alveolar edema and inflammation in preclinical studies of lung injury, but its therapeutic effects have never been investigated in acute respiratory distress syndrome (ARDS). Objectives: To assess whether sevoflurane would improve gas exchange and inflammation in ARDS. Methods: We did a parallel, open‐label single‐center randomized controlled trial at three intensive care units from a French university hospital between April 2014 and February 2016. Adult patients were randomized within 24 hours of moderate‐to‐severe ARDS onset to receive either intravenous midazolam or inhaled sevoflurane for 48 hours. The primary outcome was the PaO2/FiO2 ratio on Day 2. Secondary endpoints included alveolar and plasma levels of cytokines and soluble form of the receptor for advanced glycation end‐products, and safety. Investigators who did the analyses were masked to group allocation. Analysis was by intention to treat. Measurements and Main Results: Twenty‐five patients were assigned to the sevoflurane group and 25 to the midazolam group. On Day 2, PaO2/FiO2 ratio was higher in the sevoflurane group than in the midazolam group (mean ± SD, 205 ± 56 vs. 166 ± 59, respectively; P = 0.04). There was a significant reduction over time in cytokines and soluble form of the receptor for advanced glycation end‐products levels in the sevoflurane group, compared with the midazolam group, and no serious adverse event was observed with sevoflurane. Conclusions: In patients with ARDS, use of inhaled sevoflurane improved oxygenation and decreased levels of a marker of epithelial injury and of some inflammatory markers, compared with midazolam. Clinical trial registered with www.clinicaltrials.gov (NCT 02166853).

Net alveolar fluid clearance is associated with lung morphology phenotypes in acute respiratory distress syndrome

BACKGROUND The acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome that encompasses multiple phenotypes, e.g. with regards to lung morphology as assessed by computed tomography (CT). Focal or non-focal lung morphology may influence the response to positive end-expiratory pressure (PEEP), recruitment manoeuvres and prone position. Lung morphology has been hypothesized to be associated with alveolar fluid clearance (AFC), thus explaining various responses to such therapeutic interventions; however, this hypothesis has not been specifically studied in humans. METHODS We measured net AFC rates in 30 patients with ARDS as a secondary data analysis of a prospective single-centre study. Net AFC rates were compared between patients with focal ARDS and those with non-focal ARDS, as assessed by lung CT-scans. RESULTS Net AFC rates were significantly lower in patients with non-focal ARDS (n=23; median [interquartile range], 1.5 [0-5.5] %/h) as compared to those with focal ARDS (n=7; 10.3 [4.5-15] %/h) (P=0.01). The area under the receiver-operating characteristic curve when net AFC rates were used to differentiate the presence from absence of non-focal ARDS was 0.93 (95% confidence interval, 0.81-1). Tidal volumes and PEEP levels differed between focal and non-focal ARDS patients, but there was no difference in arterial oxygenation or in alveolar-capillary permeability. CONCLUSIONS Non-focal lung morphology may be characterized by a functional endotype consistent with marked AFC impairment. Despite study limitations and the need for validating studies in larger cohorts, such novel findings may reinforce our understanding of the association between ARDS phenotypes and therapeutic responses.

Receptor for advanced glycation end-products and ARDS prediction: a multicentre observational study

Acute respiratory distress syndrome (ARDS) prediction remains challenging despite available clinical scores. To assess soluble receptor for advanced glycation end-products (sRAGE), a marker of lung epithelial injury, as a predictor of ARDS in a high-risk population, adult patients with at least one ARDS risk factor upon admission to participating intensive care units (ICUs) were enrolled in a multicentre, prospective study between June 2014 and January 2015. Plasma sRAGE and endogenous secretory RAGE (esRAGE) were measured at baseline (ICU admission) and 24 hours later (day one). Four AGER candidate single nucleotide polymorphisms (SNPs) were also assayed because of previous reports of functionality (rs1800625, rs1800624, rs3134940, and rs2070600). The primary outcome was ARDS development within seven days. Of 500 patients enrolled, 464 patients were analysed, and 59 developed ARDS by day seven. Higher baseline and day one plasma sRAGE, but not esRAGE, were independently associated with increased ARDS risk. AGER SNP rs2070600 (Ser/Ser) was associated with increased ARDS risk and higher plasma sRAGE in this cohort, although confirmatory studies are needed to assess the role of AGER SNPs in ARDS prediction. These findings suggest that among at-risk ICU patients, higher plasma sRAGE may identify those who are more likely to develop ARDS.

Voriconazole-induced bradycardia without QT interval prolongation: a possible non-concentration-dependent adverse effect

Dear Editor, Voriconazole is commonly used for prophylaxis and treatment of invasive aspergillosis and to improve the survival of mechanically ventilated hematology patients with invasive pulmonary aspergillosis (IPA) [1]. Cardiac adverse effects can occur, but only cases of tachycardia have been described with voriconazole. Here, we report the cases of three patients admitted to the Intensive Care Unit (ICU) with suspected voriconazoleinduced bradycardia. A 63-year-old woman was admitted for pneumonia (Escherichia coli) with septic shock. She had prolonged neutropenia due to chemotherapy for a diffuse large-cell lymphoma. On day 7, an IPA was suspected, and antifungal therapy with voriconazole was started. Two days following the initiation of voriconazole therapy, we observed multiple episodes of spontaneous bradycardia (20–25 beats/ min) and a QTc up to 0.40 s. As voriconazole was the only change in the patient’s therapeutic regimen, we discontinued the administration of voriconazole and switched her to caspofungin. Normalization of the heart rate occurred during the next day and continued until discharge from the ICU. A 52-year-old woman with chemotherapy-induced myelosuppression was administered voriconazole (400 mg twice per day) for suspected IPA. The diagnosis was confirmed by a computed tomography scan, increased bronchoalveolar lavage antigens and positive test result of sputum for Aspergillus fumigatus. After 4 days of voriconazole therapy, the patient developed arrhythmias followed by sinus bradycardia (QTc = 0.38 s) that required atropine. The replacement of voriconazole with caspofungin was followed by resolution of bradycardia. A 78-year-old man was admitted to the ICU for acute respiratory failure after abdominal surgery. One month later IPA due to Aspergillus fumicatus was diagnosed. Voriconazole therapy was initiated (400 mg twice per day). He also received propofol, remifentanil, haloperidol, nefopam, piperacillin–tazobactam and gabapentine. Three days later, however, the patient experienced several episodes of spontaneous and extreme bradycardia with complete atrioventricular block and a QTc up to 0.36 s on the electrocardiogram (Fig. 1), requiring the administration of isoprenaline. The serum potassium level was 3.6 mmol/L. Voriconazole was administrated intravenously at 300 mg twice per day for 1 week. Plasma voriconazole concentrations (as determined by high-performance liquid chromatography) were 2.86, 3.08 and 3.20 mg/L on the first 3 days following the initiation of therapy, respectively (normal range 1–5.5 mg/L) [2]. We replaced voriconazole with caspofungin, and the patient recovered a sinus cardiac rhythm after 12 h, which he maintained up to discharge from the ICU without any new episodes. In these three patients, severe episodes of bradycardia were not associated with QTc prolongation, torsades de pointes or ventricular tachycardia. All patients were treated

Plasma sRAGE is independently associated with increased mortality in ARDS: a meta-analysis of individual patient data

PurposeThe soluble receptor for advanced glycation end-products (sRAGE) is a marker of lung epithelial injury and alveolar fluid clearance (AFC), with promising values for assessing prognosis and lung injury severity in acute respiratory distress syndrome (ARDS). Because AFC is impaired in most patients with ARDS and is associated with higher mortality, we hypothesized that baseline plasma sRAGE would predict mortality, independently of two key mediators of ventilator-induced lung injury.MethodsWe conducted a meta-analysis of individual data from 746 patients enrolled in eight prospective randomized and observational studies in which plasma sRAGE was measured in ARDS articles published through March 2016. The primary outcome was 90-day mortality. Using multivariate and mediation analyses, we tested the association between baseline plasma sRAGE and mortality, independently of driving pressure and tidal volume.ResultsHigher baseline plasma sRAGE [odds ratio (OR) for each one-log increment, 1.18; 95% confidence interval (CI) 1.01–1.38; P = 0.04], driving pressure (OR for each one-point increment, 1.04; 95% CI 1.02–1.07; P = 0.002), and tidal volume (OR for each one-log increment, 1.98; 95% CI 1.07–3.64; P = 0.03) were independently associated with higher 90-day mortality in multivariate analysis. Baseline plasma sRAGE mediated a small fraction of the effect of higher ΔP on mortality but not that of higher VT.ConclusionsHigher baseline plasma sRAGE was associated with higher 90-day mortality in patients with ARDS, independently of driving pressure and tidal volume, thus reinforcing the likely contribution of alveolar epithelial injury as an important prognostic factor in ARDS. Registration: PROSPERO (ID: CRD42018100241).

Inhibition of the Receptor for Advanced Glycation End-Products in Acute Respiratory Distress Syndrome: A Randomised Laboratory Trial in Piglets

Background The receptor for advanced glycation end products (RAGE) modulates the pathogenesis of acute respiratory distress syndrome (ARDS). RAGE inhibition was recently associated with attenuated lung injury and restored alveolar fluid clearance (AFC) in a mouse model of ARDS. However, clinical translation will first require assessment of this strategy in larger animals. Methods Forty-eight anaesthetised Landrace piglets were randomised into a control group and three treatment groups. Animals allocated to treatment groups underwent orotracheal instillation of hydrochloric acid i) alone; ii) in combination with intravenous administration of a RAGE antagonist peptide (RAP), a S100P-derived peptide that prevents activation of RAGE by its ligands, or iii) in combination with intravenous administration of recombinant soluble (s)RAGE that acted as a decoy receptor. The primary outcome measure was net AFC at 4 h. Arterial oxygenation was assessed hourly for 4 h and alveolar-capillary permeability, alveolar inflammation, lung histology and lung mRNA expression of the epithelial sodium channel (α1-ENaC), α1-Na,K-ATPase and aquaporin (AQP)-5 were assessed at 4 h. Findings Treatment with either RAP or sRAGE improved net AFC rates (median [interquartile range], 21.2 [18.8–21.7] and 19.5 [17.1–21.5] %/h, respectively, versus 12.6 [3.2–18.8] %/h in injured, untreated controls), improved oxygenation and decreased alveolar inflammation and histological evidence of tissue injury after acid-induced ARDS. RAGE inhibition also restored lung mRNA expression of α1-Na,K-ATPase and AQP-5. Interpretation RAGE inhibition restored AFC and attenuated lung injury in a piglet model of acid-induced ARDS. Funding Auvergne Regional Council, Agence Nationale de la Recherche, Direction Générale de l’Offre de Soins. Research in Context Evidence before this study The acute respiratory distress syndrome (ARDS), a clinical syndrome of diffuse pulmonary oedema and inflammation, currently lacks effective therapies and is associated with high mortality and morbidity. The degrees of lung epithelial injury and of alveolar fluid clearance (AFC) impairment, as evaluated by plasma levels of soluble receptor for glycation end-products (RAGE), are major prognostic factors in ARDS and potential therapeutic targets for ongoing research. For example, targeting RAGE with recombinant sRAGE or an anti-RAGE monoclonal antibody has proven beneficial in a translational mouse model of acid-induced ARDS. Added value of this study In a piglet model of acid-induced ARDS, treatment with RAGE antagonist peptide or recombinant sRAGE restored AFC and attenuated the features of lung injury, thereby confirming, in the closest evolutionary model species to humans, previous evidence from rodent models that modulation of RAGE may be a therapeutic option for ARDS. Although this is an important step towards future clinical translation, future studies should assess the best methods to modulate RAGE and further confirm the safety of manipulating this pathway in patients with ARDS.