Effect of statin therapy on mortality in patients with ventilator-associated pneumonia: a randomized clinical trial.

IMPORTANCE: Observational studies have reported that statin use may be associated with improved outcomes of various infections. Ventilator-associated pneumonia (VAP) is the most common infection in the intensive care unit (ICU) and is associated with substantial mortality. OBJECTIVE: To determine whether statin therapy can decrease day-28 mortality in patients with VAP. DESIGN, SETTING, AND PARTICIPANTS: Randomized, placebo-controlled, double-blind, parallel-group, multicenter trial performed in 26 intensive care units in France from January 2010 to March 2013. For power to detect an 8% absolute reduction in the day-28 mortality rate, we planned to enroll 1002 patients requiring invasive mechanical ventilation for more than 2 days and having suspected VAP, defined as a modified Clinical Pulmonary Infection Score of 5 or greater. The futility stopping rules were an absolute increase in day-28 mortality of at least 2.7% with simvastatin compared with placebo after enrollment of the first 251 patients. INTERVENTIONS: Participants were randomized to receive simvastatin (60 mg) or placebo, started on the same day as antibiotic therapy and given until ICU discharge, death, or day 28, whichever occurred first. MAIN OUTCOMES AND MEASURES: Primary outcome was day-28 mortality. Day-14, ICU, and hospital mortality rates were determined, as well as duration of mechanical ventilation and Sequential Organ Failure Assessment (SOFA) scores on days 3, 7, and 14. RESULTS: The study was stopped for futility at the first scheduled interim analysis after enrollment of 300 patients, of whom all but 7% in the simvastatin group and 11% in the placebo group were naive to statin therapy at ICU admission. Day-28 mortality was not lower in the simvastatin group (21.2% [95% CI, 15.4% to 28.6%) than in the placebo group (15.2% [95% CI, 10.2% to 22.1%]; P = .10; hazard ratio, 1.45 [95% CI, 0.83 to 2.51]); the between-group difference was 6.0% (95% CI, -3.0% to 14.9%). In statin-naive patients, day-28 mortality was 21.5% (95% CI, 15.4% to 29.1%) with simvastatin and 13.8% (95% CI, 8.8% to 21.0%) with placebo (P = .054) (between-group difference, 7.7% [95%CI, -1.8% to 16.8%). There were no significant differences regarding day-14, ICU, or hospital mortality rates; duration of mechanical ventilation; or changes in SOFA score. CONCLUSIONS AND RELEVANCE: In adults with suspected VAP, adjunctive simvastatin therapy compared with placebo did not improve day-28 survival. These findings do not support the use of statins with the goal of improving VAP outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01057758.

Adult-brain-derived neural stem cells grafting into a vein bridge increases postlesional recovery and regeneration in a peripheral nerve of adult pig.

We attempted transplantation of adult neural stem cells (ANSCs) inside an autologous venous graft following surgical transsection of nervis cruralis with 30 mm long gap in adult pig. The transplanted cell suspension was a primary culture of neurospheres from adult pig subventricular zone (SVZ) which had been labeled in vitro with BrdU or lentivirally transferred fluorescent protein. Lesion-induced loss of leg extension on the thigh became definitive in controls but was reversed by 45-90 days after neurosphere-filled vein grafting. Electromyography showed stimulodetection recovery in neurosphere-transplanted pigs but not in controls. Postmortem immunohistochemistry revealed neurosphere-derived cells that survived inside the venous graft from 10 to 240 post-lesion days and all displayed a neuronal phenotype. Newly formed neurons were distributed inside the venous graft along the severed nerve longitudinal axis. Moreover, ANSC transplantation increased CNPase expression, indicating activation of intrinsic Schwann cells. Thus ANSC transplantation inside an autologous venous graft provides an efficient repair strategy.

[Severe lactic acidosis due to metformin: report of 3 cases]. / Acidose lactique sévère par intoxication accidentelle à la metformine : à propos de 3 observations.

Metformin, an oral antidiabetic drug, is the sole representative of the biguanide class available in France. Because of its beneficial effects on weight and cardiovascular level, it represents the standard treatment for type 2 diabetic obese patients. Lactic acidosis associated with metformin is a rare but serious complication that can occur in these patients, particularly when intercurrent episode promotes the accumulation of this molecule. We report three cases in which the toxic origin of acidosis has been objectified by the plasma assay and intra-erythrocyte metformin. Curative treatment is based on renal replacement therapy, but the main treatment is preventive, requiring compliance with the cons-indications and rules of prescription of this drug.

5-FU-induced neurotoxicity in cancer patients with profound DPD deficiency syndrome: a report of two cases.

PURPOSE: 5-Fluorouracil (5-FU) is a mainstay for treating various solid tumours in adults, including digestive and head and neck cancers. 5-FU-related toxicities usually include haematological, digestive and cutaneous features. Additionally, 5-FU has been described as being potentially neurotoxic in patients, but these side effects are quite rare in clinical practice. Here, we report two cases of sudden and unpredictable drug-induced neurotoxicities that occurred in patients undergoing their first course of 5-FU-based chemotherapy. PATIENTS AND METHODS: None of these patients had any previous neurological disorder history, and both were treated following standard regimen (LV-5-FU2 and TPF for patient 1 and 2, respectively). Neurotoxicity included drowsiness, acute confusion plus dysarthria for the first patient and seizure, confusion and signs of metabolic encephalopathy for the second one. In addition, typical 5-FU-related severe toxicities (e.g. neutropenia and mucosities) were observed. Both patients slowly recovered from these neurological toxicities under supportive treatment. It was assumed that overexposure to 5-FU could explain the severe toxicities encountered. To test this hypothesis, we retrospectively evaluated the dihydropyrimidine dehydrogenase (DPD) activity of these patients on a phenotypic basis. RESULTS: Evaluation of the uracil-to-di-hydrouracil (U/UH2) ratio in plasma revealed a profound DPD deficiency syndrome in both patients. CONCLUSION: These cases suggest that 5-FU standard dosage administration may lead to strong overexposure, responsible for the severe toxicities observed, including the neurological features. It implies that DPD deficiency can cause neurotoxicity in 5-FU-treated patients and advocates for the prospective screening of DPD deficiency before starting any 5-FU-containing chemotherapy so as to prevent such side effects in the future.

Effect of head posture on pediatric oropharyngeal structures: implications for airway management in infants and children.

PURPOSE OF REVIEW: Although head and neck posture has direct effects on the upper airway in infants and children, many of these effects remain unclear or not well established. As airway patency and airway access are critical in sedated and/or unconscious children, recent developments in this area should be made known to pediatric anesthesiologists, intensive care physicians and other emergency caregivers. RECENT FINDINGS: All recent studies observed large interindividual variability in anatomical measurements, especially in trachea length. More evidence has been gained that lateral position improves upper airway patency in sedated children. Several studies brought indirect information on head posture for laryngoscopy and intubation. SUMMARY: The site of obstruction of the airway in sedated children in different postures is now more clear. Implications of head flexion and extension in intubated children have been extensively studied, and clinical consequences have been detailed. Due to large interindividual anatomic variability, depth marks set on the tubes by their manufacturers and guidelines regarding calculations of insertion depth should be made with caution in infants and neonates. Despite several studies, there is still little scientific evidence regarding proper head posture for laryngoscopy and intubation.

Effects of head posture on the oral, pharyngeal and laryngeal axis alignment in infants and young children by magnetic resonance imaging.

BACKGROUND: Objective anatomical studies supporting the different recommendations for laryngoscopy in infants and young children are scarce. The objective of this study was to measure by magnetic resonance imaging (MRI) the consequences of head extension on the oral, pharyngeal and laryngeal axes in infants and young children. METHODS: Thirty patients (age: 33 +/- 28 months; weight 14 +/- 9 kg), under general inhalated anesthesia delivered via a laryngeal mask airway, were studied in two anatomic positions: head in the resting position and in simple extension. The following measurements were made on each scan: the face and the neck axes, the pharyngeal axis, the laryngeal axis, and the line of vision of glottis. The various angles between these axes were defined: delta angle between line of vision and laryngeal axis, and beta angle between pharyngeal axis and laryngeal axis. From an anatomical point of view, laryngoscopy and passage of a naso-tracheal tube would be facilitated if these angles are narrow. RESULTS: Placing the patient from the resting position into extension led to a narrowing of the angle delta but a widening of the angle beta. CONCLUSIONS: In infants and young children, under general anesthesia and with a laryngeal mask airway in place, just a slight head extension improves alignment of the line of vision of the glottis and the laryngeal axis (narrowing of angle delta) but worsened the alignment of the pharyngeal and laryngeal axes (widening of angle beta).