Laurence Roszyk

Plasma neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in adult critically ill patients: A prospective study

PURPOSE The aim of the study was to assess the ability of plasma neutrophil gelatinase-associated lipocalin (pNGAL) to predict acute kidney injury (AKI) in adult intensive care unit (ICU) patients. METHODS All consecutives patients admitted to 3 ICUs were enrolled in this prospective-observational study. Plasma neutrophil gelatinase-associated lipocalin was analyzed at ICU admission. Risk, injury, failure, loss, and end-stage kidney (RIFLE) criteria were calculated at admission and for each day during the first week. Patients were classified according to whether they met the threshold for RIFLE criteria (RIFLE 0 or 1) at admission and during the first week. Four groups were identified: RIFLE (0-0), (1-1), (1-0), and (0-1). RESULTS During this 1-month period, 88 patients were included in the study. Thirty-six patients met the criteria for RIFLE 0-0 with a mean pNGAL of 98 +/- 60 nmol/L, 22 for RIFLE 1-1 with a mean pNGAL of 516 +/- 221 nmol/L, and 20 patients had no AKI at admission but develop AKI at 48 hours (24-96 hours) (RIFLE 0-1) with a pNGAL of 342 +/- 183 nmol/L. Ten patients met the criteria for RIFLE 1-0 and had a mean pNGAL of 169 +/- 100 nmol/L. Using a cutoff of 155 nmol/L, sensitivity and specificity to predict AKI were 82% and 97%, respectively (area under the curve [AUC] = 0.92 [0.852-0.972]; P = .001). Looking at the patients without AKI at admission (n = 56) and who developed (n = 20) or did not develop (n = 36) AKI, receiver operating characteristic curve analysis was as follows: AUC = 0.956 (0.864-0.992). Sensitivity was 85% and specificity was 97%. Of the 7 patients who required renal replacement therapy, all of them had pNGAL of more than 303 nmol/L (AUC = 0.788 [0.687-0.868]). CONCLUSION Plasma neutrophil gelatinase-associated lipocalin at ICU admission is an early biomarker of AKI in adult ICU patients. Plasma neutrophil gelatinase-associated lipocalin increased 48 hours before RIFLE criteria.

Pressure support ventilation attenuates ventilator-induced protein modifications in the diaphragm

IntroductionControlled mechanical ventilation (CMV) induces profound modifications of diaphragm protein metabolism, including muscle atrophy and severe ventilator-induced diaphragmatic dysfunction. Diaphragmatic modifications could be decreased by spontaneous breathing. We hypothesized that mechanical ventilation in pressure support ventilation (PSV), which preserves diaphragm muscle activity, would limit diaphragmatic protein catabolism.MethodsForty-two adult Sprague-Dawley rats were included in this prospective randomized animal study. After intraperitoneal anesthesia, animals were randomly assigned to the control group or to receive 6 or 18 hours of CMV or PSV. After sacrifice and incubation with 14C-phenylalanine, in vitro proteolysis and protein synthesis were measured on the costal region of the diaphragm. We also measured myofibrillar protein carbonyl levels and the activity of 20S proteasome and tripeptidylpeptidase II.ResultsCompared with control animals, diaphragmatic protein catabolism was significantly increased after 18 hours of CMV (33%, P = 0.0001) but not after 6 hours. CMV also decreased protein synthesis by 50% (P = 0.0012) after 6 hours and by 65% (P < 0.0001) after 18 hours of mechanical ventilation. Both 20S proteasome activity levels were increased by CMV. Compared with CMV, 6 and 18 hours of PSV showed no significant increase in proteolysis. PSV did not significantly increase protein synthesis versus controls. Both CMV and PSV increased protein carbonyl levels after 18 hours of mechanical ventilation from +63% (P < 0.001) and +82% (P < 0.0005), respectively.ConclusionsPSV is efficient at reducing mechanical ventilation-induced proteolysis and inhibition of protein synthesis without modifications in the level of oxidative injury compared with continuous mechanical ventilation. PSV could be an interesting alternative to limit ventilator-induced diaphragmatic dysfunction.

Response to recruitment maneuver influences net alveolar fluid clearance in acute respiratory distress syndrome.

Background:Alveolar fluid clearance is impaired in the majority of patients with acute respiratory distress syndrome (ARDS). Experimental studies have shown that a reduction of tidal volume increases alveolar fluid clearance. This study was aimed at assessing the impact of the response to a recruitment maneuver (RM) on net alveolar fluid clearance. Methods:In 15 patients with ARDS, pulmonary edema fluid and plasma protein concentrations were measured before and after an RM, consisting of a positive end-expiratory pressure maintained 10 cm H2O above the lower inflection point of the pressure–volume curve during 15 min. Cardiorespiratory parameters were measured at baseline (before RM) and 1 and 4 h later. RM-induced lung recruitment was measured using the pressure–volume curve method. Net alveolar fluid clearance was measured by measuring changes in bronchoalveolar protein concentrations before and after RM. Results:In responders, defined as patients showing an RM-induced increase in arterial oxygen tension of 20% of baseline value or greater, net alveolar fluid clearance (19 ± 13%/h) and significant alveolar recruitment (113 ± 101 ml) were observed. In nonresponders, neither net alveolar fluid clearance (−24 ± 11%/h) nor alveolar recruitment was measured. Responders and nonresponders differed only in terms of lung morphology: Responders had a diffuse loss of aeration, whereas nonresponders had a focal loss of aeration, predominating in the lower lobes. Conclusion:In the absence of alveolar recruitment and improvement in arterial oxygenation, RM decreases the rate of alveolar fluid clearance, suggesting that lung overinflation may be associated with epithelial dysfunction.

Soluble form of the receptor for advanced glycation end products is a marker of acute lung injury but not of severe sepsis in critically ill patients

Objectives:Levels of the soluble form of the receptor for advanced glycation end products (sRAGE) are elevated during acute lung injury. However, it is not known whether this increase is linked to its involvement in alveolar epithelium injury or in systemic inflammation. Whether sRAGE is a marker of acute lung injury and acute respiratory distress syndrome, regardless of associated severe sepsis or septic shock, remains unknown in the intensive care unit setting. Design:Prospective, observational, clinical study. Setting:Intensive care unit of an academic medical center. Patients:A total of 64 consecutive subjects, divided into four groups: acute lung injury/acute respiratory distress syndrome (n = 15); acute lung injury/acute respiratory distress syndrome plus severe sepsis/septic shock (n = 18); severe sepsis/septic shock (n = 16); and mechanically ventilated controls (n = 15). Interventions:None. Measurements and Main Results:Plasma sRAGE levels were measured at baseline and on days 3, 6, and 28 (or at intensive care unit discharge, whichever occurred first). Baseline plasma levels of sRAGE were significantly higher in patients with acute lung injury/acute respiratory distress syndrome, with (median, 2951 pg/mL) or without (median, 3761 pg/mL) severe sepsis, than in patients with severe sepsis (median, 488 pg/mL) only and in mechanically ventilated controls (median, 525 pg/mL). Levels of sRAGE were correlated with acute lung injury/acute respiratory distress syndrome severity and decreased over time but were not associated with outcome. Lower baseline plasma sRAGE was associated with focal loss of aeration based on computed tomography lung morphology. Conclusions:sRAGE levels were elevated during acute lung injury/acute respiratory distress syndrome, regardless of the presence or absence of severe sepsis. The plasma level of sRAGE was correlated with clinical and radiographic severity in acute respiratory distress syndrome patients and decreased over time, suggesting resolution of the injury to the alveolar epithelium. Further study is warranted to test the clinical utility of this biomarker in managing such patients and to better understand its relationship with lung morphology during acute lung injury/acute respiratory distress syndrome.

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.

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).

Treatment of metabolic syndrome by combination of physical activity and diet needs an optimal protein intake: a randomized controlled trial.

BackgroundThe recommended dietary allowance (RDA) for protein intake has been set at 1.0-1.3 g/kg/day for senior. To date, no consensus exists on the lower threshold intake (LTI = RDA/1.3) for the protein intake (PI) needed in senior patients ongoing both combined caloric restriction and physical activity treatment for metabolic syndrome. Considering that age, caloric restriction and exercise are three increasing factors of protein need, this study was dedicated to determine the minimal PI in this situation, through the determination of albuminemia that is the blood marker of protein homeostasis.MethodsTwenty eight subjects (19 M, 9 F, 61.8 ± 6.5 years, BMI 33.4 ± 4.1 kg/m2) with metabolic syndrome completed a three-week residential programme (Day 0 to Day 21) controlled for nutrition (energy balance of −500 kcal/day) and physical activity (3.5 hours/day). Patients were randomly assigned in two groups: Normal-PI (NPI: 1.0 g/kg/day) and High-PI (HPI: 1.2 g/kg/day). Then, patients returned home and were followed for six months. Albuminemia was measured at D0, D21, D90 and D180.ResultsAt baseline, PI was spontaneously 1.0 g/kg/day for both groups. Albuminemia was 40.6 g/l for NPI and 40.8 g/l for HPI. A marginal protein under-nutrition appeared in NPI with a decreased albuminemia at D90 below 35 g/l (34.3 versus 41.5 g/l for HPI, p < 0.05), whereas albuminemia remained stable in HPI.ConclusionDuring the treatment based on restricted diet and exercise in senior people with metabolic syndrome, the lower threshold intake for protein must be set at 1.2 g/kg/day to maintain blood protein homeostasis.

Rapid decrease in plasma D-lactate as an early potential predictor of diminished 28-day mortality in critically ill septic shock patients

Abstract Background: Splanchnic ischemia plays a major role in the development of organ failure during septic shock. Plasma D-lactate has been proposed as a better marker of splanchnic hypoperfusion than L-lactate. We studied the prognostic ability of plasma D- and L-lactate levels. Methods: A prospective study was performed in an intensive care unit and included patients with septic shock. Two samples for plasma D- and L-lactate determination were collected: the first within 6h after the patient met the criteria for septic shock (day 1) and the second 24h later (day 2). Results: In univariate analysis, day 1 plasma D- and L-lactate values were associated with 28-day mortality. For plasma D- and L- lactate, the area under the receiver operating characteristic curve was 0.68±0.09 and 0.84±0.07 on day 1 (p=0.09), and 0.74±0.10 and 0.90±0.07 on day 2 (p=0.06), respectively. In survivors, D-lactate levels decreased between day 1 and day 2 (p=0.03), but L-lactate did not (p=0.29). In septic shock patients, plasma D- and L-lactate levels reliably discriminate between survivors and non-survivors. The prognostic ability of plasma L-lactate was better than that of plasma D-lactate. Conclusion: A rapid decrease in plasma D-lactate during the course of septic shock could indicate reduced 28-day mortality.

Association between intraoperative ventilator settings and plasma levels of soluble receptor for advanced glycation end‐products in patients without pre‐existing lung injury

The soluble form of the receptor for advanced glycation end‐products (sRAGE) is elevated and correlated with severity in patients with acute respiratory distress syndrome (ARDS). The impact of ventilator settings on plasma levels of sRAGE, in patients with or without pre‐existing lung injury, remains under‐investigated to date. Our objective was to assess the effects of a lung‐protective ventilation strategy (combining low tidal volume, positive end‐expiratory pressure and recruitment maneuvers), as compared with a non‐protective approach (with high tidal volume and zero end‐expiratory pressure), on plasma levels of sRAGE in patients without lung injury undergoing major abdominal surgery.