Predictive factors for severe long-term chronic kidney disease after acute kidney injury requiring renal replacement therapy in critically ill patients: an ancillary study of the ELVIS randomized controlled trial.

BACKGROUND: Acute kidney injury (AKI) requiring renal replacement therapy (RRT) is a serious complication in the ICU that results in increased mortality and risk of chronic kidney disease (CKD). Some studies suggest RRT modality may have an impact on long-term renal recovery after AKI. However, other predictive factors of severe long-term CKD in ICU patients with AKI requiring RRT are unknown. METHODS: We performed an ancillary study of the multicenter ELVIS trial in the population with AKI requiring RRT. Patients alive 3 months after RRT initiation were eligible. Serum creatinine levels available at 3, 6 and 12 months and 3 and 5 years were recorded. CKD stage was determined according to the glomerular filtration rate as estimated by the CKD-EPI formula. At each timepoint, two groups of patients were compared, a no/mild CKD group with normal or mildly to moderately decreased renal function (stages 1, 2 and 3 of the international classification) and a severe CKD group (stages 4 and 5). Our objective was to identify predictive factors of severe long-term CKD. RESULTS: Of the 287 eligible patients, 183 had follow-up at 3 months, 136 (74.3%) from the no/mild CKD group and 47 (25.7%) from the severe CKD group, and 122 patients at 5 years comprising 96 (78.7%) from the no/mild CKD group and 26 (21.3%) from the severe CKD group. Multivariate analysis showed that a long RRT period was associated with severe CKD up to 12 months (ORM12 = 1.03 95% CI [1.02-1.05] per day) and that a high SOFA score at the initiation of RRT was not associated with severe CKD up to 5 years (ORM60 = 0.85 95% CI [0.77-0.93] per point). CONCLUSION: Severe long-term CKD was found in 21% of ICU survivors who underwent RRT for AKI. The duration of the RRT in AKI patients was identified as a new predictive factor for severe long-term CKD. This finding should be taken into consideration in future studies on the prognosis of ICU patients with AKI requiring RRT. Trial registration ELVIS trial was registered with ClinicalTrials.gov, number: NCT00875069 (June 16, 2014), and this ancillary study was registered with ClinicalTrials.gov, number: NCT03302624 (October 6, 2017).

Driving pressure and acute respiratory distress syndrome in critically ill patients.

BACKGROUND AND OBJECTIVE: Elevated driving pressure (ΔP) may be associated with increased risk of acute respiratory distress syndrome (ARDS) in patients admitted via the emergency department and with post-operative pulmonary complications in surgical patients. This study investigated the association of higher ΔP with the onset of ARDS in a high-risk, intensive care unit (ICU) population. METHODS: This is a secondary analysis of a prospective multicentre observational study. Data for this ancillary study were obtained from intubated adult patients with at least one ARDS risk factor upon ICU admission enrolled in a previous multicentre observational study. Patients were followed up for the development of ARDS within 7 days (primary outcome). Univariate and multivariate analyses tested the association between ΔP (measured at ICU admission (baseline) or 24 h later (day 1)) and the development of ARDS. RESULTS: A total of 221 patients were included in this study, among whom 34 (15%) developed ARDS within 7 days. These patients had higher baseline ΔP than those who did not (mean ± SD: 12.5 ± 3.1 vs 9.8 ± 3.4 cm H2 O, respectively, P = 0.0001). The association between baseline ΔP and the risk of developing ARDS was robust to adjustment for baseline tidal volume, positive-end expiratory pressure, illness severity, serum lactate and sepsis, pneumonia, severe trauma and shock as primary ARDS risk factors (odds ratio: 1.20; 95% CI: 1.03-1.41; P = 0.02). The same results were found with day 1 ΔP. CONCLUSION: Among at-risk ICU patients, higher ΔP may identify those who are more likely to develop ARDS.

Invasive Infections Caused by Nannizziopsis spp. Molds in Immunocompromised Patients.

We report 2 new cases of invasive infections caused by Nannizziopsis spp. molds in France. Both patients had cerebral abscesses and were immunocompromised. Both patients had recently spent time in Africa.

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).

Guidewire exchange vs new site placement for temporary dialysis catheter insertion in ICU patients: is there a greater risk of colonization or dysfunction?

BACKGROUND: Intensive care unit (ICU) patients require dialysis catheters (DCs) for renal replacement therapy (RRT). They carry a high risk of developing end-stage renal disease, and therefore their vascular access must be preserved. Guidewire exchange (GWE) is often used to avoid venipuncture insertion (VPI) at a new site. However, the impact of GWE on infection and dysfunction of DCs in the ICU is unknown. Our aim was to compare the effect of GWE and VPI on DC colonization and dysfunction in ICU patients. METHODS: Using data from the ELVIS randomized controlled trial (RCT) (1496 ICU adults requiring DC for RRT or plasma exchange) we performed a matched-cohort analysis. Cases were DCs inserted by GWE (n = 178). They were matched with DCs inserted by VPI. Matching criteria were participating centre, simplified acute physiology score (SAPS) II +/-10, insertion site (jugular or femoral), side for jugular site, and length of ICU stay before DC placement. We used a marginal Cox model to estimate the effect of DC insertion (GWE vs. VPI) on DC colonization and dysfunction. RESULTS: DC colonization rate was not different between GWE-DCs and VPI-DCs (10 (5.6 %) for both groups) but DC dysfunction was more frequent with GWE-DCs (67 (37.6 %) vs. 28 (15.7 %); hazard ratio (HR), 3.67 (2.07-6.49); p < 0.01). Results were similar if analysis was restricted to DCs changed for dysfunction. CONCLUSIONS: GWE for DCs in ICU patients, compared with VPI did not contribute to DC colonization or infection but was associated with more than twofold increase in DC dysfunction. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, number NCT00563342 . Registered 2 April 2009.

Ethanol lock and risk of hemodialysis catheter infection in critically ill patients. A randomized controlled trial.

RATIONALE: Ethanol rapidly eradicated experimental biofilm. Clinical studies of ethanol lock to prevent catheter-related infections (CRIs) suggest preventive efficacy. No such studies have been done in intensive care units (ICU). OBJECTIVES: To determine whether ethanol lock decreases the risk of major CRI in patients with short-term dialysis catheters (DCs). METHODS: A randomized, double-blind, placebo-controlled trial was performed in 16 ICUs in seven university hospitals and one general hospital in France between June 2009 and December 2011. Adults with insertion of a nontunneled, nonantimicrobial-impregnated double-lumen DC for an expected duration greater than 48 hours, to perform renal-replacement therapy or plasma exchange, were randomly allocated (1:1) to receive a 2-minute catheter lock with either 60% wt/wt ethanol solution (ethanol group) or 0.9% saline solution (control group) at the end of DC insertion and after each renal-replacement therapy or plasma exchange session. The main outcome was major CRI defined as either catheter-related clinical sepsis without bloodstream infection or catheter-related bloodstream infection during the ICU stay. MEASUREMENTS AND MAIN RESULTS: The intent-to-treat analysis included 1,460 patients (2,172 catheters, 12,944 catheter-days, and 8,442 study locks). Median DC duration was 4 days (interquartile range, 2-8) and was similar in both groups. Major CRI incidence did not differ between the ethanol and control groups (3.83 vs. 2.64 per 1,000 catheter-days, respectively; hazard ratio, 1.55; 95% confidence interval, 0.83-2.87; P = 0.17). No significant differences occurred for catheter colonization (P = 0.57) or catheter-related bloodstream infection (P = 0.99). CONCLUSIONS: A 2-minute ethanol lock does not decrease the frequency of infection of DCs in ICU patients. Clinical trial registered with www.clinicaltrials.gov (NCT 00875069).

Body composition and muscle strength at the end of ICU stay are associated with 1-year mortality, a prospective multicenter observational study.

BACKGROUND & AIMS: After a prolonged intensive care unit (ICU) stay patients experience increased mortality and morbidity. The primary aim of this study was to assess the prognostic value of nutritional status, body mass composition and muscle strength, as assessed by body mass index (BMI), bioelectrical impedance analysis (BIA), handgrip (HG) test, and that of the biological features to predict one-year survival at the end of a prolonged ICU stay. METHODS: This was a multicenter prospective observational study. Survivor patients older than 18 years with ICU length of stay >72 h were eligible for inclusion. BIA and HG were performed at the end of the ICU stay. Malnutrition was defined by BMI and fat-free mass index (FFMI). The primary endpoint was one-year mortality. Multivariable logistic regression was performed to determine parameters associated with mortality. RESULTS: 572 patients were included with a median age of 63 years [53.5; 71.1], BMI of 26.6 kg/m2 [22.8; 31.3], SAPS II score of 43 [31; 58], and ICU length of stay of 9 days [6; 15]. Malnutrition was observed in 142 (24.9%) patients. During the 1-year follow-up after discharge, 96 (18.5%) patients died. After adjustment, a low HG test score (aOR = 1.44 [1.11; 1.89], p = 0.01) was associated with 1-year mortality. Patients with low HG score, malnutrition, and Albuminemia <30 g/L had a one-year death rate of 41.4%. Conversely, patients with none of these parameters had a 1-year death rate of 4.1%. CONCLUSION: BIA to assess FFMI, HG and albuminemia at the end of ICU stay could be used to predict 1-year mortality. Their ability to identify patients eligible for a structured recovery program could be studied.

Outcome of patients treated with molecular adsorbent recirculating system albumin dialysis: A national multicenter study.

BACKGROUND AND AIM: The molecular adsorbent recirculating system (MARS) is the most widely used device to treat liver failure. Nevertheless, data from widespread real-life use are lacking. METHODS: This was a retrospective multicenter study conducted in all French adult care centers that used MARS between 2004 and 2009. The primary objective was to evaluate patient survival according to the liver disease and listing status. Factors associated with mortality were the secondary objectives. RESULTS: A total of 383 patients underwent 393 MARS treatments. The main indications were acute liver failure (ALF, 32.6%), and severe cholestasis (total bilirubin >340 µmol/L) (37.2%), hepatic encephalopathy (23.7%), and/or acute kidney injury-hepatorenal syndrome (22.9%) most often among patients with chronic liver disease. At the time of treatment, 34.4% of the patients were listed. Overall, the hospital survival rate was 49% (95% CI: 44-54%) and ranged from 25% to 81% depending on the diagnosis of the liver disease. In listed patients versus those not listed, the 1-year survival rate was markedly better in the setting of nonbiliary cirrhosis (59% vs 15%), early graft nonfunction (80% vs 0%), and late graft dysfunction (72% vs 0%) (all P < 0.001). Among nonbiliary cirrhotic patients, hospital mortality was associated with the severity of liver disease (HE and severe cholestasis) and not being listed for transplant. In ALF, paracetamol etiology and ≥3 MARS sessions were associated with better transplant-free survival. CONCLUSION: Our study suggests that MARS should be mainly used as a bridge to liver transplantation. Survival was correlated with being listed for most etiologies and with the intensity of treatment in ALF.

Low doses of ketamine reduce delirium but not opiate consumption in mechanically ventilated and sedated ICU patients: A randomised double-blind control trial.

CONTEXT: Low doses of ketamine are commonly used to decrease opiates tolerance, hyperalgesia and delirium in perioperative theatre but these properties have never been studied in intensive care unit (ICU) patients. PURPOSE: To determine the impact of ketamine infusion on opiates consumption when added to standard care in ICU patients requiring sedation for mechanical ventilation. METHODS: Patients admitted in a general ICU of a university hospital and undergoing mechanical ventilation (n = 162) with nurse-driven sedation protocol were randomly assigned into ketamine (2 mg/kg/h) or placebo in a double-blinded control trial. Patients were assessed for sedation and analgesia levels, opiates consumption and delirium (using the Confusion Assessment Method for ICU). RESULTS: Daily consumption of remifentanil (7.9 ± 1.0 vs. 9.3 ± 1.0 µg/kg/h, P = 0.548) and increase in remifentanil doses required for equianalgesia (0.107 ± 0.17 and 0.11 ± 0.18 µg/kg/min, P = 0.78) were not different between ketamine and control groups. The incidence was higher in the placebo group 30/82 (37%) than in the ketamine group 17/80 (21%) (P = 0.03). The duration of delirium was lower in ketamine group (5.3 ± 4.7 vs. 2.8 ± 3 days, P = 0.005). Mortality rates, ventilator-free days and ICU length of stay (LOS) were non-statistically different in both groups. CONCLUSIONS: When the best practices of sedation (nurse-driven sedation, a consistent light-to-moderate sedation level, and delirium monitoring) are used for all patients, the addition of low doses of ketamine does not decrease opiate consumption but reduces delirium incidence and its duration in medico-surgical ICU patients with no effect on mortality rate and ICU LOS.

Clinical and Biological Predictors of Plasma Levels of Soluble RAGE in Critically Ill Patients: Secondary Analysis of a Prospective Multicenter Observational Study.

RATIONALE: Although soluble forms of the receptor for advanced glycation end products (RAGE) have been recently proposed as biomarkers in multiple acute or chronic diseases, few studies evaluated the influence of usual clinical and biological parameters, or of patient characteristics and comorbidities, on circulating levels of soluble RAGE in the intensive care unit (ICU) setting. OBJECTIVES: To determine, among clinical and biological parameters that are usually recorded upon ICU admission, which variables, if any, could be associated with plasma levels of soluble RAGE. METHODS: Data for this ancillary study were prospectively obtained from adult patients with at least one ARDS risk factor upon ICU admission enrolled in a large multicenter observational study. At ICU admission, plasma levels of total soluble RAGE (sRAGE) and endogenous secretory (es)RAGE were measured by duplicate ELISA and baseline patient characteristics, comorbidities, and usual clinical and biological indices were recorded. After univariate analyses, significant variables were used in multivariate, multidimensional analyses. MEASUREMENTS AND MAIN RESULTS: 294 patients were included in this ancillary study, among whom 62% were admitted for medical reasons, including septic shock (11%), coma (11%), and pneumonia (6%). Although some variables were associated with plasma levels of RAGE soluble forms in univariate analysis, multidimensional analyses showed no significant association between admission parameters and baseline plasma sRAGE or esRAGE. CONCLUSIONS: We found no obvious association between circulating levels of soluble RAGE and clinical and biological indices that are usually recorded upon ICU admission. This trial is registered with NCT02070536.

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.

Efficacy and safety of sedation with dexmedetomidine in critical care patients: a meta-analysis of randomized controlled trials.

INTRODUCTION: Dexmedetomidine may help physicians target a low level of sedation. Unfortunately, the impact of dexmedetomidine on major endpoints remains unclear in intensive care unit (ICU). MATERIAL AND METHODS: To evaluate the association between dexmedetomidine use with efficacy and safety outcomes, two reviewers independently identified randomized controlled trials comparing dexmedetomidine with other sedative agents in non-post-cardiac surgery critically ill patients in the PubMed and Cochrane databases. Random effects models were considered if heterogeneity was detected using the DerSimonian and Laird estimation method. Statistical heterogeneity between results was assessed by examining forest plots, confidence intervals (CI) and by using the I(2) statistic. The risk of bias was assessed using the risk of bias tool. RESULTS: This meta-analysis included 1994 patients from 16 randomized controlled trials. Comparators were lorazepam, midazolam and propofol. Dexmedetomidine was associated with a reduction in ICU length of stays (WMD=-0.304; 95% CI [-0.477, -0.132]; P=0.001), mechanical ventilation duration (WMD=-0.313, 95% CI [-0.523, -0.104]; P=0.003) and delirium incidence (RR=0.812, 95% CI [0.680, 0.968]; P=0.020). Dexmedetomidine is also associated with an increase in the incidence of bradycardia (RR=1.947, 95% CI [1.387, 2.733]; P=0.001) and hypotension (RR=1.264; 95% CI [1.013, 1.576]; P=0.038). CONCLUSIONS AND RELEVANCE: In this first meta-analysis including only randomized controlled trials related to ICU patients, dexmedetomidine was associated with a 48h reduction in ICU length of stay, mechanical ventilation duration and delirium occurrence despite a significant heterogeneity among studies. Dexmedetomidine was also associated with an increase in bradycardia and hypotension.

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.

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.

Low Molecular Weight Heparin Induced Skin Necrosis without Platelet Fall Revealing Immunoallergic Heparin Induced Thrombocytopenia.

Low molecular weight heparins (LMWH) are commonly used in the ICU setting for thromboprophylaxis as well as curative decoagulation as required during renal replacement therapy (RRT). A rare adverse event revealing immunoallergic LMWH induced thrombopenia (HIT) is skin necrosis at injection sites. We report the case of a patient presenting with skin necrosis witnessing an HIT after RRT, without thrombocytopenia. The mechanism remains unclear. Anti-PF4/heparin antibodies, functional tests (HIPA and/or SRA), and skin biopsy are of great help to evaluate differential diagnosis with a low pretest probability 4T's score.